Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Mislocalization and abnormal deposition of TDP-43 into the cytoplasm (TDP-43 proteinopathy) is a hallmark in neurons of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the pathogenic mechanism of the diseases linked to TDP-43 is largely unknown. We hypothesized that the failure of mRNA transport to neuronal axons by TDP-43 may contribute to neurodegeneration in ALS and FTLD, and sought to examine the function of TDP-43 by identifying its target mRNA for axonal transport. We found that mRNAs related to translational function including ribosomal proteins (RPs) were decreased by shRNA-based TDP-43 knock-down in neurites of cortical neurons. TDP-43 binds to and transports the RP mRNAs through their 5' untranslated region, which contains a common 5' terminal oligopyrimidine tract motif and a downstream GC-rich region. We showed by employing in vitro and in vivo models that the RP mRNAs were translated and incorporated into native ribosomes locally in axons to maintain functionality of axonal ribosomes, which is required for local protein synthesis in response to stimulation and stress to axons. We also found that RP mRNAs were reduced in the pyramidal tract of sporadic ALS cases harboring TDP-43 pathology. Our results elucidated a novel function of TDP-43 to control transport of RP mRNAs and local translation by ribosomes to maintain morphological integrity of neuronal axons, and proved the influence of this function of TDP-43 on neurodegeneration in ALS and FTLD associated with TDP-43 proteinopathy.

DOI： 10.1007/s00401-020-02205-y

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Other Link： http://link.springer.com/article/10.1007/s00401-020-02205-y/fulltext.html

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Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.

DOI： 10.1126/scitranslmed.abb7086

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

The polyglutamine (polyQ) diseases are a group of inherited neurodegenerative diseases that include Huntington's disease, various spinocerebellar ataxias, spinal and bulbar muscular atrophy, and dentatorubral pallidoluysian atrophy. They are caused by the abnormal expansion of a CAG repeat coding for the polyQ stretch in the causative gene of each disease. The expanded polyQ stretches trigger abnormal β-sheet conformational transition and oligomerization followed by aggregation of the polyQ proteins in the affected neurons, leading to neuronal toxicity and neurodegeneration. Disease-modifying therapies that attenuate both symptoms and molecular pathogenesis of polyQ diseases remain an unmet clinical need. Here we identified arginine, a chemical chaperone that facilitates proper protein folding, as a novel compound that targets the upstream processes of polyQ protein aggregation by stabilizing the polyQ protein conformation. We first screened representative chemical chaperones using an in vitro polyQ aggregation assay, and identified arginine as a potent polyQ aggregation inhibitor. Our in vitro and cellular assays revealed that arginine exerts its anti-aggregation property by inhibiting the toxic β-sheet conformational transition and oligomerization of polyQ proteins before the formation of insoluble aggregates. Arginine exhibited therapeutic effects on neurological symptoms and protein aggregation pathology in Caenorhabditis elegans, Drosophila, and two different mouse models of polyQ diseases. Arginine was also effective in a polyQ mouse model when administered after symptom onset. As arginine has been safely used for urea cycle defects and for mitochondrial myopathy, encephalopathy, lactic acid and stroke syndrome patients, and efficiently crosses the blood-brain barrier, a drug-repositioning approach for arginine would enable prompt clinical application as a promising disease-modifier drug for the polyQ diseases.

DOI： 10.1093/brain/awaa115

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OBJECTIVE: To investigate the efficacy of rovatirelin, a thyrotropin-releasing hormone analogue, for ataxias in patients with spinocerebellar degeneration (SCD). METHODS: Two multicentre, randomised, double-blind, placebo-controlled phase 3 studies (KPS1301, KPS1305) enrolled patients with predominant cerebellar ataxia, including SCA6, SCA31 or cortical cerebellar atrophy. KPS1301 enrolled patients with truncal ataxia and KPS1305 enrolled patients with truncal and limb ataxia. Each study included 4 weeks of pretreatment, a 28-week or 24-week treatment period and 4 weeks of follow-up. Patients were randomised (1:1:1) to rovatirelin (1.6 or 2.4 mg) or placebo in KPS1301, and randomised (1:1) to rovatirelin 2.4 mg or placebo in KPS1305. The primary endpoint was change in Scale for the Assessment and Rating of Ataxia (SARA) total scores. Pooled analysis was performed in patients who met the SARA recruitment criteria of KPS1305. RESULTS: From October 2013 to May 2014, KPS1301 enrolled 411 patients; 374 were randomised to rovatirelin 1.6 mg (n=125), rovatirelin 2.4 mg (n=126) or placebo (n=123). From November 2016 to August 2017, KPS1305 enrolled 241 patients; 203 were randomised to rovatirelin 2.4 mg (n=101) or placebo (n=102). The primary endpoint showed no significant difference between rovatirelin and placebo in these two studies. In the pooled analysis (n=278), the difference between rovatirelin 2.4 mg (n=140) and placebo (n=138) was -0.61 (-1.64 vs -1.03; 95% CI -1.16 to -0.06; p=0.029) in the adjusted mean change in the SARA total score. CONCLUSIONS: Rovatirelin is a potentially effective treatment option for SCD. TRIAL REGISTRATION NUMBER: NCT01970098; NCT02889302.

DOI： 10.1136/jnnp-2019-322168

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OBJECTIVE: The pallidonigroluysian (PNL) system, the primary component of corticosubcortical circuits, is generally spared in amyotrophic lateral sclerosis (ALS). We evaluated the clinicopathological features of an unusual form of ALS with PNL degeneration (PNLD) and assessed whether ALS with PNLD represents a distinct ALS subtype. METHODS: From a cohort of 97 autopsied cases of sporadic ALS with phosphorylated 43kDa TAR DNA-binding protein (TDP-43) inclusions, we selected those with PNLD and analyzed their clinicopathological features. RESULTS: Eleven cases (11%) that showed PNLD were divided into 2 subtypes depending on the lesion distribution: (1) extensive type (n = 6), showing widespread TDP-43 pathology and multisystem degeneration, both involving the PNL system; and (2) limited type (n = 5), showing selective PNL and motor system involvement, thus being unclassifiable in terms of Brettschneider's staging or Nishihira's typing of ALS. The limited type showed a younger age at onset and predominant PNLD that accounted for the early development of extrapyramidal signs. The limited type exhibited the heaviest pathology in the subthalamus and external globus pallidus, suggesting that TDP-43 inclusions propagated via indirect or hyperdirect pathways, unlike ALS without PNLD, where the direct pathway is considered to convey TDP-43 aggregates from the cerebral cortex to the substantia nigra. INTERPRETATION: The PNL system can be involved in the disease process of ALS, either nonselectively as part of multisystem degeneration, or selectively. ALS with selective involvement of the PNL and motor systems exhibits unique clinicopathological features and TDP-43 propagation routes, thus representing a distinct subtype of ALS. ANN NEUROL 2020;87:302-312.

DOI： 10.1002/ana.25652

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Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is clinically characterized by early-onset dementia, stroke, spondylosis deformans, and alopecia. In CARASIL cases, brain magnetic resonance imaging reveals severe white matter hyperintensities (WMHs), lacunar infarctions, and microbleeds. CARASIL is caused by a homozygous mutation in high-temperature requirement A serine peptidase 1 (HTRA1). Recently, it was reported that several heterozygous mutations in HTRA1 also cause cerebral small vessel disease (CSVD). Although patients with heterozygous HTRA1-related CSVD (symptomatic carriers) are reported to have a milder form of CARASIL, little is known about the clinical and genetic differences between the two diseases. Given this gap in the literature, we collected clinical information on HTRA1-related CSVD from a review of the literature to help clarify the differences between symptomatic carriers and CARASIL and the features of both diseases. Forty-six symptomatic carriers and 28 patients with CARASIL were investigated. Twenty-eight mutations in symptomatic carriers and 22 mutations in CARASIL were identified. Missense mutations in symptomatic carriers are more frequently identified in the linker or loop 3 (L3)/loop D (LD) domains, which are critical sites in activating protease activity. The ages at onset of neurological symptoms/signs were significantly higher in symptomatic carriers than in CARASIL, and the frequency of characteristic extraneurological findings and confluent WMHs were significantly higher in CARASIL than in symptomatic carriers. As previously reported, heterozygous HTRA1-related CSVD has a milder clinical presentation of CARASIL. It seems that haploinsufficiency can cause CSVD among symptomatic carriers according to the several patients with heterozygous nonsense/frameshift mutations. However, the differing locations of mutations found in the two diseases indicate that distinct molecular mechanisms influence the development of CSVD in patients with HTRA1-related CSVD. These findings further support continued careful examination of the pathogenicity of mutations located outside the linker or LD/L3 domain in symptomatic carriers.

DOI： 10.3389/fneur.2020.00545

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by accumulation of fragmented insoluble TDP-43 and loss of TDP-43 from the nucleus. Increased expression of exogenous TARDBP (encoding TDP-43) induces TDP-43 pathology and cytotoxicity, suggesting the involvement of aberrant expression of TDP-43 in the pathogenesis of ALS. In normal conditions, however, the amount of TDP-43 is tightly regulated by the autoregulatory mechanism involving alternative splicing of TARDBP mRNA. To investigate the influence of autoregulation dysfunction, we inhibited the splicing of cryptic intron 6 using antisense oligonucleotides in vivo. This inhibition doubled the Tardbp mRNA expression, increased the fragmented insoluble TDP-43, and reduced the number of motor neurons in the mouse spinal cord. In human induced pluripotent stem cell-derived neurons, the splicing inhibition of intron 6 increased TARDBP mRNA and decreased nuclear TDP-43. These non-genetically modified models exhibiting rise in the TARDBP mRNA levels suggest that TDP-43 autoregulation turbulence might be linked to the pathogenesis of ALS.

DOI： 10.1016/j.nbd.2019.104534

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Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an autosomal-dominant disorder involving the cerebral, retinal, renal, and other systemic microvessels due to frameshift mutations in the TREX1 gene. Under physiological conditions, the TREX1 protein is localized in the cellular cytoplasm and perinuclear area, but translocates into the nucleus in response to oxidative DNA damage. It has been speculated that aberrant localization of the protein may be associated with systemic microangiopathy in patients with RVCL. However, cellular expression of TREX1 in the brain and visceral organs of patients with RVCL has been unclear. Here, we report the clinicopathologic features of an autopsied patient with a heterozygous T249fs mutation in TREX1. The patient showed the clinical phenotype of vasculopathy with retinopathy, nephropathy, and stroke. CT with contrast enhancement demonstrated a tumorous lesion in the subcortical white matter. Histologically, the lesion consisted of confluent foci of necrosis with calcification and fibrous thickening of small vessel walls. TREX1 immunohistochemistry demonstrated positivity in the nuclei of cells in the CNS and visceral organs, indicating aberrant localization of the truncated protein, and the expression was remarkable in oligodendrocytes within the lesion, suggesting possible involvement of the protein in the pathomechanism of vasculopathy leading to white matter degeneration.

DOI： 10.1093/jnen/nly115

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Background: Mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Most carriers for HTRA1 mutations are asymptomatic, but more than 10 mutations have been reported in symptomatic carriers. The molecular differences between the mutations identified in symptomatic carriers and mutations identified only in CARASIL patients are unclear. HTRA1 is a serine protease that forms homotrimers, with each HTRA1 subunit activating the adjacent HTRA1 via the sensor domain of loop 3 (L3) and the activation domain of loop D (LD). Previously, we analyzed four HTRA1 mutant proteins identified in symptomatic carriers and found that they were unable to form trimers or had mutations in the LD or L3 domain. The mutant HTRA1s with these properties are presumed to inhibit trimer-dependent activation cascade. Indeed, these mutant HTRA1s inhibited wild-type (WT) protease activity. In this study, we further analyzed 15 missense HTRA1s to clarify the molecular character of mutant HTRA1s identified in symptomatic carriers. Methods: We analyzed 12 missense HTRA1s identified in symptomatic carriers (hetero-HTRA1) and three missense HTRA1s found only in CARASIL (CARASIL-HTRA1). The protease activity of the purified recombinant mutant HTRA1s was measured using fluorescein isothiocyanate-labeled casein as substrate. Oligomeric structure was evaluated by size-exclusion chromatography. The protease activities of mixtures of WT with each mutant HTRA1 were also measured. Results: Five hetero-HTRA1s had normal protease activity and were excluded from further analysis. Four of the seven hetero-HTRA1s and one of the three CARASIL-HTRA1s were unable to form trimers. The other three hetero-HTRA1s had mutations in the LD domain. Together with our previous work, 10 of 11 hetero-HTRA1s and two of six CARASIL-HTRA1s were either defective in trimerization or had mutations in the LD or L3 domain (P = 0.006). By contrast, eight of 11 hetero-HTRA1s and two of six CARASIL-HTRA1 inhibited WT protease activity (P = 0.162). Conclusions: HTRA1 mutations identified in symptomatic carriers have the property of interfering the trimer-dependent activation cascade of HTRA1.

DOI： 10.3389/fneur.2019.00693

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Abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm and its disappearance from the nucleus are pathological features of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) and are directly involved in the pathogenesis of these conditions. TDP-43 is an essential nuclear protein that readily aggregates in a concentration-dependent manner. Therefore, cells must strictly maintain an appropriate amount of nuclear TDP-43. In one relevant maintenance mechanism, TDP-43 binds to its pre-mRNA and promotes alternative splicing, resulting in mRNA degradation via nonsense-mediated mRNA decay. The level of nuclear TDP-43 is tightly regulated by these mechanisms, which control the amount of mRNA that may be translated. Based on the results of previous experiments, we developed an in silico model that mimics the intracellular dynamics of TDP-43 and examined TDP-43 metabolism under various conditions. We discovered an inherent trade-off in this mechanism between transcriptional redundancy, which maintains the robustness of TDP-43 metabolism, and vulnerability to specific interfering factors. These factors include an increased tendency of TDP-43 to aggregate, impaired nuclear-cytoplasmic TDP-43 transport, and a decreased efficiency of degrading abnormal proteins, all of which are functional abnormalities related to the gene that causes familial ALS/FTD. When these conditions continue at a certain intensity, the vulnerability of the autoregulatory machinery becomes apparent over time, and transcriptional redundancy enters a vicious cycle that ultimately results in TDP-43 pathology. The results obtained using this in silico model reveal the difference in TDP-43 metabolism between normal and disease states. Furthermore, using this model, we simulated the effect of a decrease in TDP-43 transcription and found that this decrease improved TDP-43 pathology and suppressed the abnormal propagation of TDP-43. Therefore, we propose a potential therapeutic strategy to suppress transcriptional redundancy, which is the driving force of the pathological condition caused by the specific factors described above, in patients with ALS presenting with TDP-43 pathology. An ALS animal model exhibiting TDP-43 pathology without overexpression of exogenous TDP-43 should be developed to investigate the effect of alleviating the transcriptional redundancy of TARDBP.

DOI： 10.3389/fnins.2018.00028

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder. In motor neurons of ALS, TAR DNA binding protein-43 (TDP-43), a nuclear protein encoded by TARDBP, is absent from the nucleus and forms cytoplasmic inclusions. TDP-43 auto-regulates the amount by regulating the TARDBP mRNA, which has three polyadenylation signals (PASs) and three additional alternative introns within the last exon. However, it is still unclear how the autoregulatory mechanism works and how the status of autoregulation in ALS motor neurons without nuclear TDP-43 is. Here we show that TDP-43 inhibits the selection of the most proximal PAS and induces splicing of multiple alternative introns in TARDBP mRNA to decrease the amount of cytoplasmic TARDBP mRNA by nonsense-mediated mRNA decay. When TDP-43 is depleted, the TARDBP mRNA uses the most proximal PAS and is increased in the cytoplasm. Finally, we have demonstrated that in ALS motor neurons-especially neurons with mislocalized TDP-43-the amount of TARDBP mRNA is increased in the cytoplasm. Our observations indicate that nuclear TDP-43 contributes to the autoregulation and suggests that the absence of nuclear TDP-43 induces an abnormal autoregulation and increases the amount of TARDBP mRNA. The vicious cycle might accelerate the disease progression of ALS.

DOI： 10.1093/nar/gkw499

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OBJECTIVE: To elucidate the molecular mechanism of mutant HTRA1-dependent cerebral small vessel disease in heterozygous individuals. METHODS: We recruited 113 unrelated index patients with clinically diagnosed cerebral small vessel disease. The coding sequences of the HTRA1 gene were analyzed. We evaluated HTRA1 protease activities using casein assays and oligomeric HTRA1 formation using gel filtration chromatography. RESULTS: We found 4 heterozygous missense mutations in the HTRA1 gene (p.G283E, p.P285L, p.R302Q, and p.T319I) in 6 patients from 113 unrelated index patients and in 2 siblings in 2 unrelated families with p.R302Q. The mean age at cognitive impairment onset was 51.1 years. Spondylosis deformans was observed in all cases, whereas alopecia was observed in 3 cases; an autopsied case with p.G283E showed arteriopathy in their cerebral small arteries. These mutant HTRA1s showed markedly decreased protease activities and inhibited wild-type HTRA1 activity, whereas 2 of 3 mutant HTRA1s reported in cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) (A252T and V297M) did not inhibit wild-type HTRA1 activity. Wild-type HTRA1 forms trimers; however, G283E and T319I HTRA1, observed in manifesting heterozygotes, did not form trimers. P285L and R302Q HTRA1s formed trimers, but their mutations were located in domains that are important for trimer-associated HTRA1 activation; in contrast, A252T and V297M HTRA1s, which have been observed in CARASIL, also formed trimers but had mutations outside the domains important for trimer-associated HTRA1 activation. CONCLUSIONS: The mutant HTRA1s observed in manifesting heterozygotes might result in an impaired HTRA1 activation cascade of HTRA1 or be unable to form stable trimers.

DOI： 10.1212/WNL.0000000000002694

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objectives:The objective of this study was to clarify the characteristic brain MRI findings for genetically diagnosed CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy).Methods:Seven patients with CARASIL carrying HTRA1 mutations (representing 6 Japanese families) were included in this study. Eighteen brain MRIs were reviewed and evaluated with a new rating scale based on scoring for abnormal hyperintense lesions and atrophy.Results:At the last follow-up MRI, all patients had hyperintense lesions on T2-weighted images of the frontal white matter, anterior temporal lobe, external capsules, and thalami. Patients with longer time from the onset of cognitive impairment had higher MRI severity score. The atrophy advanced, followed by white matter lesion progression. During the early stage, hyperintense lesions were observed in the frontal white matter, external capsule, and pons. During the late stage, the arc-shaped hyperintense lesion from the pons to the middle cerebellar peduncles, which we designated the arc sign, became evident. The arc sign was a characteristic finding for CARASIL in the advanced stage.Conclusions:These characteristic MRI findings for CARASIL are useful for selecting patients for genetic testing. The rating scale correlates well with disease duration and might be useful for assessing disease progression.

DOI： 10.1212/WNL.0000000000001803

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Disappearance of TAR-DNA-binding protein 43 kDa (TDP-43) from the nucleus contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS), but the nuclear function of TDP-43 is not yet fully understood. TDP-43 associates with nuclear bodies including Gemini of coiled bodies (GEMs). GEMs contribute to the biogenesis of uridine-rich small nuclear RNA (U snRNA), a component of splicing machinery. The number of GEMs and a subset of U snRNAs decrease in spinal muscular atrophy, a lower motor neuron disease, suggesting that alteration of U snRNAs may also underlie the molecular pathogenesis of ALS. Here, we investigated the number of GEMs and U11/12-type small nuclear ribonucleoproteins (snRNP) by immunohistochemistry and the level of U snRNAs using real-time quantitative RT-PCR in ALS tissues. GEMs decreased in both TDP-43-depleted HeLa cells and spinal motor neurons in ALS patients. Levels of several U snRNAs decreased in TDP-43-depleted SH-SY5Y and U87-MG cells. The level of U12 snRNA was decreased in tissues affected by ALS (spinal cord, motor cortex and thalamus) but not in tissues unaffected by ALS (cerebellum, kidney and muscle). Immunohistochemical analysis revealed the decrease in U11/12-type snRNP in spinal motor neurons of ALS patients. These findings suggest that loss of TDP-43 function decreases the number of GEMs, which is followed by a disturbance of pre-mRNA splicing by the U11/U12 spliceosome in tissues affected by ALS.

DOI： 10.1093/hmg/ddt262

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Early onset ataxia with ocular motor apraxia and hypoalbuminaemia/ataxia-oculomotor apraxia 1 is a recessively inherited ataxia caused by mutations in the aprataxin gene. We previously reported that patients with frameshift mutations exhibit a more severe phenotype than those with missense mutations. However, reports on genotype-phenotype correlation in early onset ataxia with ocular motor apraxia and hypoalbuminaemia are controversial. To clarify this issue, we studied 58 patients from 39 Japanese families, including 40 patients homozygous for c.689_690insT and nine patients homozygous or compound heterozygous for p.Pro206Leu or p.Val263Gly mutations who were compared with regard to clinical phenotype. We performed Kaplan-Meier analysis and log-rank tests for the ages of onset of gait disturbance and the inability to walk without assistance. The cumulative rate of gait disturbance was lower among patients with p.Pro206Leu or p.Val263Gly mutations than among those homozygous for the c.689_690insT mutation (P = 0.001). The cumulative rate of inability to walk without assistance was higher in patients homozygous for the c.689_690insT mutation than in those with p.Pro206Leu or p.Val263Gly mutations (P = 0.004). Using a Cox proportional hazards model, we found that the homozygous c.689_690insT mutation was associated with an increased risk for onset of gait disturbance (adjusted hazard ratio: 6.60) and for the inability to walk without assistance (adjusted hazard ratio: 2.99). All patients homozygous for the c.689_690insT mutation presented ocular motor apraxia at < 15 years of age. Approximately half the patients homozygous for the c.689_690insT mutation developed cognitive impairment. In contrast, in the patients with p.Pro206Leu or p.Val263Gly mutations, only similar to 50% of the patients exhibited ocular motor apraxia and they never developed cognitive impairment. The stepwise multivariate regression analysis using sex, age and the number of c.689_690insT alleles as independent variables revealed that the number of c.689_690insT alleles was independently and negatively correlated with median motor nerve conduction velocities, ulnar motor nerve conduction velocities and values of serum albumin. In the patient with c.[689_690insT]+[840delT], p.[Pro206Leu]+[Pro206Leu] and p.[Pro206Leu]+[Val263Gly] mutations, aprataxin proteins were not detected by an antibody to the N-terminus of aprataxin. Furthermore Pro206Leu and Val263Gly aprataxin proteins are unstable. However, the amount of the 689_690insT aprataxin messenger RNA was also decreased, resulting in more dramatic reduction in the amount of aprataxin protein from the c.689_690insT allele. In conclusion, patients with early onset ataxia with ocular motor apraxia and hypoalbuminaemia homozygous for the c.689_690insT mutation show a more severe phenotype than those with a p.Pro206Leu or p.Val263Gly mutation.

DOI： 10.1093/brain/awr069

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Cerebral small-vessel disease is a common disorder in elderly populations; however, its molecular basis is not well understood. We recently demonstrated that mutations in the high-temperature requirement A (HTRA) serine peptidase 1 (HTRA1) gene cause a hereditary cerebral small-vessel disease, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). HTRA1 belongs to the HTRA protein family, whose members have dual activities as chaperones and serine proteases and also repress transforming growth factor-beta (TGF-beta) family signaling. We demonstrated that CARASIL-associated mutant HTRA1s decrease protease activity and fail to decrease TGF-beta family signaling. However, the precise molecular mechanism for decreasing the signaling remains unknown. Here we show that increased expression of ED-A fibronectin is limited to cerebral small arteries and is not observed in coronary, renal arterial or aortic walls in patients with CARASIL. Using a cell-mixing assay, we found that HTRA1 decreases TGF-beta 1 signaling triggered by proTGF-beta 1 in the intracellular space. HTRA1 binds and cleaves the pro-domain of proTGF-beta 1 in the endoplasmic reticulum (ER), and cleaved proTGF-beta 1 is degraded by ER-associated degradation. Consequently, the amount of mature TGF-beta 1 is reduced. These results establish a novel mechanism for regulating the amount of TGF-proTGF-beta 1, specifically, the intracellular cleavage of proTGF-beta 1 in the ER.

DOI： 10.1093/hmg/ddr063

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Language：English   Publisher：OXFORD UNIV PRESS  

Although the genetic basis of polyglutamine diseases has been recognized for 20 years, their molecular basis is still unclear. We have no therapeutic strategies for these intractable neurodegenerative disorders. To adequately treat patients, we must clarify the molecular basis of polyglutamine diseases. Three main issues address their molecular pathogenesis: whether the specific structure of expanded polyglutamine diseases results in cellular toxicity; what type of dysfunction causes them; and how the toxic structure causes dysfunction, that is, the link between structure and dysfunction. For structures, expanded polyglutamine proteins undergo transformation from monomers to oligomers and inclusions. One can hypothesize that one of these structures might cause the polyglutamine disease. Although the expanded polyglutamine protein is toxic, it does not explain the selective vulnerability of specific neurons in each polyglutamine disease. The normal function of each protein, including protein-protein interaction and modification, might also be crucial for pathogenesis. For dysfunction, various molecular mechanisms have been proposed, including dysregulation of transcription, impairment of the ubiquitin-proteasome system, mitochondrial dysfunction, dysregulation of intracellular Ca2+ homeostasis, impairment of axonal transport and genotoxic stress. These hypotheses might correlate with each other. In addition, the disease pathogenesis of might not be exclusive to one particular structure or dysfunction. To develop a therapeutic strategy for patients with polyglutamine disease, identifying the most toxic structure and the earliest event in the pathogenesis is important. We review the current understanding of the toxic structure and dysfunction by expanded polyglutamine proteins and suggest directions for future studies of polyglutamine diseases.

DOI： 10.1093/jmcb/mjq005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MASSACHUSETTS MEDICAL SOC  

BACKGROUND
The genetic cause of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), which is characterized by ischemic, non-hypertensive, cerebral small-vessel disease with associated alopecia and spondylosis, is unclear.
METHODS
In five families with CARASIL, we carried out linkage analysis, fine mapping of the region implicated in the disease, and sequence analysis of a candidate gene. We also conducted functional analysis of wild-type and mutant gene products and measured the signaling by members of the transforming growth factor beta (TGF-beta) family and gene and protein expression in the small arteries in the cerebrum of two patients with CARASIL.
RESULTS
We found linkage of the disease to the 2.4-Mb region on chromosome 10q, which contains the HtrA serine protease 1 (HTRA1) gene. HTRA1 is a serine protease that represses signaling by TGF-beta family members. Sequence analysis revealed two nonsense mutations and two missense mutations in HTRA1. The missense mutations and one of the nonsense mutations resulted in protein products that had comparatively low levels of protease activity and did not repress signaling by the TGF-beta family. The other nonsense mutation resulted in the loss of HTRA1 protein by nonsense-mediated decay of messenger RNA. Immunohistochemical analysis of the cerebral small arteries in affected persons showed increased expression of the extra domain-A region of fibronectin and versican in the thickened tunica intima and of TGF-beta 1 in the tunica media.
CONCLUSIONS
CARASIL is associated with mutations in the HTRA1 gene. Our findings indicate a link between repressed inhibition of signaling by the TGF-beta family and ischemic cerebral small-vessel disease, alopecia, and spondylosis.

DOI： 10.1056/NEJMoa0801560

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. Accumulating evidence has shown that 43kDa TAR-DNA-binding protein (TDP-43) is the disease protein in ALS and frontotemporal lobar degeneration. We previously reported a familial ALS with Bumina bodies and TDP-43-positive skein-like inclusions in the lower motor neurons; these findings are indistinguishable from those of sporadic ALS. In three affected individuals in two generations of one family, we found a single base-pair change from A to G at position 1028 in TDP-43, which resulted in a Gln-to-Arg substitution at position 343. Our findings provide a new insight into the molecular pathogenesis of ALS.

DOI： 10.1002/ana.21392

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Expanded polyglutamine (polyQ) repeats cause neurodegenerative disorders, but their cytotoxic structures remain to be elucidated. Although soluble polyQ oligomers have been proposed as a cytotoxic structure, the cytotoxicity of soluble polyQ oligomers, not inclusion bodies (IBs), has not been proven in living cells. To clarify the cytotoxicity of soluble polyQ oligomers, we carried our fluorescence resonance energy transfer (FRET) confocal microscopy and distinguished oligomers from monomers and IBs in a single living cell. FRET signals were detected when donor and acceptor fluorescent proteins were attached to the same side, not the opposite side, of polyQ repeats, which agrees with a parallel beta-sheet or a head-to-tail cylindrical beta-sheet model. These FRET signals disappeared in semi-intact cells, indicating that these polyQ oligomers are soluble. PolyQ monomers assembled into soluble oligomers in a length-dependent manner, which was followed by the formation of IBs. Notably, survival assay of neuronally differentiated cells revealed that cells with soluble oligomers died faster than those with IBs or monomers. These results indicate that a length-dependent formation of oligomers is an essential mechanism underlying neurodegeneration in polyQ-mediated disorders.

DOI： 10.1093/hmg/ddm311

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Aprataxin is the causative gene product for early-onset ataxia with ocular motor apraxia and hypoalbuminemia/ ataxia with oculomotor apraxia type 1 (EAOH/AOA1), the clinical symptoms of which are predominantly neurological. Although aprataxin has been suggested to be related to DNA single-strand break repair (SSBR), the physiological function of aprataxin remains to be elucidated. DNA single-strand breaks (SSBs) continually produced by endogenous reactive oxygen species or exogenous genotoxic agents, typically possess damaged 3'-ends including 3'-phosphate, 3'-phosphoglycolate, or 3'-alpha, beta-unsaturated aldehyde ends. These damaged 3'-ends should be restored to 3'-hydroxyl ends for subsequent repair processes. Here we demonstrate by in vitro assay that recombinant human aprataxin specifically removes 3'-phosphoglycolate and 3'-phosphate ends at DNA 3'-ends, but not 3'-alpha, beta-unsaturated aldehyde ends, and can act with DNA polymerase beta and DNA ligase III to repair SSBs with these damaged 3'-ends. Furthermore, disease-associated mutant forms of aprataxin lack this removal activity. The findings indicate that aprataxin has an important role in SSBR, that is, it removes blocking molecules from 3'-ends, and that the accumulation of unrepaired SSBs with damaged 3'-ends underlies the pathogenesis of EAOH/AOA1. The findings will provide new insight into the mechanism underlying degeneration and DNA repair in neurons.

DOI： 10.1093/nar/gkm158

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER MEDICAL ASSOC  

Background: Multiple system atrophy (MSA) is diverse in clinical phenotype, disease progression, and prognosis. Sudden death is a leading cause of death in patients with MSA.
Objective: To determine what clinical factors affect the progression and survival prognosis of those with MSA.
Design: A retrospective review of the medical records of 49 consecutive Japanese patients with pathologically confirmed MSA ( 29 men and 20 women; mean +/- SD age at onset, 59.8 +/- 6.5 years). Cox proportional hazards models were used to compare the risks of being in a wheel-chair-bound state, being in a bedridden state, and having a shorter survival.
Results: Thirty-one patients were diagnosed as having cerebellar type MSA, and 18 were diagnosed as having parkinsonian type MSA. Twenty-nine patients with cerebellar type MSA and 17 patients with parkinsonian type MSA had autonomic dysfunction. The median times from disease onset to being in a wheel-chair-bound state, being in a bedridden state, death, and the development of autonomic dysfunction were 3.5, 5.0, 7.0, and 2.5 years, respectively. Patients with an early development of autonomic dysfunction (within 2.5 years from the onset of MSA) had significantly higher risks of being in a wheel-chair-bound state (multivariate-adjusted hazard ratio [HR], 4.32; 95% confidence interval [CI], 2.04-9.15), being in a bedridden state (HR, 3.87; 95% CI, 1.77-8.48), having a shorter survival (HR, 3.40; 95% CI, 1.61-7.15), and sudden death (HR, 7.22; 95% CI, 1.49-35.07).
Conclusion: The early development of autonomic dysfunction is an independent predictive factor for rapid disease progression and shorter survival in patients with MSA.

DOI： 10.1001/archneur.64.2.256

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE AMERICA INC  

Friedreich ataxia (FRDA), the most common autosomal recessive neurodegenerative disease among Europeans and people of European descent, is characterized by an early onset (usually before the age of 25), progressive ataxia, sensory loss, absence of tendon reflexes and pyramidal weakness of the legs(1-4). We have recently identified a unique group of patients whose clinical presentations are characterized by autosomal recessive inheritance, early age of onset, FRDA-like clinical presentations and hypoalbuminemia. Linkage to the FRDA locus, however, was excluded. Given the similarities of the clinical presentations to those of the recently described ataxia with oculomotor apraxia (AOA) linked to chromosome 9p13, we confirmed that the disorder of our patients is also linked to the same locus(5). We narrowed the candidate region and have identified a new gene encoding a member of the histidine triad (HIT) superfamily as the 'causative' gene. We have called its product aprataxin; the gene symbol is APTX. Although many HIT proteins have been identified, aprataxin is the first to be linked to a distinct phenotype.

DOI： 10.1038/ng1001-184

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disease characterized by cerebellar ataxia associated to varying degrees with pyramidal signs, extrapyramidal signs, or peripheral amyotrophy. It is caused by unstable expansion of the CAG repeat in the MJD1 gene on chromosome 14q32.1. To determine how the neurodegenerative process in the central nervous system of patients with MJD correlates with the size of expanded CAG repeats in the MJD1 gene and other factors, we performed detailed quantitative analyses of findings of magnetic resonance imaging of the central nervous system of 21 patients with MJD of various ages and with various sizes of expanded CAG repeats. We found that atrophy of the brainstem and cerebellar vermis in MJD patients is closely correlated not only with the size of expanded CAG repeat in the MJD1 gene but also with patient age, which suggests that the neurodegenerative process in MJD is regulated by the size of expanded CAG repeats as well as by the patient age.

DOI： 10.1002/ana.410430305

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：UNIV CHICAGO PRESS  

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disease caused by unstable expansion of a CAG repeat in the DRPLA gene. We performed detailed quantitative analysis of the size and the size distribution (range) of the expanded CAG repeats in various regions of the CNS of eight autopsied patients with DRPLA. Expanded alleles (AE) showed considerable variations in size, as well as in range, depending on the region of the CNS, whereas normal alleles did not show such variations, which indicates the occurrence of somatic mosaicism of AE in the CNS. The AE in the cerebellar cortex were consistently smaller by two to five repeat units than those in the cerebellar white matter. Moreover, the AE in the cerebral cortex were smaller by one to four repeat units than those in the cerebral white matter. These results suggest that the smaller AE in the cerebellar and cerebral cortices represent those of neuronal cells. The ranges of the AE in the cerebral cortex, cerebral white matter, and cerebellar white matter showed considerable variation ranging from 9 to 23 repeat units, whereas those in the cerebellar cortex showed little variance and were similar to 7 repeat units. The ranges of the AE in the cerebral cortex, cerebral white matter, and cerebellar white matter were much broader in patients with higher ages at death than they were in patients with lower ages at death, raising the possibility that the range of AE increases with time, as the result of mitotic instability of AE.

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Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by genetic anticipation and variable combinations of symptoms including myoclonus, epilepsy, cerebellar ataxia, choreoathetosis, and dementia. Recently, we discovered that DRPLA is caused by unstable expansion of a CAG repeat of a gene on the short arm of chromosome 12. We determined the consensus DRPLA cDNA sequence containing the complete coding region for 1,185 amino acids. The CAG repeat, which is expanded in DRPLA, is located 1,462 bp downstream from the putative methionine initiation codon and encodes a poly-glutamine tract. Although poly-serine and proline tracts exist near the CAG repeats, these polyserine or proline tracts did not show any polymorphisms, which is in strong contrast to the high heterogeneity in the length of the CAG repeat. Northern blot analysis revealed a 4.7-kb transcript that is widely expressed in various tissues including heart, lung, kidney, placenta, skeletal muscle, and brain. Reverse transcription-PCR analysis revealed that the expanded alleles are transcribed to levels comparable to those of normal alleles. These results indicate that there is no difference in transcriptional efficiency between expanded and normal alleles. Furthermore, mRNA from cerebellar hemispheres of DRPLA patients showed smaller sizes of CAG repeats compared with other regions of the brain, which reflects somatic mosaicism of the expanded alleles of the DRPLA gene.

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DOI： 10.1038/ng1095-207

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING CO  

Hereditary dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurologic disorder characterized by variable combinations of myoclonus, epilepsy, cerebellar ataxia, choreoathetosis and dementia. By specifically searching published brain cDNA sequences for the presence of CAG repeats we identified unstable expansion of a CAG in a gene on chromosome 12 in all the 22 DRPLA patients examined. A good correlation between the size of the CAG repeat expansion and the ages of disease onset is found in this group. Patients with earlier onset tended to have a phenotype of progressive myoclonus epilepsy and larger expansions. We propose that the wide variety of clinical manifestations of DRPLA can now be explained by the variable unstable expansion of the CAG repeat.

DOI： 10.1038/ng0194-9

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1186/s12883-024-03892-w

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Many RNA-binding proteins (RBPs) are linked to the dysregulation of RNA metabolism in motor neuron diseases (MNDs). However, the molecular mechanisms underlying MN vulnerability have yet to be elucidated. Here, we found that such an RBP, Quaking5 (Qki5), contributes to formation of the MN-specific transcriptome profile, termed "MN-ness," through the posttranscriptional network and maintenance of the mature MNs. Immunohistochemical analysis and single-cell RNA sequencing (scRNA-seq) revealed that Qki5 is predominantly expressed in MNs, but not in other neuronal populations of the spinal cord. Furthermore, comprehensive RNA sequencing (RNA-seq) analyses revealed that Qki5-dependent RNA regulation plays a pivotal role in generating the MN-specific transcriptome through pre-messenger ribonucleic acid (mRNA) splicing for the synapse-related molecules and c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) signaling pathways. Indeed, MN-specific ablation of the Qki5 caused neurodegeneration in postnatal mice and loss of Qki5 function resulted in the aberrant activation of stress-responsive JNK/SAPK pathway both in vitro and in vivo. These data suggested that Qki5 plays a crucial biological role in RNA regulation and safeguarding of MNs and might be associated with pathogenesis of MNDs.

DOI： 10.1073/pnas.2401531121

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Brain biopsies are often considered for patients who cannot be diagnosed with various laboratory test results. However, physicians tend to be hesitant regarding their application in possibly non-neoplastic brain diseases, due to the invasiveness and risks. The aim was to determine the indications for brain biopsies in cases of neurological diseases of unknown etiology. We retrospectively evaluated diagnostic accuracy, laboratory findings (including a liquid biopsy for malignant lymphoma), magnetic resonance imaging (MRI) characteristics and the post-treatment outcomes of patients undergoing brain biopsies for neurological diseases of unknown etiology. The data of patients who had undergone a brain biopsy during their admission to Niigata University Hospital, between 2011 and 2024, were reviewed. Moreover, the laboratory data and MRI findings between patients with definitive and nonspecific biopsy diagnoses were compared. Twenty-six patients underwent a brain biopsy, and a definitive diagnosis was obtained in 14 patients (53.8%). Even in cases where a nonspecific diagnosis was made, biopsy findings helped rule out malignancy and guide clinical diagnosis and treatment decisions. The liquid biopsy for malignant lymphoma was performed in eight patients, with one yielding a positive result, consistent with primary central nervous system lymphoma. The sensitivity and specificity of liquid biopsy were 0.5 and 1, respectively. Diffusely contrasted cortical lesions and the presence of mass effects on MRI, were significantly associated with a definitive diagnosis, compared to a nonspecific diagnosis. In conclusion, brain MRI and liquid biopsies can assist in determining the appropriate indications for brain biopsies in neurological diseases of unknown etiology.

DOI： 10.1016/j.jns.2024.123150

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Abstract

Patients with neuronal intranuclear inclusion disease (NIID) can present with encephalitis‐like symptoms such as recurrent paroxysmal fever and unconsciousness. To date, no specific triggers for these symptoms have been reported. In our case, an 78‐year‐old woman became unconscious and developed fever after cerebral angiography. The patient had experienced four episodes of unconsciousness and fever in the past 7 years. Postangiography, she immediately became unconscious and developed fever. No vascular abnormalities were found and magnetic resonance imaging of the brain revealed expanding white matter lesions and hyperintense lesions along the corticomedullary junction. Genetic analysis revealed an abnormal GGC repeat expansion in NOTCH2NLC. Thus, we diagnosed the patient with NIID. We suggest that cerebral angiography is a possible trigger for encephalitis‐like symptoms in NIID.

DOI： 10.1111/ncn3.12839

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.heliyon.2024.e32512

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Abstract

The joint workshop between U.S. and Japanese researchers, supported by The U.S.–Japan Brain Research Cooperative Program, convened in January 2023 at Keio University Mita campus in Tokyo, Japan. The workshop had a threefold objective. Firstly, it aimed to facilitate robust exchanges between U.S. and Japanese researchers engaged in Neurovascular Unit (NVU) research, enhancing the global network of scholars in the field. Secondly, it aimed to encourage the initiation of collaborative research projects, fostering interdisciplinary efforts and synergistic advancements in understanding the brain vascular physiology and central nervous system. Lastly, the workshop emphasized the nurturing of young researchers, recognizing their pivotal role in shaping the future of NVU research. Throughout the workshop, participants discussed fundamental aspects of the NVU, exploring its complex connections and vital functions. By sharing their expertise and insights, the workshop attendees sought to uncover novel approaches to mitigate the burden of neurological diseases for individuals worldwide. This report provides a summary of the presentations and discussions held during the workshop, showcasing the collective efforts and progress made by the participants.

DOI： 10.1186/s12576-024-00917-4

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00401-024-02725-x

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

An 84‐year‐old man presented with somnolence, dysphagia, and right hemiplegia, all occurring within a month, approximately one year after initial admission due to subacute, transient cognitive decline suggestive of acute disseminated encephalomyelitis involving the cerebral white matter. Serial magnetic resonance imaging (MRI) studies over that period revealed three high‐intensity signal lesions on fluid‐attenuated inversion recovery images, appearing in chronological order in the left upper and left lower medulla oblongata and left pontine base. Despite some clinical improvement following methylprednisolone pulse therapy, the patient died of respiratory failure. Autopsy revealed four fresh, well‐defined lesions in the brainstem, three of which corresponded to the lesions detected radiologically. The remaining lesion was located in the dorsal medulla oblongata and involved the right solitary nucleus. This might have appeared at a later disease stage, eventually causing respiratory failure. Histologically, all four lesions showed loss of myelin, preservation of axons, and infiltration of lymphocytes, predominantly CD8‐positive T cells, consistent with the histological features of autoimmune demyelinating diseases, particularly the confluent demyelination observed in the early and acute phases of multiple sclerosis (MS). In the cerebral white matter, autoimmune demyelination appeared superimposed on ischemic changes, consistent with the cerebrospinal fluid (CSF) and MRI findings on initial admission. No anti‐AQP4 or MOG antibodies or those potentially causing autoimmune encephalitis/demyelination were detected in either the serum or CSF. Despite several similarities to MS, such as the relapsing–remitting disease course and lesion histology, the entire clinicopathological picture in the present patient, especially the advanced age at onset and development of brainstem lesions in close proximity within a short time frame, did not fit those of MS or other autoimmune diseases that are currently established. The present results suggest that exceptionally older individuals can be affected by an as yet unknown inflammatory demyelinating disease of the CNS.

DOI： 10.1111/neup.12976

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DOI： 10.1007/s00415-024-12276-6

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Abstract

The abnormal aggregation of TDP-43 into cytoplasmic inclusions in affected neurons is a major pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 is aberrantly accumulated in the neurons of most patients with sporadic ALS/FTD and other TDP-43 proteinopathies, how TDP-43 forms cytoplasmic aggregates remains unknown. In this study, we show that a deficiency in DCTN1, a subunit of the microtubule-associated motor protein complex dynactin, perturbs the dynamics of stress granules and drives the formation of TDP-43 cytoplasmic aggregation in cultured cells, leading to the exacerbation of TDP-43 pathology and neurodegeneration in vivo. We demonstrated using a Drosophila model of ALS/FTD that genetic knockdown of DCTN1 accelerates the formation of ubiquitin-positive cytoplasmic inclusions of TDP-43. Knockdown of components of other microtubule-associated motor protein complexes, including dynein and kinesin, also increased the formation of TDP-43 inclusions, indicating that intracellular transport along microtubules plays a key role in TDP-43 pathology. Notably, DCTN1 knockdown delayed the disassembly of stress granules in stressed cells, leading to an increase in the formation of pathological cytoplasmic inclusions of TDP-43. Our results indicate that a deficiency in DCTN1, as well as disruption of intracellular transport along microtubules, is a modifier that drives the formation of TDP-43 pathology through the dysregulation of stress granule dynamics.

DOI： 10.1186/s40478-024-01729-8

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INTRODUCTION: The King's Parkinson's Disease Pain Scale (KPPS)/King's Parkinson's Disease Pain Questionnaire (KPPQ) was developed as a tool to quantitatively assess pain in patients with Parkinson's disease (PwPD). Here, we conducted a Japanese multicenter validation study to verify the reliability of KPPS/KPPQ in Japanese PwPD. METHODS: PwPD, ≥20 years, with unexplained pain were included; those with a definitive primary cause of pain other than PD were excluded. A total of 151 patients who fulfilled the criteria were analyzed, and test-retest reliability was investigated in 25 individuals. RESULTS: The 151 patients included 101 women (66.9 %); mean age 68.3 ± 9.9 years, mean disease duration 9.2 ± 5.2 years. The most frequent pain type in the KPPS classification was musculoskeletal pain (82.8 %). There was a positive correlation between KPPS total score and the Non-Motor Symptoms Scale (NMSS) total score, NMSS item 27, the Parkinson's disease sleep scale-version 2 (PDSS-2) total score, PDSS-2 item 10, the Parkinson's Disease Questionnaire-8 (PDQ-8) summary index and PDQ-8 item 7. Cronbach's alpha of KPPS was 0.626 (0.562-0.658) and the intraclass correlation coefficient of test-retest reliability was 0.740. Cronbach's alpha of KPPQ was 0.660 (0.617-0.705) and a test-retest reliability of kappa coefficient was 0.593 (0.0-1.0). CONCLUSIONS: KPPS correlated well with other scales for assessing pain. KPPS correlated well with patients' quality of life, non-motor symptoms, and sleep disturbances. The reproducibility of KPPS/KPPQ makes it suitable for continuous evaluation of the same patient. On the other hand, the internal consistency of KPPS/KPPQ is rather low.

DOI： 10.1016/j.parkreldis.2024.106012

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[This corrects the article DOI: 10.3389/fncel.2023.1225504.].

DOI： 10.3389/fncel.2024.1372045

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Background: Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by autonomic failure and various motor symptoms. While MSA-C (cerebellar type) predominates in East Asia, MSA-P (parkinsonian type) predominates in Europe and North America. This nationwide patient registry aimed to (1) conduct a prospective natural history study of MSA in Japan, (2) facilitate patient recruitment for clinical trials, and (3) deposit bioresources and clinical information in a biobank. Methods: Thirteen institutions participated in this study. Clinical information was obtained by neurologists from the patients visiting the hospital every 12 months to assess the UMSARS Part 2 scores and by telephone interviews by nurses every 6 months to assess UMSARS Part 1 scores and to determine whether clinical events had occurred. Results: Demographic data from 329 MSA patients (216 MSA-C and 113 MSA-P) were analyzed. The mean age at symptom onset was 58.2 years (standard deviation, 8.9); the mean duration of symptoms at enrollment was 3.5 years (standard deviation, 2.2). The mean 12-month changes in the UMSARS Part 1 and Part 2 scores were 7.9 (standard deviation, 5.6) and 6.4 (standard deviation, 5.9), respectively. The patient registry proved useful in recruiting participants for clinical trials, including those with gene variants. Clinical information and biospecimens were deposited in a biobank. Discussion: The study highlighted the importance of telephone interviews in minimizing drop-out rates in natural history studies and demonstrated similar MSA progression rates across populations. The deposited bioresources are available to researchers upon request, aiming to contribute to future MSA researches.

DOI： 10.1111/ncn3.12809

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Background: The Columbia Muscle Cramp Scale (CMCS) is a useful tool for evaluating muscle cramps commonly observed in patients with amyotrophic lateral sclerosis (ALS). The CMCS comprises five subdomains: triggering factors, frequency, location, severity, and the degree to which cramps affect overall daily living. Aim: This study aimed to evaluate the reliability of the CMCS, which was translated into Japanese. Methods: Thirty patients with ALS (17 men and 13 women) from seven facilities were evaluated twice by two different evaluators (doctors, nurses, physical therapists, occupational therapists, and speech-language-hearing therapists). The degree of inter- and intra-rater agreement was evaluated using kappa statistics. Weighted kappa statistics and 95% confidence intervals accounted for multiple-order responses. Results: The average age was 60.4 (standard deviation: 10.4, range: 39–77) years. The kappa statistics for the inter-rater reliability of the CMCS items showed moderate to very good agreement, ranging from 0.56 (cramp triggering) to 0.91 (daily activity) at visit 1 and 0.51 (severity) to 0.96 (daily activity) at visit 2. The kappa statistics for the intra-rater reliability of the CMCS items also showed moderate to good agreement, ranging from 0.45 (frequency) to 0.79 (cramp triggering). Conclusion: The Japanese version of the CMCS demonstrated intra- and inter-rater reliability agreement and is expected to be useful for evaluating muscle cramps in patients with ALS.

DOI： 10.1111/ncn3.12838

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DOI： 10.1186/s40478-023-01692-w

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DOI： 10.20944/preprints202312.1336.v1

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BACKGROUND: Metformin (MET) treatment prior to stroke might have neuroprotective effects other than hypoglycemic effects. This study evaluated whether MET treatment prior to stroke is associated with neurological severity and functional outcome in patients with stroke who were not indicated for endovascular treatment and whether the effects of MET differ for each ischemic stroke subtype. METHODS: We investigated 160 type 2 diabetes mellitus patients with ischemic stroke without endovascular treatment who were taking some oral antidiabetic agents prior to stroke in two tertiary hospitals. Lower neurological severity was defined as a National Institutes of Health Stroke Scale score of 3 or lower on admission, and favorable functional outcome was defined as a modified Rankin Scale score = 0-2 at discharge. We analyzed the effects of MET on the neurological severity and functional outcome in each ischemic stroke subtype on logistic regression analysis with adjustments for multiple confounding factors. RESULTS: MET treatment prior to stroke was associated with lower stroke severity and favorable functional outcome. In the stroke subtypes, MET use affected both neurological severity (P = 0.037) and functional outcome (P = 0.041) in only patients with small-vessel disease (SVD). CONCLUSIONS: MET may be useful to improve the outcome of patients with SVD.

DOI： 10.1016/j.jns.2023.122812

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DOI： 10.1136/jnnp-2023-332419

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Language：Japanese   Publisher：(一社)日本神経学会  

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BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by sudden onset thunderclap headache and multiple segmental reversible cerebral vasoconstrictions that improve within 3 months. The postpartum period is a well-known precipitating factor for the onset of RCVS. Cerebral venous thrombosis (CVT) causes thunderclap headaches in the postpartum period. While headache in CVT is sometimes exacerbated in the supine position, the severity of the headache in RCVS is usually independent of body position. In this study, we report a case of RCVS with thunderclap headache exacerbated in the supine position, and headache attacks that resolved quickly in the standing position during the postpartum period. CASE PRESENTATION: A 33-year-old woman presented with a sudden increase in blood pressure and thunderclap headache on the fifth postpartum day (day 1: the first sick day). The headache was severe and pulsatile, with onset in the supine position in bed, and peaked at approximately 10 s. It was accompanied by nausea and chills but there were no scintillating scotomas or ophthalmic symptoms. The headache resolved in the standing or sitting position but was exacerbated and became unbearable within a few seconds when the patient was in the supine position. Therefore, she was unable to lie supine at night. Computed tomography angiography (CTA) of the head on day 2 and magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) on day 3 showed no abnormalities. However, considering the possibility of RCVS, verapamil was initiated on day 3. The headache resolved the following day. MRA of the head on day 10 revealed diffuse and segmental stenoses in the bilateral middle and posterior cerebral arteries and basilar artery. Therefore, the patient was diagnosed with RCVS. The headache gradually resolved and disappeared completely on day 42. Cerebral vasoconstriction was also improved on MRA on day 43. CONCLUSIONS: This postpartum RCVS case was notable for the exacerbation of headaches in the supine position. For the diagnosis of thunderclap headache in the postpartum period, RCVS should be considered in addition to CVT when the patient presents with a headache that is exacerbated in the supine position.

DOI： 10.1186/s12883-023-03381-6

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Publishing type：Part of collection (book)   Publisher：Springer Nature Singapore  

DOI： 10.1007/978-981-99-4886-4_13

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：日本神経眼科学会  

脊髄小脳変性症(spinocerebellar degeneration:SCD)は主に小脳と脳幹が侵される神経変性疾患である.SCDは遺伝性と孤発性に分類され,多くの疾患を含み,それぞれ臨床的特徴も異なる.SCDで障害される小脳,脳幹は眼球運動の各要素,衝動性眼球運動,滑動性追従眼球運動,前庭眼反射,視運動性眼運動,輻湊,固視に関わる部位である.このため,SCDでは眼球運動障害の頻度が高く,しばしば疾患ごとに特徴的な眼球運動障害も認められる.神経眼科的評価としてこれらの特徴を理解する事は,SCDの診断に重要である.(著者抄録)

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(株)羊土社  

筋萎縮性側索硬化症(ALS)は運動ニューロンの喪失を特徴とする神経変性疾患である.ALSの運動ニューロン細胞質で認める凝集体の構成成分としてTDP-43やFUS,C9orf72遺伝子変異によるジペプチドリピート(DPR)などのタンパク質があり,これらは液-液相分離(LLPS)とよばれる物理現象とかかわっている.LLPSは膜のないオルガネラの形成など生理的な機能を担う一方で,その破綻は凝集体の形成に関与している.本稿ではALS病態に関連したLLPSの生理的な役割と,凝集体が引き起こす病態について概説し,今後の研究の展望を述べる.(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)  

Abnormal expansions of GGGGCC repeat sequence in the noncoding region of the C9orf72 gene is the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). The expanded repeat sequence is translated into dipeptide repeat proteins (DPRs) by noncanonical repeat-associated non-AUG (RAN) translation. Since DPRs play central roles in the pathogenesis of C9-ALS/FTD, we here investigate the regulatory mechanisms of RAN translation, focusing on the effects of RNA-binding proteins (RBPs) targeting GGGGCC repeat RNAs. Using C9-ALS/FTD model flies, we demonstrated that the ALS/FTD-linked RBP FUS suppresses RAN translation and neurodegeneration in an RNA-binding activity-dependent manner. Moreover, we found that FUS directly binds to and modulates the G-quadruplex structure of GGGGCC repeat RNA as an RNA chaperone, resulting in the suppression of RAN translation in vitro. These results reveal a previously unrecognized regulatory mechanism of RAN translation by G-quadruplex-targeting RBPs, providing therapeutic insights for C9-ALS/FTD and other repeat expansion diseases.

DOI： 10.7554/eLife.84338

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Language：English  

DOI： 10.1002/acn3.51817

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.neurobiolaging.2023.03.007

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: Patients with advanced chronic kidney disease (CKD) are generally discouraged from consuming high amounts of vegetables and fruits given the potential risk of hyperkalemia. In the general population, however, lower vegetable and fruit intake is associated with higher mortality. This Japanese hospital-based prospective cohort study including non-CKD and CKD participants examined whether the frequency of vegetable and fruit intake is associated with mortality, and whether the presence of CKD modifies this association. METHODS: Participants were 2,006 patients who visited the outpatient department of a general hospital between June 2008 and December 2016 (55% men; mean age, 69 years). Among these participants, 902 (45%) and 131 (7%) were non-dialysis-dependent patients with CKD and hemodialysis patients, respectively. The frequency of vegetable and fruit intake was determined by a self-report questionnaire using an ordinal scale, "never or rarely," "sometimes," and "every day." Multivariable Cox proportional hazards analysis was conducted, adjusting for potential confounders. RESULTS: Vegetable and fruit intake frequency decreased with worsening CKD stage (P for trend < .001). Baseline serum potassium levels stratified by CKD stage were similar across the three vegetable and fruit intake frequency groups. During a median follow-up of 5.7 years, 561 participants died (47.1/1,000 person-years). Adjusted hazard ratios relative to the "every day" group were 1.25 (95% confidence interval, 1.04-1.52) and 1.60 (95% confidence interval, 1.23-2.08) for the "sometimes" and "never or rarely" groups, respectively, after adjusting for demographic factors, comorbidities, and CKD status. When stratified by CKD status, a similar, albeit non-significant, dose-dependent relationship was observed between vegetable and fruit intake frequency and all-cause mortality irrespective of CKD status, with no effect modification by CKD status (Pinteraction = .69). CONCLUSION: A lower frequency of vegetable and fruit intake is significantly associated with a higher risk of death regardless of CKD status.

DOI： 10.1053/j.jrn.2023.01.011

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 74-year-old woman who presented with a skin eruption involving the left lateral leg along the L5 dermatome and widespread eruptions on the buttocks and trunk was diagnosed with disseminated herpes zoster (HZ). She also had left lower extremity muscle weakness. The pattern of distribution of muscle weakness and gadolinium-enhanced magnetic resonance imaging findings indicated polyradiculoneuritis mainly affecting the L5 spinal root. Moreover, we observed severe weakness of the left tibialis anterior muscle. Weakness of the other L5 myotomes reduced after antiviral treatment; however, left tibialis anterior muscle weakness persisted. We concluded that lumbosacral polyradiculoneuritis was attributable to varicella-zoster virus (VZV) infection, which also caused fibular neuropathy in this case. Retrograde transport of the VZV may have infected the fibular nerve throughout the sites of skin eruption. It is important to be mindful of simultaneous nerve root and peripheral nerve involvement in cases of motor paralysis associated with HZ infection.

DOI： 10.5692/clinicalneurol.cn-001848

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND PURPOSE: Spinal cord lesions are observed in 40% of all central nervous system lesions in intravascular large B-cell lymphoma (IVLBCL). However, because IVLBCL is a very rare disease, its clinical features are not well defined, which may delay appropriate diagnosis and treatment, whilst the acute to subacute course of brain lesions in patients with IVLBCL is well established. Therefore, this study aimed to clarify the clinical features of spinal cord lesions in patients with IVLBCL. METHODS: The medical records of patients with IVLBCL admitted to our hospital between 2010 and 2020 were searched. The inclusion criteria were preceding neurological symptoms without non-neurological symptoms and pathologically confirmed IVLBCL in various organs. Clinical features of spinal cord involvement in patients with IVLBCL were assessed and distinguished from those of brain involvement. RESULTS: Sixteen consecutive patients with IVLBCL were divided into two groups: six patients with spinal involvement (spinal cord type) and 10 patients with brain involvement (brain type). In the spinal cord type, four patients had chronic progression and two had subacute progression. Acute progression (0% vs. 80.0%) and sudden onset (0% vs. 50.0%) occurred significantly less frequently in the spinal cord than in the brain. All spinal cord lesions involved the conus medullaris. CONCLUSIONS: Spinal cord involvement in IVLBCL has a predominantly chronic progressive course that is exclusive to brain involvement. Conus medullaris lesions are suggestive of IVLBCL and are useful for early and accurate diagnosis and treatment.

DOI： 10.1111/ene.15941

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s13311-023-01398-w

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Other Link： https://link.springer.com/article/10.1007/s13311-023-01398-w/fulltext.html

Publishing type：Research paper (scientific journal)   Publisher：Society of Nuclear Medicine  

DOI： 10.2967/jnumed.123.265593

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Language：English   Publishing type：Research paper (scientific journal)  

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder that is caused by the abnormal expansion of non-coding trinucleotide GGC repeats in NOTCH2NLC. NIID is clinically characterized by a broad spectrum of clinical presentations. To date, the relationship between expanded repeat lengths and clinical phenotype in patients with NIID remains unclear. Thus, we aimed to clarify the genetic and clinical spectrum and their association in patients with NIID. For this purpose, we genetically analyzed Japanese patients with adult-onset NIID with characteristic clinical and neuroimaging findings. Trinucleotide repeat expansions of NOTCH2NLC were examined by repeat-primed and amplicon-length PCR. In addition, long-read sequencing was performed to determine repeat size and sequence. The expanded GGC repeats ranging from 94 to 361 in NOTCH2NLC were found in all 15 patients. Two patients carried biallelic repeat expansions. There were marked heterogenous clinical and imaging features in NIID patients. Patients presenting with cerebellar ataxia or urinary dysfunction had a significantly larger GGC repeat size than those without. This significant association disappeared when these parameters were compared with the total trinucleotide repeat number. ARWMC score was significantly higher in patients who had a non-glycine-type trinucleotide interruption within expanded poly-glycine motifs than in those with a pure poly-glycine expansion. These results suggested that the repeat length and sequence in NOTCH2NLC may partly modify some clinical and imaging features of NIID.

DOI： 10.3390/brainsci13060955

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Language：English   Publishing type：Research paper (scientific journal)  

Clinical case studies and reporting are important to the discovery of new disorders and the advancement of medical sciences. Both clinicians and basic scientists play equally important roles leading to treatment discoveries for both cures and symptoms. In the field of movement disorders, exceptional observation of patients from clinicians is imperative, not just for phenomenology but also for the variable occurrences of these disorders, along with other signs and symptoms, throughout the day and the disease course. The Movement Disorders in Asia Task Force (TF) was formed to help enhance and promote collaboration and research on movement disorders within the region. As a start, the TF has reviewed the original studies of the movement disorders that were preliminarily described in the region. These include nine disorders that were first described in Asia - Segawa disease, PARK-Parkin, X-linked dystonia-parkinsonism (XDP), dentatorubral-pallidoluysian atrophy (DRPLA), Woodhouse-Sakati syndrome, benign adult familial myoclonic epilepsy (BAFME), Kufor-Rakeb disease, tremulous dystonia associated with mutation of the calmodulin-binding transcription activator 2 (CAMTA2) gene, and paroxysmal kinesigenic dyskinesia (PKD). We hope that the information provided will honor the original researchers and help us learn and understand how earlier neurologists and basic scientists together discovered new disorders and made advances in the field, which impact us all to this day.

DOI： 10.14802/jmd.23065

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Background

In the sporadic form of amyotrophic lateral sclerosis (ALS), the pathogenicity of rare variants in the causative genes characterizing the familial form remains largely unknown. To predict the pathogenicity of such variants, in silico analysis is commonly used. In some ALS causative genes, the pathogenic variants are concentrated in specific regions, and the resulting alterations in protein structure are thought to significantly affect pathogenicity. However, existing methods have not taken this issue into account. To address this, we have developed a technique termed MOVA (method for evaluating the pathogenicity of missense variants using AlphaFold2), which applies positional information for structural variants predicted by AlphaFold2. Here we examined the utility of MOVA for analysis of several causative genes of ALS.

Methods

We analyzed variants of 12 ALS-related genes (TARDBP, FUS, SETX, TBK1, OPTN, SOD1, VCP, SQSTM1, ANG, UBQLN2, DCTN1, and CCNF) and classified them as pathogenic or neutral. For each gene, the features of the variants, consisting of their positions in the 3D structure predicted by AlphaFold2, pLDDT score, and BLOSUM62 were trained into a random forest and evaluated by the stratified fivefold cross validation method. We compared how accurately MOVA predicted mutant pathogenicity with other in silico prediction methods and evaluated the prediction accuracy at TARDBP and FUS hotspots. We also examined which of the MOVA features had the greatest impact on pathogenicity discrimination.

Results

MOVA yielded useful results (AUC ≥ 0.70) for TARDBP, FUS, SOD1, VCP, and UBQLN2 of 12 ALS causative genes. In addition, when comparing the prediction accuracy with other in silico prediction methods, MOVA obtained the best results among those compared for TARDBP, VCP, UBQLN2, and CCNF. MOVA demonstrated superior predictive accuracy for the pathogenicity of mutations at hotspots of TARDBP and FUS. Moreover, higher accuracy was achieved by combining MOVA with REVEL or CADD. Among the features of MOVA, the x, y, and z coordinates performed the best and were highly correlated with MOVA.

Conclusions

MOVA is useful for predicting the virulence of rare variants in which they are concentrated at specific structural sites, and for use in combination with other prediction methods.

DOI： 10.1186/s12859-023-05338-5

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Other Link： https://link.springer.com/article/10.1186/s12859-023-05338-5/fulltext.html

Language：English  

Genetic Creutzfeldt-Jakob disease (gCJD) with a V180I mutation (V180I gCJD) is the most common type of gCJD in Japan, characterized by an older age at onset, slower progression, and moderate to severe cortical degeneration with spongiform changes and sparing of the brainstem and cerebellum. Degeneration of the inferior olivary nucleus (IO) is rarely observed in patients with CJD but is known to occur in fatal familial insomnia (FFI) and MM2-thalamic-type sporadic CJD (sCJD-MM2T) involving type 2 prion protein (M2T prion). Here we report on an 81-year-old Japanese woman who initially developed depressive symptoms followed by progressive cognitive impairment, myoclonus, and hallucinations and died after a clinical course of 23 months. Insomnia was not evident. Genetic analysis of the prion protein (PrP) identified a V180I mutation with methionine/valine heterozygosity at codon 129. Pathologic analysis demonstrated extensive spongiform degeneration, neuronal loss in the cortices, and weak synaptic-type PrP deposition. Except for IO degeneration, the clinicopathologic features and Western blotting PrP band pattern were compatible with those of previously reported V180I gCJD cases. Quantitative analysis revealed that the neuronal density of the IO, especially in the dorsal area, was considerably reduced to the same extent as that of a patient with sCJD-MM2T but preserved in other patients with V180I gCJD and sCJD-MM1 (this patient, 2.3 ± 0.53/mm2 ; a patient with sCJD-MM2T, 4.2 ± 2; a patient with V180I gCJD, 60.5 ± 9.3; and a patient with sCJD-MM1, 84.5 ± 17.9). Use of the protein misfolding cyclic amplification (PMCA) method confirmed the presence of the M2T prion strain, suggesting that the latter might be associated with IO degeneration in V180I gCJD. Autopsy studies are necessary to better understand the nature of CJD, since even if patients present with the common clinical picture, pathologic analysis might provide new insights, as was the case here.

DOI： 10.1111/neup.12908

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Several genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS. METHODS: We enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants. We used Cox proportional hazards regression analysis with an additive model adjusted for sex, age at onset and the first two principal components calculated from genotyped data to conduct a genome-wide association study. We further analysed messenger RNA (mRNA) and phenotype expression in motor neurons derived from induced pluripotent stem cells (iPSC-MNs) of patients with ALS. RESULTS: Three novel loci were significantly associated with the survival of patients with sporadic ALS-FGF1 at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10-9), THSD7A at 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10-8) and LRP1 at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10-8). FGF1 and THSD7A variants were associated with decreased mRNA expression of each gene in iPSC-MNs and reduced in vitro survival of iPSC-MNs obtained from patients with ALS. The iPSC-MN in vitro survival was reduced when the expression of FGF1 and THSD7A was partially disrupted. The rs60565245 was not associated with LRP1 mRNA expression. CONCLUSIONS: We identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression of FGF1 and THSD7A and the viability of iPSC-MNs from patients. The iPSC-MN model reflects the association between patient prognosis and genotype and can contribute to target screening and validation for therapeutic intervention.

DOI： 10.1136/jnnp-2022-330851

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Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

Background and Objectives

As the number of repeats in the expansion increases, polyglutamine diseases tend to show at a younger age. From this relationship, attempts have been made to predict age at onset by parametric survival analysis. However, a method for a more accurate prediction has been desirable. In this study, we examined 2 methods for survival analysis using machine learning and 6 conventional methods for parametric survival analysis of spinocerebellar ataxia (SCA)3 and dentatorubral-pallidoluysian atrophy (DRPLA).

Methods

We compared the performance of 2 machine learning methods of survival analysis (random survival forest [RSF] and DeepSurv) and 6 methods of parametric survival analysis (Weibull, exponential, Gaussian, logistic, loglogistic, and log Gaussian). Training and evaluation were performed using the leave-one-out cross-validation method, and evaluation criteria included root mean squared error (RMSE), mean absolute error (MAE), and the integrated Brier score. The latter was used as the primary end point, and the survival analysis model yielding the best result was used to predict the asymptomatic probability.

Results

Among the models examined, the RSF and DeepSurv machine learning methods had a higher prediction accuracy than the parametric methods of survival analysis. For both SCA3 and DRPLA, RSF had a higher accuracy than DeepSurv for the assessment of RMSE (SCA3: 7.37, DRPLA: 10.78), MAE (SCA3: 5.52, DRPLA: 8.17), and the integrated Brier score (SCA3: 0.05, DRPLA: 0.077). Using RSF, we determined the age-specific probability distribution of age at onset based on CAG repeat size and current age.

Discussion

In this study, we have demonstrated the superiority of machine learning methods for predicting age at onset of SCA3 and DRPLA using survival analysis. Such accurate prediction of onset will be useful for genetic counseling of carriers and for devising methods to verify the effects of interventions for unaffected individuals.

DOI： 10.1212/nxg.0000000000200075

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Language：English  

To elucidate the molecular basis of multiple system atrophy (MSA), a neurodegenerative disease, we conducted a genome-wide association study (GWAS) in a Japanese MSA case/control series followed by replication studies in Japanese, Korean, Chinese, European and North American samples. In the GWAS stage rs2303744 on chromosome 19 showed a suggestive association ( P = 6.5 × 10 -7 ) that was replicated in additional Japanese samples ( P = 2.9 × 10 -6 . OR = 1.58; 95% confidence interval, 1.30 to 1.91), and then confirmed as highly significant in a meta-analysis of East Asian population data ( P = 5.0 × 10 -15 . Odds ratio= 1.49; 95% CI 1.35 to 1.72). The association of rs2303744 with MSA remained significant in combined European/North American samples ( P =0.023. Odds ratio=1.14; 95% CI 1.02 to 1.28) despite allele frequencies being quite different between these populations. rs2303744 leads to an amino acid substitution in PLA2G4C that encodes the cPLA2γ lysophospholipase/transacylase. The cPLA2γ-Ile143 isoform encoded by the MSA risk allele has significantly decreased transacylase activity compared with the alternate cPLA2γ-Val143 isoform that may perturb membrane phospholipids and α-synuclein biology.

DOI： 10.1101/2023.05.02.23289328

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Functionally impaired variants of COQ2, encoding an enzyme in biosynthesis of coenzyme Q10 (CoQ10), were found in familial multiple system atrophy (MSA) and V393A in COQ2 is associated with sporadic MSA. Furthermore, reduced levels of CoQ10 have been demonstrated in MSA patients. METHODS: This study was a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial. Patients with MSA were randomly assigned (1:1) to either ubiquinol (1500 mg/day) or placebo. The primary efficacy outcome was the change in the unified multiple system atrophy rating scale (UMSARS) part 2 at 48 weeks. Efficacy was assessed in all patients who completed at least one efficacy assessment (full analysis set). Safety analyses included patients who completed at least one dose of investigational drug. This trial is registered with UMIN-CTR (UMIN000031771), where the drug name of MSA-01 was used to designate ubiquinol. FINDINGS: Between June 26, 2018, and May 27, 2019, 139 patients were enrolled and randomly assigned to the ubiquinol group (n = 69) or the placebo group (n = 70). A total of 131 patients were included in the full analysis set (63 in the ubiquinol group; 68 in the placebo group). This study met the primary efficacy outcome (least square mean difference in UMSARS part 2 score (-1.7 [95% CI, -3.2 to -0.2]; P = 0.023)). The ubiquinol group also showed better secondary efficacy outcomes (Barthel index, Scale for the Assessment and Rating of Ataxia, and time required to walk 10 m). Rates of adverse events potentially related to the investigational drug were comparable between ubiquinol (n = 15 [23.8%]) and placebo (n = 21 [30.9%]). INTERPRETATION: High-dose ubiquinol was well-tolerated and led to a significantly smaller decline of UMSARS part 2 score compared with placebo. FUNDING: Japan Agency for Medical Research and Development.

DOI： 10.1016/j.eclinm.2023.101920

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Language：Japanese   Publisher：(一社)日本神経治療学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J02615&link_issn=&doc_id=20230825280022&doc_link_id=10.15082%2Fjsnt.40.3_259&url=https%3A%2F%2Fdoi.org%2F10.15082%2Fjsnt.40.3_259&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(一社)日本神経治療学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J02615&link_issn=&doc_id=20230825280022&doc_link_id=10.15082%2Fjsnt.40.3_259&url=https%3A%2F%2Fdoi.org%2F10.15082%2Fjsnt.40.3_259&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：English   Publishing type：Research paper (scientific journal)  

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is an inherited cerebral small vessel disease (CSVD) caused by biallelic mutations in the high-temperature requirement serine peptidase A1 (HTRA1) gene. Even heterozygous mutations in HTRA1 are recently revealed to cause cardinal clinical features of CSVD. Here, we report the first establishment of a human induced pluripotent stem cell (hiPSC) line from a patient with heterozygous HTRA1-related CSVD. Peripheral blood mononuclear cells (PBMCs) were reprogrammed by the transfection of episomal vectors encoding human OCT3/4 (POU5F1), SOX2, KLF4, L-MYC, LIN28, and a murine dominant-negative mutant of p53 (mp53DD). The established iPSCs had normal morphology as human pluripotent stem cells and normal karyotype (46XX). Moreover, we found that the HTRA1 missense mutation (c.905G>A, p.R302Q) was heterozygous. These iPSCs expressed pluripotency-related markers and had the potential to differentiate into all three germ layers in vitro. HTRA1 and the supposed disease-associated gene NOG were differentially expressed in the patient iPSCs at mRNA levels compared to those of control lines. The iPSC line would facilitate in vitro research for understanding the cellular pathomechanisms caused by the HTRA1 mutation including its dominant-negative effect.

DOI： 10.1186/s41232-023-00273-7

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Language：Japanese   Publisher：信州医学会  

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Language：Japanese   Publisher：信州医学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: CSF1R-related leukoencephalopathy is an adult-onset leukoencephalopathy caused by mutations in CSF1R. The present study aimed to explore the broader genetic spectrum of CSF1R-related leukoencephalopathy in association with clinical and imaging features. METHODS: Mutational analysis of CSF1R was performed for 100 consecutive patients with adult-onset leukoencephalopathy. Sequence and copy number variation (CNV) analyses of CSF1R were performed. The genomic ranges of the deletions were determined by long-read sequencing. Ligand-dependent autophosphorylation of CSF1R was examined in cells expressing the CSF1R mutants identified in this study. RESULTS: We identified CSF1R mutations in 15 patients, accounting for 15% of the adult-onset leukoencephalopathy cases. Seven novel and five previously reported CSF1R mutations were identified. The novel mutations, including three missense and one in-frame 3-bp deletion, were located in the tyrosine kinase domain (TKD) of CSF1R. Functional assays revealed that none of the novel mutations in the TKD showed autophosphorylation of CSF1R. We identified two partial deletions of CSF1R that resulted in the lack of the C-terminal region, including the distal TKD, in two patients. Variable clinical features including cognitive impairment, psychiatric symptoms, and gait disturbance were observed. Various degrees of the white matter lesions and corpus callosum abnormalities on MRI and characteristic calcifications on CT were observed as imaging features. CONCLUSIONS: Our results highlighted the importance of examining the CNV of CSF1R even when Sanger or exome sequencing reveal no CSF1R mutations. Genetic examination of sequences and CNV analyses of CSF1R are recommended for an accurate diagnosis of CSF1R-related leukoencephalopathy.

DOI： 10.1111/ene.15796

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(株)中外医学社  

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Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.2176-23

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Language：English   Publishing type：Research paper (scientific journal)  

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective degeneration of upper and lower motor neurons. Currently, there are no effective biomarkers and fundamental therapies for this disease. Dysregulation in RNA metabolism plays a critical role in the pathogenesis of ALS. With the contribution of Next Generation Sequencing, the functions of non-coding RNAs (ncRNAs) have gained increasing interests. Especially, micro RNAs (miRNAs), which are tissue-specific small ncRNAs of about 18-25 nucleotides, have emerged as key regulators of gene expression to target multiple molecules and pathways in the central nervous system (CNS). Despite intensive recent research in this field, the crucial links between ALS pathogenesis and miRNAs remain unclear. Many studies have revealed that ALS-related RNA binding proteins (RBPs), such as TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS), regulate miRNAs processing in both the nucleus and cytoplasm. Of interest, Cu2+/Zn2+ superoxide dismutase (SOD1), a non-RBP associated with familial ALS, shows partially similar properties to these RBPs via the dysregulation of miRNAs in the cellular pathway related to ALS. The identification and validation of miRNAs are important to understand the physiological gene regulation in the CNS, and the pathological implications in ALS, leading to a new avenue for early diagnosis and gene therapies. Here, we offer a recent overview regarding the mechanism underlying the functions of multiple miRNAs across TDP-43, FUS, and SOD1 with the context of cell biology, and challenging for clinical applications in ALS.

DOI： 10.3389/fnins.2023.1131758

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Language：English   Publishing type：Research paper (scientific journal)  

Theoretically, direct chemical reprogramming of somatic cells into neurons in the infarct area represents a promising regenerative therapy for ischemic stroke. Previous studies have reported that human fibroblasts and astrocytes transdifferentiate into neuronal cells in the presence of small molecules without introducing ectopic transgenes. However, the optimal combination of small molecules for the transdifferentiation of macrophages into neurons has not yet been determined. The authors hypothesized that a combination of small molecules could induce the transdifferentiation of monocyte-derived macrophages into neurons and that the administration of this combination may be a regenerative therapy for ischemic stroke because monocytes and macrophages are directly involved in the ischemic area. Transcriptomes and morphologies of the cells were compared before and after stimulation using RNA sequencing and immunofluorescence staining. Microscopic analyses were also performed to identify cell markers and evaluate functional recovery by blinded examination following the administration of small molecules after ischemic stroke in CB-17 mice. In this study, an essential combination of six small molecules [CHIR99021, Dorsomorphin, Forskolin, isoxazole-9 (ISX-9), Y27632, and DB2313] that transdifferentiated monocyte-derived macrophages into neurons in vitro was identified. Moreover, administration of six small molecules after cerebral ischemia in model animals generated a new neuronal layer in the infarct cortex by converting macrophages into neuronal cells, ultimately improving neurological function. These results suggest that altering the transdifferentiation of monocyte-derived macrophages by the small molecules to adjust their adaptive response will facilitate the development of regenerative therapies for ischemic stroke.

DOI： 10.3389/fncel.2023.1225504

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Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

DOI： 10.1093/jnen/nlac120

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Language：English   Publishing type：Research paper (scientific journal)  

The examination of urinary sediment crystals, the sedimentary components of urine, is useful in screening tests, and is always performed in medical examinations. The examination of urinary sediment crystals is typically done by classifying them under a microscope. Although automated analyzers are commercially available, manual classification is required, which is time-consuming and varies depending on the technologist performing the test and the laboratory. A set of test images was created, consisting of training, validation, and test images. The training images were transformed and augmented using various methods. The test images were classified to determine the patterns that could be correctly classified. Convolutional neural networks were used for training. Furthermore, we also considered the case where the crystal subcategories were not treated as separate. Learning with all parameters except the random cropping parameter showed the highest accuracy value. Treating the subcategories together or separately did not seem to affect the accuracy value. The accuracy of the best pattern was 0.918. When matched to a real-world case, the percentage of correct answers was 88%. Although the number of images was limited, good results were obtained in the classification of crystal images with optimal parameter tuning. The parameter optimization performed in this study can be used as a reference for future studies, with the goal of image classification by deep learning in clinical practice.

DOI： 10.1038/s41598-022-25385-x

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Publishing type：Research paper (scientific journal)   Publisher：BMJ  

Background

This study aimed to clarify the frequency and clinical features of monogenic cerebral small vessel disease (mgCSVD) among patients with adult-onset severe CSVD in Japan.

Methods

This study included patients with adult-onset severe CSVD with an age of onset ≤55 years (group 1) or &gt;55 years and with a positive family history (group 2). After conducting conventional genetic tests forNOTCH3andHTRA1, whole-exome sequencing was performed on undiagnosed patients. Patients were divided into two groups according to the results of the genetic tests: monogenic and undetermined. The clinical and imaging features were compared between the two groups.

Results

Group 1 and group 2 included 75 and 31 patients, respectively. In total, 30 patients hadNOTCH3mutations, 11 patients hadHTRA1mutations, 6 patients hadABCC6mutations, 1 patient had aTREX1mutation, 1 patient had aCOL4A1mutation and 1 patient had aCOL4A2mutation. The total frequency of mutations inNOTCH3,HTRA1andABCC6was 94.0% in patients with mgCSVD. In group 1, the frequency of a family history of first relatives, hypertension and multiple lacunar infarctions (LIs) differed significantly between the two groups (monogenic vs undetermined; family history of first relatives, 61.0% vs 25.0%, p=0.0015; hypertension, 34.1% vs 63.9%, p=0.0092; multiple LIs, 87.8% vs 63.9%, p=0.0134).

Conclusions

More than 90% of mgCSVDs were diagnosed by screening forNOTCH3,HTRA1andABCC6. The target sequences for these three genes may efficiently diagnose mgCSVD in Japanese patients.

DOI： 10.1136/jnnp-2022-329917

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DOI： 10.1016/j.clineuro.2022.107502.

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Language：Japanese   Publisher：(一社)日本脳循環代謝学会  

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Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

Objectives

Leigh syndrome is a progressive encephalopathy characterized by symmetrical lesions in brain. This study aimed to investigate the clinicopathologic and genetic characteristics of a family with Leigh syndrome and hereditary neuropathy with liability to pressure palsy (HNPP).

Methods

Data from a Japanese family's clinical features, MRIs, muscle biopsy, and an autopsy were analyzed. A whole-exome sequence was performed, as well as real-time PCR analysis to determine copy number variations and Western blot analyses.

Results

The proband and her 2 siblings developed spastic paraplegia and mental retardation during childhood. The proband and her sister had peripheral neuropathy, whereas their father developed compression neuropathy. Leigh encephalopathy was diagnosed neuropathologically. Brain MRI revealed changes in cerebral white matter as well as multiple lesions in the brainstem and cerebellum. Muscle biopsy revealed type 2 fiber uniformity and decreased staining of cytochrome c oxidase. The COX10 missense mutation was identified through whole-exome sequence. A 1.4-Mb genomic deletion extending from intron 5 of COX10 to PMP22 was detected.

Discussion

These findings suggest that in this family, Leigh syndrome is associated with a mitochondrial respiratory chain complex IV deficiency caused by biallelic COX10 mutations coexisting with HNPP caused by heterozygous PMP22 deletion.

DOI： 10.1212/nxg.0000000000200030

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.jns.2022.120456

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Language：English   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経治療学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J02615&link_issn=&doc_id=20221114240031&doc_link_id=10.15082%2Fjsnt.39.6_S118&url=https%3A%2F%2Fdoi.org%2F10.15082%2Fjsnt.39.6_S118&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：English   Publisher：(一社)日本神経学会  

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Language：English   Publishing type：Research paper (scientific journal)  

TAR DNA-binding protein 43 kDa (TDP-43), a nuclear protein, plays an important role in the molecular pathogenesis of amyotrophic lateral sclerosis (ALS). The long-disordered C-terminal region (CTR) of TDP-43 is known to be aggregation-prone and a hotspot for ALS mutations, so elucidation of the physiological function of CTR will provide insights into the pathogenesis of ALS. The CTR has two Gly, aromatic, and Ser-rich (GaroS) segments and an amyloidogenic core divided into a hydrophobic patch (HP) and a Gln/Asn (Q/N)-rich segment. Although TDP-43 lacking the CTR is known to be unstable, as observed in knock-in mice, it is unclear which of these segments contributes to the stability of TDP-43. Here, we generated 12 mouse lines lacking the various sub-regions of CTR by genome editing and compared the embryonic lethality of homozygotes, and protein and mRNA expression levels of TDP-43. We demonstrated the functional diversity of the four segments of CTR, finding that the presence of the Q/N-rich segment greatly restored the protein stability of TDP-43. In addition, we found that the second GaroS deletion did not affect protein stability and mouse development.

DOI： 10.1038/s41598-022-19153-0

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Language：Japanese   Publisher：日本神経心理学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder. The usefulness of biomarkers in diagnosing MSA has been recently reported, but few studies have investigated the correlations among cerebrospinal fluid (CSF) biomarkers or the relationship between CSF biomarkers and the clinical parameters of patients with MSA. Thus, this was the aim of our study. METHODS: We performed cross-sectional study of CSF biomarkers in 50 patients with MSA and 20 control subjects. Ten of the patients with MSA were longitudinally followed for a period of 2 ± 1 years (mean ± standard deviation) as a substudy. We quantified CSF biomarkers including α-synuclein (α-syn), β-amyloid42 (Aβ42), total tau (t-tau) and phosphorylated tau (p-tau), neurofilament light chain (NfL), and neuron-glia2 (NG2), and assessed their relationship with clinical parameters (clinical subtypes, motor symptoms, nonmotor symptoms, and disease progression). RESULTS: The levels of CSF α-syn, Aβ42, and p-tau were significantly lower, while those of NfL were higher in the patients with MSA than in the control subjects. Importantly, we found the significant elevation of soluble NG2 in the CSF of patients with MSA. CSF NfL showed the optimal diagnostic performance for MSA with levels at baseline significantly associated with longitudinal motor progression. With the exception of t-tau, there were no differences in the levels of CSF biomarkers between the MSA-parkinsonism and MSA-cerebellar subtypes. CONCLUSIONS: Our results suggest CSF levels of NG2 and NfL as possible diagnostic and prognostic biomarkers in MSA. Further study is necessary to validate these findings.

DOI： 10.1016/j.parkreldis.2022.07.007

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

AIM: This prospective cohort study aimed to (i) examine stroke incidence and stroke subtypes by chronic kidney disease (CKD) stage, (ii) examine whether CKD patients with or without proteinuria have a high risk of stroke independent of traditional cardiovascular risk factors, and (iii) determine precise estimates of stroke risk by CKD stage while accounting for competing mortality risk. METHODS: Participants were 2023 patients enrolled in the Project in Sado for Total Health between June 2008 and December 2016 (55% men; mean age, 69 years), of whom 52% had CKD (stage 1-2, 10%; G3a, 48%; G3b, 17%; G4-5, 11% and G5D, 14%). RESULTS: During a median follow-up of 5.7 years, 157 participants developed stroke and 448 died without developing stroke. Most stroke cases were ischaemic among non-dialysis-dependent CKD participants, but the relative frequency of ischaemic stroke was near that of intracerebral haemorrhage among dialysis-dependent CKD participants. After adjustment, stage 1-2 (hazard ratio [HR], 2.97; 95% confidence interval [CI], 1.60-5.51) and stage G3-5 participants with proteinuria (HR, 2.50; 95% CI, 1.56-4.02), but not stage G3-5 participants without proteinuria (HR, 0.64; 95% CI, 0.38-1.08), had a higher stroke risk compared to non-CKD participants. In competing risk analyses, the association was attenuated but remained significant. CONCLUSION: Although the distribution of stroke subtypes differed, CKD participants with proteinuria and those with CKD stage 5D had a 2- and 4-times higher risk of stroke, respectively, than that of non-CKD participants, after accounting for competing mortality risk and traditional risk factors.

DOI： 10.1111/nep.14049

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：{MDPI} {AG}  

Multiple-system atrophy (MSA) is primarily an autonomic disorder with parkinsonism or cerebellar ataxia. Clinical diagnosis of MSA at an early stage is challenging because the symptoms change over the course of the disease. Recently, various artificial intelligence-based programs have been developed to improve the diagnostic accuracy of neurodegenerative diseases, but most are limited to the evaluation of diagnostic imaging. In this study, we examined the validity of diagnosis of MSA using a pointwise linear model (deep learning-based method). The goal of the study was to identify features associated with disease differentiation that were found to be important in deep learning. A total of 3377 registered MSA cases from FY2004 to FY2008 were used to train the model. The diagnostic probabilities of SND (striatonigral degeneration), SDS (Shy-Drager syndrome), and OPCA (olivopontocerebellar atrophy) were estimated to be 0.852 ± 0.107, 0.650 ± 0.235, and 0.858 ± 0.270, respectively. In the pointwise linear model used to identify and visualize features involved in individual subtypes, autonomic dysfunction was found to be a more prominent component of SDS compared to SND and OPCA. Similarly, respiratory failure was identified as a characteristic of SDS, dysphagia was identified as a characteristic of SND, and brain-stem atrophy was identified as a characteristic of OPCA.

DOI： 10.3390/biology11070951

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Importance: The effectiveness of currently approved drugs for amyotrophic lateral sclerosis (ALS) is restricted; there is a need to develop further treatments. Initial studies have shown ultrahigh-dose methylcobalamin to be a promising agent. Objective: To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS enrolled within 1 year of onset. Design, Setting, and Participants: This was a multicenter, placebo-controlled, double-blind, randomized phase 3 clinical trial with a 12-week observation and 16-week randomized period, conducted from October 17, 2017, to September 30, 2019. Patients were recruited from 25 neurology centers in Japan; those with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1- or 2-point decrease in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score, a percent forced vital capacity greater than 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulatory. The target participant number was 64 in both the methylcobalamin and placebo groups. Patients were randomly assigned through an electronic web-response system to methylcobalamin or placebo. Interventions: Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks. Main Outcomes and Measures: The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set. Results: A total of 130 patients (mean [SD] age, 61.0 [11.7] years; 74 men [56.9%]) were randomly assigned to methylcobalamin or placebo (65 each). A total of 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Of these, 124 patients proceeded to the open-label extended period. The least square means difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (-2.66 vs -4.63; 95% CI, 0.44-3.50; P = .01). The incidence of adverse events was similar between the 2 groups. Conclusions and Relevance: Results of this randomized clinical trial showed that ultrahigh-dose methylcobalamin was efficacious in slowing functional decline in patients with early-stage ALS and with moderate progression rate and was safe to use during the 16-week treatment period. Trial Registration: ClinicalTrials.gov Identifier: NCT03548311.

DOI： 10.1001/jamaneurol.2022.0901

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Language：Japanese   Publisher：東北整形災害外科学会  

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DOI： 10.1002/mds.29032

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Language：Japanese   Publisher：(株)中外医学社  

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Language：Japanese   Publisher：(一社)日本神経学会  

日本神経学会では,脳神経内科領域の研究・教育・診療,特に研究の方向性や学会としてのあるべき姿について審議し,水澤代表理事が中心となり国などに対して提言を行うために作成委員*が選ばれ,2013年に「脳神経疾患克服に向けた研究推進の提言」が作成された.2014年に将来構想委員会が設立され,これらの事業が継続.今回将来構想委員会で,2020年から2021年の最新の提言が作成された.この各論Iでは,遺伝子研究,トランスレーショナルリサーチ,核酸医薬,iPS研究,介護・福祉など,多様性を増す脳神経内科領域の臨床と研究について,最新トピックスを交えて取り上げる.(著者抄録)

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2022&ichushi_jid=J01550&link_issn=&doc_id=20220609450001&doc_link_id=10.5692%2Fclinicalneurol.cn-001695&url=https%3A%2F%2Fdoi.org%2F10.5692%2Fclinicalneurol.cn-001695&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(一社)日本神経学会  

日本神経学会では,脳神経内科領域の研究・教育・診療,特に研究の方向性や学会としてのあるべき姿について審議し,水澤代表理事が中心となり国などに対して提言を行うために作成委員*が選ばれ,2013年に「脳神経疾患克服に向けた研究推進の提言」が作成された.2014年に将来構想委員会が設立され,これらの事業が継続.今回将来構想委員会で,2020年から2021年の最新の提言が作成された.この各論IIでは,疾患ごとに脳神経内科領域を分類し,各分野の専門家がわかりやすく解説するとともに,最近のトピックスについて冒頭に取り上げた.(著者抄録)

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2022&ichushi_jid=J01550&link_issn=&doc_id=20220609450002&doc_link_id=10.5692%2Fclinicalneurol.cn-001696&url=https%3A%2F%2Fdoi.org%2F10.5692%2Fclinicalneurol.cn-001696&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：English   Publisher：SPRINGER JAPAN KK  

DOI： 10.1007/s00774-022-01315-9

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Language：Japanese   Publisher：Societas Neurologica Japonica  

The Japanese Society of Neurology discusses research, education, and medical care in the field of neurology and makes recommendations to the national government. Dr. Mizusawa, the former representative director of the Japanese Society of Neurology, selected committee members and made "Recommendations for Promotion of Research for Overcoming Neurological Diseases" in 2013. After that, the Future Vision Committee was established in 2014, and these recommendations have been revised once every few years by the committee. This time, the Future Vision Committee made the latest recommendations from 2020 to 2021. In this section II, we will discuss clinical and research topics of neurology categorized by the diseases. In each field, the hot topic of the disease was described by the expert.

DOI： 10.5692/clinicalneurol.cn-001696

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Language：Japanese   Publisher：Societas Neurologica Japonica  

The Japanese Society of Neurology discusses research, education, and medical care in the field of neurology and makes recommendations to the national government. Dr. Mizusawa, the former representative director of the Japanese Society of Neurology, selected committee members and made "Recommendations for Promotion of Research for Overcoming Neurological Diseases" in 2013. After that, the Future Vision Committee was established in 2014, and these recommendations have been revised once every few years by the committee. This time, the Future Vision Committee made the latest recommendations from 2020 to 2021. In this section I, we will discuss clinical and research topics of neurology categorized by the methodology, including genetic research, translational research, nucleic acid therapies, iPS research, and nursing/welfare.

DOI： 10.5692/clinicalneurol.cn-001695

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Language：Japanese   Publishing type：Research paper (scientific journal)  

We report the case of a 65-year-old man who gradually developed numbness in both hands, lower limb muscle weakness and atrophy, and orthostatic hypotension over two and a half years. These symptoms indicated hereditary ATTR amyloidosis (ATTRv amyloidosis), and the final diagnosis was established through proof of TTR gene mutation (V30M). We initiated patisiran therapy, and a continuous 6-minute walking test performed 3 weeks from the start of therapy demonstrated improvement in the walking distance. This is a single case report showing the improvement in the motor and sensory function on administration of patisiran monotherapy from an early stage.

DOI： 10.5692/clinicalneurol.cn-001693

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Language：Japanese   Publisher：(一社)日本神経学会  

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AIMS: Neuronal and glial inclusions comprising transactive response DNA-binding protein of 43 kDa (TDP-43) have been identified in the brains of patients with corticobasal degeneration (CBD), and a possible correlation between the presence of these inclusions and clinical phenotypes has been speculated. However, the significance of TDP-43 pathology in the pathomechanism of CBD has remained unclear. Here, we investigated the topographical relationship between TDP-43 inclusions and neuronal loss in CBD. METHODS: We estimated semi-quantitatively neuronal loss and TDP-43 pathology in the form of neuronal cytoplasmic inclusions (NCIs), astrocytic inclusions (AIs), oligodendroglial cytoplasmic inclusions (GCIs), and dystrophic neurites in 22 CNS regions in 10 patients with CBD. Then, the degree of correlation between the severity of neuronal loss and the quantity of each type of TDP-43 inclusion was assessed. We also investigated tau pathology in a similar manner. RESULTS: TDP-43 pathology was evident in nine patients. The putamen and globus pallidus were the regions most frequently affected (80%). NCIs were the most prominent form, and their quantity was significantly correlated with the severity of neuronal loss in more than half of the regions examined. The quantities of TDP-43 NCIs and tau NCIs were correlated in only a few regions. The number of regions where the quantities of TDP-43 AIs and GCIs were correlated with the severity of neuronal loss was apparently small in comparison with that of NCIs. CONCLUSIONS: TDP-43 alterations in neurons, not closely associated with tau pathology, may be involved in the pathomechanism underlying neuronal loss in CBD. There was a significant topographical correlation between neuronal cytoplasmic aggregation of TDP-43 and neuronal loss in CBD, suggesting that TDP-43 protein aberration might be associated with neuronal degeneration in CBD. There was no close correlation between the burden of TDP-43 and that of tau in neurons.

DOI： 10.1111/nan.12786

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Language：English  

DOI： 10.1007/s00774-022-01315-9

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Language：English   Publishing type：Research paper (scientific journal)  

Activation of human endogenous retrovirus-K (HERV-K) is one of the proposed risk factors for amyotrophic lateral sclerosis (ALS). The HERV-K envelope protein has been reported to show neurotoxicity, and development of therapy with reverse transcriptase inhibitors is being investigated. On the other hand, some reports have failed to show HERV-K activation in ALS. In this study, we analyzed the expression of HERV-K mRNA in the motor cortex and spinal cord of 15 Japanese patients with sporadic ALS and 19 controls using reverse transcriptase droplet digital PCR. This revealed no significant increase of HERV-K expression in ALS-affected tissues, suggesting that the association between ALS and HERV-K remains questionable.

DOI： 10.1016/j.neures.2022.01.009

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BACKGROUND: Adrenoleukodystrophy (ALD) is an X-linked recessive disorder and 30-40% of patients develop progressive cerebral neurodegeneration. For symptomatic ALD patients, allogeneic stem cell transplantation (SCT) is considered the standard treatment modality to stabilize or prevent the progression of neurological symptoms. METHODS: We retrospectively analyzed the transplant outcomes of 99 pediatric patients with cerebral ALD in Japan. The conditioning regimens included Regimen A: fludarabine/melphalan/low-dose total body irradiation (TBI) with brain sparing (n = 39), Regimen B; busulfan/cyclophosphamide ± others (n = 23), Regimen C: melphalan/total lymphoid irradiation/thoracoabdominal irradiation ± anti-T lymphocyte globulin ± fludarabine (n = 27), and Regimen D: others (n = 10). RESULTS: The 5-year overall survival (OS) and event-free survival (EFS) of all patients were 90.0% and 72.9%, respectively. The 5-year OS was 100.0% for Regimen A, 91.1% for Regimen B, 84.4% for Regimen C, and 67.5% for Regimen D (p = 0.028). The 5-year EFS was 78.3% for Regimen A, 78.0% for Regimen B, 70.4% for Regimen C, and 48.0% for Regimen D (p = 0.304). The OS marginally improved after 2007 compared with before 2006 (95.3% vs. 85.2%, p = 0.066), due to the improvement of cord blood transplantation (CBT) outcomes after 2007 compared with before 2006 (96.6% vs. 68.4%, p = 0.005). On magnetic resonance imaging of the brain, a reduced Loes score after SCT was only observed in one of the 15 bone marrow transplantation (BMT) patients, but in 5 of the 15 CBT patients (p = 0.173). CONCLUSIONS: Our study revealed that a reduced conditioning regimen with fludarabine/melphalan/low-dose TBI provides better outcomes, and the results of CBT significantly improved after 2007.

DOI： 10.1111/petr.14125

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Language：English   Publishing type：Research paper (scientific journal)  

TDP-43 is a causative factor of amyotrophic lateral sclerosis (ALS). Cytoplasmic TDP-43 aggregates in neurons are a hallmark pathology of ALS. Under various stress conditions, TDP-43 localizes sequentially to two cytoplasmic protein aggregates: stress granules (SGs) first, and then aggresomes. Accumulating evidence suggests that delayed clearance of TDP-43-positive SGs is associated with pathological TDP-43 aggregates in ALS. We found that USP10 promotes the clearance of TDP-43-positive SGs in cells treated with proteasome inhibitor, thereby promoting the formation of TDP-43-positive aggresomes, and the depletion of USP10 increases the amount of insoluble TDP-35, a cleaved product of TDP-43, in the cytoplasm. TDP-35 interacted with USP10 in an RNA-binding dependent manner; however, impaired RNA-binding of TDP-35 reduced the localization in SGs and aggresomes and induced USP10-negative TDP-35 aggregates. Immunohistochemistry showed that most of the cytoplasmic TDP-43/TDP-35-aggregates in the neurons of ALS patients were USP10-negative. Our findings suggest that USP10 inhibits aberrant aggregation of TDP-43/TDP-35 in the cytoplasm of neuronal cells by promoting the clearance of TDP-43/TDP-35-positive SGs and facilitating the formation of TDP-43/TDP-35-positive aggresomes.

DOI： 10.1128/MCB.00393-21

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

INTRODUCTION: Polypharmacy is associated with an increased risk of fracture in aging populations, but no study has accounted for the impact of kidney function on this association. This study aimed to examine the association between polypharmacy and incident fragility fracture based on chronic kidney disease (CKD) status. MATERIALS AND METHODS: Participants were 2023 patients (55% men; mean age, 69 years) of Sado General Hospital enrolled in the Project in Sado for Total Health (PROST) between June 2008 and December 2016. Among these, 65%, 28%, and 7% had non-CKD, non-dialysis-dependent CKD, and dialysis-dependent CKD, respectively. Multivariable Cox proportional hazards analysis was conducted with adjustments for potential confounders. RESULTS: Prevalences of polypharmacy (≥ 5 medications) and hyperpolypharmacy (≥ 10 medications) among participants were 43% and 9% for non-CKD, 62% and 23% for non-dialysis-dependent CKD, and 85% and 34% for dialysis-dependent CKD, respectively. During a median follow-up of 5.6 years, 256 fractures occurred. More medications were associated with a higher risk of fractures. Specifically, compared to participants without polypharmacy, adjusted hazard ratios were 1.32 (95% CI 0.96-1.79) and 1.99 (1.35-2.92) for those with polypharmacy and hyperpolypharmacy, respectively, after adjusting for osteoporosis risk factors, CKD status, and comorbidities. No effect modification by CKD status was observed (interaction P = 0.51). Population-attributable fractions of hyperpolypharmacy for fracture were 9.9% in the total cohort and 42.1% in dialysis-dependent CKD patients. CONCLUSION: Hyperpolypharmacy is associated with an increased risk of fragility fracture regardless of CKD status, and has a strong impact on incident fragility fractures in dialysis-dependent CKD patients.

DOI： 10.1007/s00774-021-01272-9

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Objectives: Patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) show various clinical symptoms, including migraine, recurrent stroke, and cognitive impairment. We investigated the associations between magnetic resonance imaging (MRI) markers of small vessel disease and neuropsychological tests and identified the MRI characteristics for predicting cognitive impairment in patients with CADASIL. Methods: Subjects included 60 CADASIL patients diagnosed with genetic tests and registered in the Japanese CADASIL REDCap database between June 2016 and December 2020. Patient information including clinical data, modified Rankin Scale (mRS); MRI findings of small vessel disease including periventricular and deep white matter lesions (WML), lacunar infarcts, and cerebral microbleeds (CMBs); and neuropsychological tests, including the Japanese version of the Mini-Mental State Examination (MMSE), the Japanese version of the Montreal Cognitive Assessment (MoCA-J), and the Frontal Assessment Battery (FAB), were evaluated. Results: Data from 44 CADASIL patients were eligible for this study, compared between patients with and without dementia. Regarding the neuroimaging findings, the Fazekas score of periventricular and deep WML was higher in patients with dementia (periventricular, p = 0.003; deep, p = 0.009). The number of lacunar infarcts was higher in patients with dementia (p = 0.001). The standardized partial regression coefficient (SPRC) in MoCA-J was 0.826 (95% CI, 0.723-0.942; p = 0.005) for the number of CMBs. The SPRC in MMSE was 0.826 (95% CI, 0.719-0.949; p = 0.007) for the number of CMBs. The SPRC for FAB decreased significantly to 0.728 (95% CI, 0.551-0.960; p = 0.024) for the number of lacunar infarcts. Receiver operating characteristic (ROC) curves for dementia showed that in the number of lacunar infarcts, a cut-off score of 5.5 showed 90.9% sensitivity and 61.1% specificity. For the number of CMBs, a cut-off score of 18.5 showed 45.5% sensitivity and 100% specificity. Conclusion: The characteristic MRI findings were that CADASIL patients with dementia had severe WML, both periventricular and deep, and a larger number of lacunar infarcts than those without dementia. The risk of dementia may be associated with ≥ 6 lacunar infarcts, ≥19 CMBs, or a Fazekas scale score of 3 in periventricular and deep WML.

DOI： 10.3389/fnagi.2022.876437

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/mdc3.13382

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Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The cardinal neuropathological features of PD include selective and progressive loss of pigmented neurons in the substantia nigra, deficiencies in dopaminergic signaling in the striatum, and occurrence of phosphorylated α-synuclein-identified Lewy bodies in the nervous system. Parkinsonism, the clinical presentation of movement disorders seen in PD, is a feature shared commonly by other pathologically distinct neurodegenerative diseases, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA). Consequently, it is sometimes difficult to distinguish PD from such parkinsonism-related neurological disorders. In addition, parkinsonism is not always a feature of certain neurodegenerative diseases, and it can sometimes develop as a result of various forms of drug intoxication or cerebrovascular disease. Here, we describe the clinicopathological features of three patients (cases 1, 2, and 3) diagnosed as having PSP, MSA, and PD, respectively, in each of whom the postmortem histopathological diagnosis differed from the final clinical diagnosis. Neuropathologically, they had suffered from coexistent disorders: PD, MSA, and argyrophilic grain disease (case 1); PD (case 2); and vascular parkinsonism (case 3). The variety of patients showing features of parkinsonism underlines the importance of careful long-term follow up followed by postmortem neuropathological evaluation.

DOI： 10.1111/neup.12777

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Language：Japanese   Publishing type：Research paper (scientific journal)  

The Japanese Society of Neurology discusses research, education, and medical care in the field of neurology and makes recommendations to the national government. Dr. Mizusawa, the former representative director of the Japanese Society of Neurology, selected committee members and made "Recommendations for Promotion of Research for Overcoming Neurological Diseases" in 2013. After that, the Future Vision Committee was established in 2014, and these recommendations have been revised once every few years by the committee. This time, the Future Vision Committee made the latest recommendations from 2020 to 2021. In this document, the general part is 1) What is neurological disease? 2) Current status of neurological disease overcoming research, 3) Significance and necessity of neurological disease overcoming research, 4) Research promotion system for overcoming neurological disease, 5) the roadmap for overcoming neuromuscular diseases, 6) a summary version of these recommendations are explained using figures that are easy for the general public to understand.

DOI： 10.5692/clinicalneurol.cn-001639

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Language：Japanese   Publisher：(一社)日本脳循環代謝学会  

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Language：English   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本神経治療学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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DOI： 10.1007/s10286-021-00826-1

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Language：Japanese   Publisher：(一社)日本神経学会  

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DOI： 10.1136/jnnp-2021-326257

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Lipohyalinosis is an important concept in the independence of lacunar stroke; however, its role has been overemphasized and has led to much confusion in the understanding of lacunar stroke. Classical lipohyalinosis has declined following the widespread availability of antihypertensive therapy, and lacunar stroke secondary to age-related hyaline atherosclerosis is more commonly observed in clinical practice. Clinically diagnosed lacunar stroke is associated with several etiopathogenetic contributors. Excluding cardiogenic embolism, lacunar stroke can be categorized based on the detection of an atheroma. Atheroma imaging is possible in recent years, and strokes that are not associated with an atheroma are shown to present with deep white matter hyperintensity on MRI. Additionally, risk gene analysis has confirmed a group of risk genes associated with the extracellular matrix in lacunar stroke with white matter hyperintensity on MRI. These findings suggest the role of a variety of etiopathogenetic mechanisms underlying lacunar stroke and that lacunar stroke with deep white matter hyperintensity on MRI may be attributable to unique pathogenetic contributors. This group is known to be strongly associated with genetic contributors. Hopefully, lacunar stroke will be diagnosed from this perspective with the development of interventional strategies tailored to the pathogenesis of this condition.

DOI： 10.11477/mf.1416201876

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PURPOSE: To assess the effect of maintenance therapy on visual outcomes in preventing recurrences one year after first onset in patients with aquaporin-4 antibody (AQP4Ab)-positive optic neuritis. STUDY DESIGN: Retrospective study. METHODS: The medical charts of 56 patients with optic neuritis (22 with AQP4Ab-positive and 34 with AQP4Ab-negative) at Niigata University Medical and Dental Hospital were retrospectively analyzed. Clinical characteristics, including visual acuity and number of recurrences one year after first onset, were compared among patients who were AQP4Ab-positivie with and those without maintenance therapy such as oral prednisolone and azathioprine, as well as those who were AQP4Ab-negative. RESULTS: The mean ages were 49.3 and 45.2 years in the AQP4Ab-positive and the AQP4Ab-negative groups. The female to male ratio was 21:1 and 18:16 in the two groups, respectively. Multiple between-group comparison showed a statistically significant difference in visual acuity one year after first onset between the AQP4Ab-positive without maintenance therapy group and the AQP4Ab-negative group (0.05 (median, same applies below) vs. 1.0, p < 0.01). There was also a statistically significant difference in the number of recurrences in the year after first onset between the AQP4Ab-positive with and without maintenance therapy groups (1 vs. 0, p < 0.01). CONCLUSION: This study demonstrates that patients with AQP4Ab-positive optic neuritis without maintenance therapy had the poorest visual acuity and the most recurrences one year after first onset. These results indicate that reducing the number of recurrences with maintenance therapy could improve the visual outcomes in patients with AQP4Ab-positive optic neuritis.

DOI： 10.1007/s10384-021-00858-0

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 50-year-old man with mitral regurgitation presented with right frontal subcortical hemorrhage. Although he had no fever and his white blood cell count was in the normal range, CT angiography demonstrated a micro cerebral aneurysm, and all three blood cultures were positive for Staphylococcus warneri (S. warneri). Thus, we diagnosed him with infective endocarditis. His condition improved successfully by immediate antibiotics and cerebral aneurysm clipping. S. warneri is a member of coagulase-negative staphylococci that are low-virulence and resident flora of the skin. S. warneri rarely causes infective endocarditis on native valves. Infective endocarditis caused by S. warneri manifests insidious course without inflammatory reactions such as fever and leukocytosis, and thus, diagnosis can be delayed. Attention should be paid to a patient who develops subcortical hemorrhage without a history of hypertension or inflammatory reactions as in this case.

DOI： 10.5692/clinicalneurol.cn-001613

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OBJECTIVES: Microtubule inhibitors (MTIs) are widely used as anti-cancer drugs for various types of tumors. Vinorelbine, an MTI, is utilized in postoperative adjuvant chemotherapy, especially for lung adenocarcinoma. However, no molecular markers are able to identify patients for whom MTIs would be effective. In this study, we attempted to identify practical markers to predict the efficacy of MTI-based adjuvant chemotherapy. MATERIALS AND METHODS: We explored a novel combination of molecular marker candidates, based on gene expression network analysis constructed using an omics panel of 26 lung adenocarcinoma cell lines. We then applied the obtained classification method to predict the efficacy of MTI treatment in patients who received adjuvant chemotherapy. RNA sequencing (RNA-seq) analysis was conducted using surgical specimens from 24 Japanese lung adenocarcinoma patients treated postoperatively with vinorelbine. RESULTS: We identified four modules within the network with module activities that were significantly associated with sensitivity to MTIs. Two modules were associated with high sensitivity to MTIs: genes with low differentiation or transdifferentiation of lung adenocarcinomas. On the other hand, MTI-low sensitivity modules were enriched in common epithelial genes and markers of well-differentiated lung adenocarcinomas. We also classified lung adenocarcinoma cases using the module activities associated with MTI efficacy and stratify the cases with MTI resistance. CONCLUSION: We demonstrate that the constructed classification method is useful for identifying patients with MTI resistance which results in a high risk of cancer relapse.

DOI： 10.1016/j.lungcan.2021.06.011

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Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) is a neurodegenerative disorder caused by mutation in the aprataxin (APTX)-coding gene APTX, which is involved in DNA single-strand break repair (SSBR). The neurological abnormalities associated with EAOH are similar to those observed in patients with ataxia-telangiectasia. However, the immunological abnormalities in patients with EAOH have not been described. In this study, we report that EAOH patients have immunological abnormalities, including lymphopenia; decreased levels of CD4+ T-cells, CD8+ T-cells, and B-cells; hypogammaglobulinemia; low T-cell recombination excision circles and kappa-deleting element recombination circles; and oligoclonality of T-cell receptor β-chain variable repertoire. These immunological abnormalities vary among the EAOH patients. Additionally, mild radiosensitivity in the lymphocytes obtained from the patients with EAOH was demonstrated. These findings suggested that the immunological abnormalities and mild radiosensitivity evident in patients with EAOH could be probably caused by the DNA repair defects.

DOI： 10.1016/j.clim.2021.108776

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

DOI： 10.1093/gastro/goaa061

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Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease characterized by the formation of cytoplasmic ubiquitinated TDP-43 protein aggregates in motor neurons. Stress granules (SGs) are stress-induced cytoplasmic protein aggregates containing various neuropathogenic proteins, including TDP-43. Several studies have suggested that SGs are the initial site of the formation of pathogenic ubiquitinated TDP-43 aggregates in ALS neurons. Mutations in the optineurin (OPTN) and TIA1 genes are causative factors of familial ALS with TDP-43 aggregation pathology. We found that both OPTN depletion and ALS-associated OPTN mutations upregulated the TIA1 level in cells recovered from heat shock, and this upregulated TIA1 increased the amount of ubiquitinated TDP-43. Ubiquitinated TDP-43 induced by OPTN depletion was localized in SGs. Our study suggests that ALS-associated loss-of-function mutants of OPTN increase the amount of ubiquitinated TDP-43 in neurons by increasing the expression of TIA1, thereby promoting the aggregation of ubiquitinated TDP-43.

DOI： 10.1016/j.isci.2021.102733

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DOI： 10.1186/s40478-021-01217-3

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DOI： 10.1186/s40478-021-01202-w

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The utility of acylals as building blocks for selective cross-benzoin synthesis was explored in this study. The synthesis of α-acetoxyketones (O-acyl cross-benzoins) was achieved via selective N-heterocyclic carbene-catalyzed cross-benzoin reactions using acylals as aldehyde equivalents. Thus, the combination of ortho-substituted phenyl acylals and aromatic/aliphatic aldehydes as coupling substrates using bicyclic triazolium salts as precatalysts and potassium carbonate as a base in THF at reflux temperature selectively yielded O-acyl cross-benzoins.

DOI： 10.1021/acs.orglett.1c01134

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Mitochondrial dysfunction and lysosomal dysfunction have been implicated in Parkinson's disease (PD), but the links between these dysfunctions in PD pathogenesis are still largely unknown. Here we report that cytosolic dsDNA of mitochondrial origin escaping from lysosomal degradation was shown to induce cytotoxicity in cultured cells and PD phenotypes in vivo. The depletion of PINK1, GBA and/or ATP13A2 causes increases in cytosolic dsDNA of mitochondrial origin and induces type I interferon (IFN) responses and cell death in cultured cell lines. These phenotypes are rescued by the overexpression of DNase II, a lysosomal DNase that degrades discarded mitochondrial DNA, or the depletion of IFI16, which acts as a sensor for cytosolic dsDNA of mitochondrial origin. Reducing the abundance of cytosolic dsDNA by overexpressing human DNase II ameliorates movement disorders and dopaminergic cell loss in gba mutant PD model zebrafish. Furthermore, IFI16 and cytosolic dsDNA puncta of mitochondrial origin accumulate in the brain of patients with PD. These results support a common causative role for the cytosolic leakage of mitochondrial DNA in PD pathogenesis.

DOI： 10.1038/s41467-021-23452-x

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The natural abundance of stable isotopes is a powerful tool for evaluating biological reactions and process conditions. However, there are few stable isotope studies on the wastewater treatment process. This study carried out the first investigation on variations in natural abundance of carbon and nitrogen stable isotope ratios (δ13C and δ15N) of activated sludge in four types of advanced treatment process (extended aeration activated sludge (EAAS), aerobic-anoxic-aerobic (A2O), recycled nitrification-denitrification (RND), and modified Bardenpho (MB)) at a municipal wastewater treatment plant. The δ13C and δ15N values of influent suspended solids settled in the primary sedimentation tank (i.e., primary sludge) ranged from -25.4‰ to -24.6‰ and 0.5‰-2.9‰, respectively, during monitoring periods. The δ13C values of the activated sludge were -24.6‰ to -23.6‰ (EAAS), -25.4‰ to -24.3‰ (A2O), -25.7‰ to -24.9‰ (RND), and -25.7‰ to -24.3‰ (MB). The δ13C values of the activated sludge were similar to those of influent suspended solids. However, the δ13C values of activated sludge in EAAS was significantly higher than in A2O, RND, and MB. Meanwhile, the δ15N values of activated sludge were obviously higher than influent suspended solids; 5.8‰-7.5‰ (EAAS), 6.6‰-8.1‰ (A2O), 5.5‰-7.5‰ (RND), and 5.3‰-7.6‰ (MB). Changes in δ13C and δ15N values of the activated sludge within the treatment system were also found. These findings indicate that changes in δ13C and δ15N values of the activated sludge rely on important function for biological wastewater treatment such as nitrification, denitrification, and methane oxidation through wastewater treatment over time.

DOI： 10.1016/j.jenvman.2021.112264

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Stable isotope ratios of nitrate are a powerful tool to evaluate aquatic environment stress from treated and untreated sewage. However, there is generally a lack of knowledge on the change in stable isotope ratios within wastewater treatment plants. We investigated nitrogen and oxygen stable isotope ratios (δ15N and δ18O) of nitrate in four types of advanced treatment processes operated in parallel; (A) extended aeration activated sludge, (B) anaerobic-anoxic-aerobic (A2O), (C) recycled nitrification-denitrification, and (D) modified Bardenpho. The results exhibited spatial variation of δ15N and δ18O for nitrate within the treatment steps. The changes in δ15N and δ18O may result from the reactor conditions (aerobic, anoxic, and anaerobic) and the order of these processes. As decreasing nitrate concentration in the anoxic stages, the δ15N/δ18O ratio for nitrate increased at a rate of 1.3 to 1.6 coupling with the reduction in the nitrate concentration in the anoxic stages. The δ15N and δ18O signatures were attributed to process performance in regard to nitrogen removal. In particular, the modified Bardenpho process has higher nitrogen removal efficiency over other processes, producing effluent with lower nitrate concentration and higher stable isotopes (δ15N: 23.6 to 25.5‰, δ18O: 2.8 to 4.5‰). We concluded that the stable isotope signatures mirrored the treatment efficiency and effluent characteristics.

DOI： 10.1016/j.scitotenv.2020.144120

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A 64-year-old Japanese man with recurrent cerebral ischemic events and cognitive impairment was suspected of having cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) because of a family history and brain magnetic resonance imaging findings of cerebral white matter hyperintensities. The cysteine-sparing variation p.Val237Met was identified in NOTCH3. An intensive skin biopsy showed negative results (no granular osmiophilic material or positive NOTCH3 immunostaining), suggesting that the patient's definite diagnosis and pathogenicity of p.Val237Met were uncertain. We additionally reviewed previous reports of two Japanese families with p.Val237Met.

DOI： 10.2169/internalmedicine.6096-20

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DOI： 10.1016/j.clineuro.2021.106496

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Language：Japanese   Publisher：(公社)日本整形外科学会  

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BACKGROUND: Mutations in PRKN are the most common cause of autosomal recessive juvenile parkinsonism. The objective of this study was to investigate the association between genotype and pathology in patients with PRKN mutations. METHODS: We performed a sequence and copy number variation analysis of PRKN, mRNA transcripts, Parkin protein expression, and neuropathology in 8 autopsied patients. RESULTS: All the patients harbored biallelic PRKN mutations. Two patients were homozygous and heterozygous, respectively, for the missense mutation p.C431F. Seven patients had exon rearrangements, including 2 patients from a single family who harbored a homozygous deletion of exon 4, and 3 patients who carried a homozygous duplication of exons 6-7, a homozygous duplication of exons 10-11, and a heterozygous duplication of exons 2-4. In the other 2 patients, we found a compound heterozygous duplication of exon 2, deletion of exon 3, and a heterozygous duplication of exon 2. However, sequencing of cDNA prepared from mRNA revealed 2 different transcripts derived from triplication of exon 2 and deletion of exons 2-3 and from duplication of exons 2-4 and deletion of exons 3-4. Western blotting and immunohistochemistry revealed faint or no expression of Parkin in their brains. In the substantia nigra pars compacta, a subfield-specific pattern of neuronal loss and mild gliosis were evident. Lewy bodies were found in 3 patients. Peripheral sensory neuronopathy was a feature. CONCLUSIONS: Genomic and mRNA analysis is needed to identify the PRKN mutations. Variable mutations may result in no or little production of mature Parkin and the histopathologic features may be similar.

DOI： 10.1002/mds.28521

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[This corrects the article DOI: 10.3389/fneur.2019.00693.].

DOI： 10.3389/fneur.2021.756038

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BACKGROUND: Reperfusion therapies by tissue plasminogen activator (tPA) and mechanical thrombectomy (MT) have ushered in a new era in the treatment of acute ischemic stroke (AIS). However, reperfusion therapy-related HT remains an enigma. AIM: To provide a comprehensive review focused on emerging concepts of stroke and therapeutic strategies, including the use of protective agents to prevent HT after reperfusion therapies for AIS. METHODS: A literature review was performed using PubMed and the ClinicalTrials.gov database. RESULTS: Risk of HT increases with delayed initiation of tPA treatment, higher baseline glucose level, age, stroke severity, episode of transient ischemic attack within 7 days of stroke onset, and hypertension. At a molecular level, HT that develops after thrombolysis is thought to be caused by reactive oxygen species, inflammation, remodeling factor-mediated effects, and tPA toxicity. Modulation of these pathophysiological mechanisms could be a therapeutic strategy to prevent HT after tPA treatment. Clinical mechanisms underlying HT after MT are thought to involve smoking, a low Alberta Stroke Program Early CT Score, use of general anesthesia, unfavorable collaterals, and thromboembolic migration. However, the molecular mechanisms are yet to be fully investigated. Clinical trials with MT and protective agents have also been planned and good outcomes are expected. CONCLUSION: To fully utilize the easily accessible drug-tPA-and the high recanalization rate of MT, it is important to reduce bleeding complications after recanalization. A future study direction could be to investigate the recovery of neurological function by combining reperfusion therapies with cell therapies and/or use of pleiotropic protective agents.

DOI： 10.1016/j.jns.2020.117217

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Progressive supranuclear palsy (PSP) presents with a wide variety of signs/symptoms, making early initial diagnosis difficult. We investigated the clinical and neuropathological features of five patients with autopsy-proven PSP of short duration, ranging from 11 to 41 months (average, 26.2 months) due to unexpected death, focusing particularly on the distribution and severity of neuronal loss as well as neuronal and glial tau pathology in the affected brain. Clinical features were studied retrospectively through careful review of the medical records, and neuropathological examinations were carried out, along with tau immunohistochemistry using a monoclonal antibody AT8. These patients were diagnosed as having probable PSP (n = 4) and suggestive PSP (n = 1), respectively. In all cases, neuronal loss was evident in the substantia nigra, subthalamic nucleus, globus pallidus, and locus ceruleus. AT8-identified tau lesions, that is, pretangles/neurofibrillary tangles (PTs/NFTs), tufted astrocytes (TAs), and coiled bodies/neuropil threads (CBs/NTs), were distributed widely in the brain regions, especially in patients with longer disease duration. All cases showed variation in the regional tau burden among PTs/NFTs, TAs, and CBs/NTs. There was also a tendency for tau deposition to be more predominant in neuronal cells in the brainstem and cerebellum and in glial cells in the cerebral cortex and subcortical gray matter. These findings suggest that in PSP, the initial signs/symptoms are associated with degeneration and subsequent death of neurons with pathological tau deposition, and that the tau deposition in neuronal cells is independent of that in glial cells.

DOI： 10.1111/neup.12707

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Background: Previous studies have reported associations between nonalcoholic fatty liver disease, periodontitis, and obesity. Serum immunoglobulin G (IgG) antibody titer against Porphyromonas gingivalis, a major pathogen of periodontitis, is an established indicator of periodontal infection. However, the relationship between the antibody titer and liver enzyme levels has not been clarified yet. A study in the elderly was needed to evaluate the effect of long-term persistent bacterial infection on liver function. The objective of this study was to investigate the association between liver function and infection by P. gingivalis, and the effect of obesity on the association. Methods: A cross-sectional study was conducted in adult outpatients visiting Sado General Hospital, in Niigata Prefecture, Japan, from 2008 to 2010. The final participants included 192 men and 196 women (mean age 68.1 years). Multivariable logistic regression analyses were performed to assess the association between the serum IgG antibody titer and the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamine transferase (GGT) levels. Results: In women, serum IgG antibody titers against P. gingivalis was associated with elevated ALT, but not with AST or GGT, independent of covariates (p = 0.015). No significant association was found between the antibody titer and the elevated liver enzymes in men. The effect of obesity on the relationship between antibody titer and liver enzyme levels was not statistically significant. Conclusions: A cross-sectional analysis of adult outpatients suggested an association between P. gingivalis infection and ALT levels in women. The effect of obesity on this association was not statistically significant.

DOI： 10.1016/j.heliyon.2020.e05531

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：English   Publisher：(一社)日本神経学会  

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Language：English   Publisher：(一社)日本神経学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Many studies in recent years have reported cell therapies using embryonic stem cells, induced pluripotent stem cells, and bone marrow-derived mononuclear cells for cerebral ischemia. However, obtaining these cells is challenging, and these cell therapies require complicated procedures to prepare cells for administration. Notably, peripheral blood mononuclear cells (PBMCs) are a useful cell source for clinical applications because cell collection is easier. In this review, we report the therapeutic effects of PBMCs preconditioned by oxygen-glucose deprivation (OGD-PBMCs) on cerebral ischemia. Cell therapies using tissue-protective OGD-PBMCs might be a simple and ideal therapeutic strategy against ischemic stroke.

DOI： 10.11477/mf.1416201655

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10-8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10-4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10-11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.

DOI： 10.1038/s42003-020-01251-2

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Language：Japanese   Publisher：(公社)日本精神神経学会  

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Stroke remains a major cause of serious disability because the brain has a limited capacity to regenerate. In the last two decades, therapies for stroke have dramatically changed. However, half of the patients cannot achieve functional independence after treatment. Presently, cell-based therapies are being investigated to improve functional outcomes. This review aims to describe conventional cell therapies under clinical trial and outline the novel concept of polarized cell therapies based on protective cell phenotypes, which are currently in pre-clinical studies, to facilitate functional recovery after post-reperfusion treatment in patients with ischemic stroke. In particular, non-neuronal stem cells, such as bone marrow-derived mesenchymal stem/stromal cells and mononuclear cells, confer no risk of tumorigenesis and are safe because they do not induce rejection and allergy; they also pose no ethical issues. Therefore, recent studies have focused on them as a cell source for cell therapies. Some clinical trials have shown beneficial therapeutic effects of bone marrow-derived cells in this regard, whereas others have shown no such effects. Therefore, more clinical trials must be performed to reach a conclusion. Polarized microglia or peripheral blood mononuclear cells might provide promising therapeutic strategies after stroke because they have pleiotropic effects. In traumatic injuries and neurodegenerative diseases, astrocytes, neutrophils, and T cells were polarized to the protective phenotype in pre-clinical studies. As such, they might be useful therapeutic targets. Polarized cell therapies are gaining attention in the treatment of stroke and neurological diseases.

DOI： 10.3390/ijms21176194

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DOI： 10.1186/s40478-020-01008-2

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Language：Japanese   Publishing type：Research paper (scientific journal)  

We report the case of a 76-year-old woman who presented with recurrent episodes of complex visual hallucinations in her right visual field without an anopsia. The electroencephalogram showed sharp transients in the left parietotemporal region with phase reversals at T5 and P3. FLAIR MRI revealed hyperintense lesions in the left temporo-occipital lobe, located mainly in the left inferior temporal lobe. Cerebral angiography revealed an arteriovenous shunt from the left occipital artery to the left transverse sinus with cortical venous reflux. The complex visual hallucinations were resolved after transarterial embolization. We therefore hypothesize that this patient's complex visual hallucinations were caused by epileptic seizures or changes in cortical blood flow caused by the cortical venous reflux from the arteriovenous fistula. In general, epileptic hallucinations expand into the bilateral visual field. We reveal that in rare cases, complex visual hallucinations can also be limited to the unilateral visual field without an anopsia. Additionally, we reveal that a dural arteriovenous fistula can cause visual hallucinations without hemianopia.

DOI： 10.5692/clinicalneurol.60.cn-001371

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DOI： 10.1186/s40478-020-00945-2

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Myositis generally affects the proximal muscles. However, we herein report a case of a 48-year-old woman with intractable myositis affecting the intrinsic muscles of the hands. Her myositis, which developed in childhood, was refractory to treatment with steroids and several immunosuppressants, causing walking disability. After experiencing pain and swelling in the hands for six months, she was diagnosed with myositis of the intrinsic muscles of the hands and tested positive for the anti-signal recognition particle antibody. Intravenous immunoglobulin therapy improved the myositis of the hands. This case suggests that inflammation caused by intractable myositis can extend to the hands.

DOI： 10.2169/internalmedicine.3773-19

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In amyloid β-related angiitis, cortical or subcortical microbleeding or cortical superficial siderosis supports clinical diagnosis. However, here we present a 75-year-old female case of amyloid β-related angiitis that did not initially show these lesions. The patient developed right homonymous hemianopia and aphasia, and subsequently became comatose. Her brain lesions progressed extensively from the left occipital lobe to the bilateral cerebral hemispheres, with diffused leptomeningeal lesions and scattered DWI high-intensity lesions. After pathological diagnosis, steroid treatment improved her symptoms as well as imaging findings. No hemorrhagic lesions were detected in the T2*-weighted imaging performed before treatment. However, susceptibility-weighted imaging performed after treatment showed a number of lesions with microbleeding. The clinical features of amyloid β-related angiitis that do not show hemorrhagic lesions at onset should be investigated for rapid therapeutic intervention in the future.

DOI： 10.5692/clinicalneurol.cn-001340

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Language：Japanese   Publisher：(公社)日本薬学会  

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Sporadic amyotrophic lateral sclerosis (SALS) and many cases of familial ALS (FALS) demonstrate cytoplasmic transactive response DNA-binding protein 43 kDa (TDP-43)-positive inclusion bodies. Thus, TDP-43 plays a vital role in ALS pathogenesis. Functional analysis of the ALS causative genes advanced the elucidation of the mechanism associated with the formation and degradation of TDP-43 aggregates. Stress granules, which are non-membranous organelles, are attracting attention as sites of aggregate formation, with involvement of FUS and C9orf72. Concurrently, ALS causative genes related to the ubiquitin-proteasome and autophagy systems, which are aggregate degradation mechanisms, have also been reported. Therefore, therapeutic research based on the molecular pathology common to SALS and FALS has been advanced.

DOI： 10.5692/clinicalneurol.cn-001362

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DOI： 10.1212/NXG.0000000000000383

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Language：Japanese   Publisher：(一社)日本神経学会  

孤発性筋萎縮性側索硬化症(sporadic amyotrophic lateral sclerosis;SALS)、および多くの家族性ALS(familial ALS;FALS)において、神経細胞質内transactive response DNA-binding protein 43kDa(TDP-43)陽性の封入体を認める。この事実からTDP-43は本症の根幹に関わる分子である。ALS病因遺伝子の機能解析から、TDP-43の病的凝集体形成/分解に関わる発症メカニズムの解明が進められている。凝集体形成の場として、非膜性構造であるストレス顆粒が注目されており、FUSやC9orf72の関与が示されている。一方、凝集体分解機構であるユビキチン-プロテアソーム系、オートファジー系に関わるALS病因遺伝子も報告されている。SALSおよびFALSに共通する分子病態に対する治療研究が進められている。(著者抄録)

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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DOI： 10.1016/j.jns.2019.116577

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Progressive supranuclear palsy (PSP) is characterized by supranuclear gaze palsy, dystonic rigidity of the neck and upper trunk, frequent falls and mild cognitive impairment. Cerebellar ataxia is one of the exclusion criteria given by the National Institute of Neurological Disorders and Stroke and the Society for Progressive Supranuclear Palsy. As a result, pathologically proven PSP patients exhibiting cerebellar ataxia have often been misdiagnosed with spinocerebellar degeneration, specifically multiple system atrophy with predominant cerebellar ataxia (MSA-C). However, more recently, it has been recognized that patients with PSP can present with truncal and limb ataxia as their initial symptom and/or main manifestation. These patients can be classified as having PSP with predominant cerebellar ataxia (PSP-C), a new subtype of PSP. Since the development of this classification, patients with PSP-C have been identified primarily in Asian countries, and it has been noted that this condition is very rare in Western communities. Furthermore, the clinical features of PSP-C have been identified, enabling it to be distinguished from other subtypes of PSP and MSA-C. In this review, we describe the clinical and neuropathological features of PSP-C. The hypothesized pathophysiology of cerebellar ataxia in PSP-C is also discussed.

DOI： 10.14802/jmd.19061

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It is increasingly becoming apparent that cerebrovascular dysfunction contributes to the pathogenic processes involved in vascular dementia, Alzheimer's disease, and other neurodegenerative disorders. Under these pathologic conditions, the degeneration of cerebral blood vessels is frequently accompanied by a loss of mural cells from the vascular walls. Vascular mural cells play pivotal roles in cerebrovascular functions, such as regulation of cerebral blood flow and maintenance of the blood-brain barrier (BBB). Therefore, cerebrovascular mural cell impairment is involved in the pathophysiology of vascular-related encephalopathies, and protecting these cells is essential for maintaining brain health. However, our understanding of the molecular mechanism underlying mural cell abnormalities is incomplete. Several reports have indicated that dysregulated transforming growth factor β (TGFβ) signaling is involved in the development of cerebral arteriopathies. These studies have specifically suggested the involvement of TGFβ overproduction. Although cerebrovascular toxicity via vascular fibrosis by extracellular matrix accumulation or amyloid deposition is known to occur with enhanced TGFβ production, whether increased TGFβ results in the degeneration of vascular mural cells in vivo remains unknown. Here, we demonstrated that chronic TGFβ1 overproduction causes a dropout of mural cells and reduces their coverage on cerebral vessels in both smooth muscle cells and pericytes. Mural cell degeneration was also accompanied by vascular luminal dilation. TGFβ1 overproduction in astrocytes significantly increased TGFβ1 content in the cerebrospinal fluid (CSF) and increased TGFβ signaling-regulated gene expression in both pial arteries and brain capillaries. These results indicate that TGFβ is an important effector that mediates mural cell abnormalities under pathological conditions related to cerebral arteriopathies.

DOI： 10.3389/fnagi.2020.00151

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Objectives: Clinical characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) include migraine, recurrent stroke, white matter lesions, and vascular dementia. CADASIL is one of the most common hereditary cerebral small vessel diseases. Clinical presentation of CADASIL varies and a racial gap may exist between the Asian and Caucasian populations. This is the first nationwide epidemiological survey which aimed to elucidate the clinical features of CADASIL in Japan. Moreover, the registration database of CADASIL was constructed. Methods: Subjects included CADASIL patients who visited the hospitals (totally 1,448 hospitals) certified by the Japanese Society of Neurology and/or Japan Stroke Society in 2016. This study consisted of a two-step survey; patients with CADASIL were identified genetically by the first questionnaire, and their clinical features were assessed by the second questionnaire. Selected 6 hospitals registered the data of all CADASIL patients using a Research Electronic Data Capture (REDCap) system for the second questionnaire. Results: Based on the criteria, 88 patients (50 male and 38 female) with CADASIL were enrolled. The mean age of symptom onset was 49.5 years. Sixteen (18.2%) patients had an elderly onset (>60 years). Thirteen patients (13.6%) had history of migraine with aura and 33 patients (37.5%) had vascular risk factor(s). From among the 86 patients who were examined using magnetic resonance imaging, abnormal deep white matter lesions were detected in 85 patients (98.8%), WMLs extending to anterior temporal pole in 73 patients (84.9%), and cerebral microbleeds in 41 patients (47.7%). Anti-platelet therapy was received by 65 patients (73.9%). Thirty-eight patients (43.2%) underwent treatment with lomerizine hydrochloride. Thirty-four different mutations of NOTCH3 were found in exons 2, 3, 4, 5, 6, 8, 11, 14, and 19. Most of the mutations existed in exon 4 (n = 44, 60.3%). The prevalence rate of CADASIL was 1.20 to 3.58 per 100,000 adults in Japan. Conclusion: This questionnaire-based study revealed clinical features and treatment status in Japanese CADASIL patient, although it may not be an exhaustive search. We have constructed the REDCap database for these CADASIL patients.

DOI： 10.3389/fnagi.2020.00216

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An amendment to this paper has been published and can be accessed via a link at the top of the paper.

DOI： 10.1038/s41598-019-55308-2

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Language：English   Publisher：新潟医学会  

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Cell therapies that invoke pleiotropic mechanisms may facilitate functional recovery in patients with stroke. Based on previous experiments using microglia preconditioned by oxygen-glucose deprivation, we hypothesized that the administration of peripheral blood mononuclear cells (PBMCs) preconditioned by oxygen-glucose deprivation (OGD-PBMCs) to be a therapeutic strategy for ischemic stroke. Here, OGD-PBMCs were identified to secrete remodelling factors, including the vascular endothelial growth factor and transforming growth factor-β in vitro, while intra-arterial administration of OGD-PBMCs at 7 days after focal cerebral ischemia prompted expression of such factors in the brain parenchyma at 28 days following focal cerebral ischemia in vivo. Furthermore, administration of OGD-PBMCs induced an increasing number of stage-specific embryonic antigen-3-positive cells both in vitro and in vivo. Finally, it was found to prompt angiogenesis and axonal outgrowth, and functional recovery after cerebral ischemia. In conclusion, the administration of OGD-PBMCs might be a novel therapeutic strategy against ischemic stroke.

DOI： 10.1038/s41598-019-53418-5

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Language：Japanese   Publishing type：Research paper (scientific journal)  

The molecular pathogenesis of amyotrophic lateral sclerosis (ALS) has been studied through analysis of the function of the protein produced by the causative genes of familial ALS. The products of these genes are classified as RNA binding proteins, or proteins related to proteolytic systems. However, most case of familial ALS, and sporadic ALS show TAR DNA binding protein-43 (TDP-43) immune-positive cytoplasmic inclusions. Therefore, the molecular mechanism of formation of TDP-43 inclusions and dysfunction caused by TDP-43 inclusions has been studied. As for the mechanism of inclusion formation, non-membrane organelle formation by liquid-liquid phase separation (LLPS) is important. The ubiquitin-proteasome and autophagy systems are important for the degradation of these inclusions. Several genes associated with these systems have been identified as causative genes for ALS. The formation of cytoplasmic inclusions results in the loss of TDP-43 from the nucleus, resulting in abnormalities in RNA metabolism, through the alteration of spliceosomes and Gemini of coiled bodies. Furthermore, in ALS, the regulation of TDP-43 mRNA/protein expression levels has failed. Failure of the autoregulation system facilitates TDP-43 inclusion formation. Development of treatments for ALS based on these elucidated molecular mechanisms is desirable.

DOI： 10.11477/mf.1416201428

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This study aimed to determine whether enteric neurons are involved in multiple system atrophy (MSA). Four-μm-thick slices of small intestine were prepared from 10%-formalin-fixed and paraffin-embedded materials obtained from autopsied cases. Enteric neurons were stained using an anti-peripherin antibody. Immunostaining of phosphorylated α-synuclein was also performed. Areas of the cytoplasm and nucleus that showed nucleoli were measured using computer software. Both areas of myenteric neurons were significantly smaller in MSA cases (n = 3) than in control subjects (n = 3) (P < 0.0001); however, no deposits of phosphorylated α-synuclein were observed. These findings suggest that myenteric neurons in MSA are affected independent of α-synuclein accumulation.

DOI： 10.1016/j.autneu.2019.102583

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞TDP-43蛋白質の封入体形成機構は,筋萎縮性側索硬化症(ALS)の主要な分子病態機序である。ALS原因遺伝子の機能解析から,TDP-43封入体形成にはストレス顆粒形成,蛋白質分解機構,TDP-43蛋白質の自己調節機構の破綻などが関わることが見出された。これらの解明された分子病態に基づく,ALS治療方法の確立が期待される。

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Language：English   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：English   Publisher：(一社)日本神経学会  

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BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized pathologically by the occurrence of phosphorylated TDP-43 (pTDP-43)-immunoreactive neuronal and glial inclusions in the central nervous system. Recent studies have shown that pTDP-43 aggregates also occur in the skeletal muscles in a certain proportion of ALS patients. AIM: The aim of this study was to clarify the distribution and incidence of pTDP-43 aggregates in the skeletal and cardiac muscles of patients with ALS, and also those of patients with neuromuscular diseases (NMDs) and non-NMDs. MATERIAL AND METHODS: Five regions of muscle (tongue, cervical muscle, diaphragm, iliopsoas muscle and heart) were examined histologically and immunohistochemically in patients with ALS (n = 30), NMDs (n = 13) and non-NMDs (n = 7). RESULTS: Two types of pTDP-43 aggregates were distinguishable morphologically: dense filamentous and short linear inclusions. These inclusions were found in at least one of the five muscle regions in all 30 cases of ALS; skeletal muscles in 28 cases and myocardium in 12. pTDP-43 aggregates were also found in 9 of 13 patients with NMDs, including myositis, muscular dystrophy and mitochondrial myopathy, as well as in 3 of 7 patients with non-NMDs. In ALS, pTDP-43 aggregates were most frequent in the diaphragm (19 cases). The mean density of pTDP-43 aggregates in ALS was significantly higher than that in NMDs and non-NMDs. In contiguous sections stained with hematoxylin and eosin and anti-pTDP-43, muscle fibers with dense filamentous inclusions demonstrated single-fiber atrophy with vacuolar degeneration. CONCLUSION: The present findings indicate that pTDP-43 aggregates in skeletal and cardiac muscle are a myogenic pathological marker in multiple diseases including ALS.

DOI： 10.1186/s40478-019-0824-1

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AIMS: Globular glial tauopathy (GGT) is a new category within the 4-repeat tauopathies that is characterised neuropathologically by tau-positive globular glial inclusions (GGIs), namely, globular oligodendrocytic and astrocytic inclusions (GOIs and GAIs). Occurrence of tau-positive neuronal cytoplasmic inclusions (NCIs) is also a feature. GGT is classified into three pathological subtypes (Types I, II and III). We studied the tau pathology in 6 cases of GGT (Type II, n = 3; Type III, n = 3), with special reference to GAIs and NCIs. METHODS: Neuropathological examinations were conducted, along with immunohistochemistry, morphometry and three-dimensional imaging, and biochemical and genetic analysis of tau. RESULTS: The cortical GAIs in Type II and those in Type III were distinguishable from each other. In the motor cortex, GAIs were much more numerous in Type III than in Type II. Prominent occurrence of perikaryal globular structures was a feature of GAIs in Type III. By contrast, prominent occurrence of radiating process-like structures was a feature of GAIs in Type II. Overall, the GAIs were significantly smaller in Type III than in Type II. NCIs were divisible into three subgroups in terms of shape: diffuse granular, thick cord-like, and round/horseshoe-shaped structures. In all cases, NCIs were a feature of the upper and lower motor neurons. Interestingly, the round/horseshoe-shaped NCIs were observed only in Type III cases. CONCLUSIONS: These findings, which characterised GAIs and NCIs, indicated that Type II and Type III constitute two distinct pathological subtypes, and also further strengthen the concept of GGT as a distinct entity.

DOI： 10.1111/nan.12581

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Tau is a microtubule (MT)-associated protein that is localized to the axon. In Alzheimer's disease, the distribution of tau undergoes a remarkable alteration, leading to the formation of tau inclusions in the somatodendritic compartment. To investigate how this mislocalization occurs, we recently developed immunohistochemical tools that can separately detect endogenous mouse and exogenous human tau with high sensitivity, which allows us to visualize not only the pathological but also the pre-aggregated tau in mouse brain tissues of both sexes. Using these antibodies, we found that in tau-transgenic mouse brains, exogenous human tau was abundant in dendrites and somata even in the presymptomatic period, whereas the axonal localization of endogenous mouse tau was unaffected. In stark contrast, exogenous tau was properly localized to the axon in human tau knock-in mice. We tracked this difference to the temporal expression patterns of tau. Endogenous mouse tau and exogenous human tau in human tau knock-in mice exhibited high expression levels during the neonatal period and strong suppression into the adulthood. However, human tau in transgenic mice was expressed continuously and at high levels in adult animals. These results indicated the uncontrolled expression of exogenous tau beyond the developmental period as a cause of mislocalization in the transgenic mice. Superresolution microscopic and biochemical analyses also indicated that the interaction between MTs and exogenous tau was impaired only in the tau-transgenic mice, but not in knock-in mice. Thus, the ectopic expression of tau may be critical for its somatodendritic mislocalization, a key step of the tauopathy.SIGNIFICANCE STATEMENT Somatodendritic localization of tau may be an early step leading to the neuronal degeneration in tauopathies. However, the mechanisms of the normal axonal distribution of tau and the mislocalization of pathological tau remain obscure. Our immunohistochemical and biochemical analyses demonstrated that the endogenous mouse tau is transiently expressed in neonatal brains, that exogenous human tau expressed corresponding to such tau expression profile can distribute into the axon, and that the constitutive expression of tau into adulthood (e.g., human tau in transgenic mice) results in abnormal somatodendritic localization. Thus, the expression profile of tau is tightly associated with the localization of tau, and the ectopic expression of tau in matured neurons may be involved in the pathogenesis of tauopathy.

DOI： 10.1523/JNEUROSCI.2845-18.2019

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Language：Japanese   Publisher：(株)羊土社  

TDP-43やFUSに代表される、筋萎縮性側索硬化症(ALS)関連タンパク質の多くは、RNA結合タンパク質であり、複数の生体高分子と凝集し、非膜性の集合体を形成する。この現象は液-液相分離(LLPS)とよばれる。LLPSと類似の挙動を呈する非膜性の細胞構造の一つであるGEM小体は、スプライソソーム成熟に寄与する。われわれは、TDP-43発現抑制細胞とALS患者由来組織において、GEM小体数減少を示した。このことは、ALS関連タンパク質の機能喪失により、スプライソソーム機能不全を介したスプライシング破綻が生じることを示す。(著者抄録)

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The ischemic penumbra is both a concept in understanding the evolution of cerebral tissue injury outcome of focal ischemia and a potential therapeutic target for ischemic stroke. In this review, we examine the evidence that angiogenesis can contribute to beneficial outcomes following focal ischemia in model systems. Several studies have shown that, following cerebral ischemia, endothelial proliferation and subsequent angiogenesis can be detected beginning four days after cerebral ischemia in the border of the ischemic core, or in the ischemic periphery, in rodent and non-human primate models, although initial signals appear within hours of ischemia onset. Components of the neurovascular unit, its participation in new vessel formation, and the nature of the core and penumbra responses to experimental focal cerebral ischemia, are considered here. The potential co-localization of vascular remodeling and axonal outgrowth following focal cerebral ischemia based on the definition of tissue remodeling and the processes that follow ischemic stroke are also considered. The region of angiogenesis in the ischemic core and its surrounding tissue (ischemic periphery) may be a novel target for treatment. We summarize issues that are relevant to model studies of focal cerebral ischemia looking ahead to potential treatments.

DOI： 10.1177/0271678X19834158

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Globular glial tauopathies (GGTs) are four-repeat tauopathies characterized by the presence of two types of tau-positive globular glial inclusions (GGIs): globular oligodendrocytic and astrocytic inclusions (GOIs and GAIs). GGTs are classified into three different neuropathological subtypes: Types I, II and III. We report two patients with GGTs - a 76-year-old woman and a 70-year-old man - in whom the disease duration was 5 and 6 years, respectively. Both patients exhibited upper and lower motor neuron signs and involuntary movements, and the latter also had dementia with frontotemporal cerebral atrophy evident on magnetic resonance imaging. Neuropathologically, in both cases, the precentral gyrus was most severely affected, and at the gray-white matter junction there was almost complete loss of Betz cells and occurrence of GOIs and coiled bodies with numerous neuropil threads. Both patients also showed neuronal loss and GGIs (mostly GOIs) in many other central nervous system regions, including the basal ganglia. Apart from the degree of regional severity, the distribution pattern was essentially the same in both cases. However, GAIs were not conspicuous in any of the affected regions. Based on the morphology and distribution pattern of the GGIs, we diagnosed the present two patients as having GGT Type II. Electron microscopic and biochemical findings in the former were consistent with the diagnosis. Type II cases are reported to be characterized by pyramidal features reflecting predominant motor cortex and corticospinal tract degeneration. The present observations suggest that a variety of neurological features, including dementia, can occur in GGT Type II reflecting widespread degeneration beyond the motor neuron system.

DOI： 10.1111/neup.12532

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Objective: The prognosis of adrenoleukodystrophy (ALD)with neurological involvement is generally dismal; however, allogeneic stem cell transplantation (SCT) is recognized as effective to stabilize or improve the clinical symptoms of ALD. Herein, we report the clinical outcomes of patients with ALD who consecutively underwent allogeneic stem cell transplantation with reduced intensity conditioning at our institution. Patients: Sixteen patients with ALD, who were symptomatic (n = 14) or presymptomatic (n = 2), received SCT from 2010 to 2016. The stem cell source was cord blood (n = 14), or bone marrow from a human leukocyte antigen identical sibling (n = 2). The conditioning regimen prior to transplantation was reduced intensity and consisted of fludarabine (125 mg/m2), melphalan (140 mg/m2) and low dose total body irradiation (TBI) of 4Gy (n = 15) or 3Gy (n = 1). Results: Primary engraftment was obtained in 11 patients, and 4 of the 5 patients who lost the primary graft received a second cord blood transplantation and were engrafted. Five years overall and event-free survival were 90.9% and 61.1% respectively, with a median of 45 months (range 16-91). Loes score stabilized or improved by 18 months after transplantation except for patients with internal capsule involvement. Conclusion: Allogeneic SCT with reduced intensity conditioning for patients with ALD was safely performed without major transplant-related complications even in symptomatic patients and neurological symptoms were stabilized after SCT in patients without internal capsule involvement.

DOI： 10.1016/j.ymgmr.2018.11.001

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It has been reported that many elderly people have low serum levels of 25-hydroxyvitamin D [25(OH)D] and that serum 25(OH)D levels may have a relationship with cognitive function. The aim of this study was to examine the relationship between serum 25(OH)D levels and cognitive function in a Japanese population. This cross-sectional study was performed as a part of the Project in Sado for Total Health (PROST). The PROST study evaluated cognitive state and serum vitamin D level from June 2011 to November 2013 for 740 patients (431 men and 309 women). The Mini-Mental State Examination-Japanese version (MMSE-J) and serum 25(OH)D level measurements were used as assessment tools. Cognitive impairment was defined using MMSE-J ≤ 23 as a cutoff. Multiple logistic regression analyses were performed to calculate the odds ratios (ORs) for low MMSE-J scores. The average subject age was 68.1 years, the average MMSE- J score was 25.9, and the average 25(OH)D level was 24.6 ng/mL. Significant ORs for cognitive impairment were observed for both high age and low serum 25(OH)D. The adjusted OR for the lowest versus highest serum 25(OH)D quartiles was 2.70 (95% confidence interval 1.38-5.28, P = 0.0110). Low serum 25(OH)D levels were independently associated with a higher prevalence of cognitive impairment.

DOI： 10.1007/s00774-018-0934-z

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Language：Japanese   Publisher：(株)中外医学社  

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Language：English   Publisher：WILEY  

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To explore the effect of aging, a cohort study is being performed on Sado Island, which is located in the Sea of Japan. Sado Island is close to the eastern coast of Japan, yet its population speaks the western Japanese dialect. Consequently, the genetic background of the population of Sado Island is of interest. Based on Nei's genetic distance, we compared the allele frequencies of people from Sado Island to those of people from Nagahama and Miyagi, which are located in the western and northeastern parts of Honshu, respectively. The results showed that the populations of Miyagi and Nagahama are genetically closer to each other than to the population of Sado Island. Because the Sado and Honshu Islands are isolated by a channel, it is possible that genetic drift occurred within Sado Island, which would explain the uniqueness of the people of this region.

DOI： 10.1038/s41439-019-0058-6

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.prdoa.2019.11.002

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Objective: To characterize the genetic and clinical features of patients with autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) carrying duplication and deletion upstream of lamin B1 (LMNB1). Methods: Ninety-three patients with adult-onset leukoencephalopathy of unknown etiology were genetically analyzed for copy numbers of LMNB1 and its upstream genes. We examined LMNB1 expression by reverse transcription-qPCR using total RNA extracted from peripheral leukocytes. Clinical and MRI features of the patients with ADLD were retrospectively analyzed. Results: We identified 4 patients from 3 families with LMNB1 duplication. The duplicated genomic regions were different from those previously reported. The mRNA expression level of LMNB1 in patients with duplication was significantly increased. The clinical features of our patients with LMNB1 duplication were similar to those reported previously, except for the high frequency of cognitive impairment in our patients. We found 2 patients from 1 family carrying a 249-kb genomic deletion upstream of LMNB1. Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication. The presence of cerebellar symptoms and lesions may be characteristic in our patients with the deletion compared with the previously reported family with the deletion. Magnetic resonance images of patients with the deletion exhibited a widespread distribution of white matter lesions including the anterior temporal region. Conclusions: We identified 4 Japanese families with ADLD carrying duplication or deletion upstream of LMNB1. There are differences in clinical and MRI features between the patients with the duplication and those with the deletion upstream of LMNB1.

DOI： 10.1212/NXG.0000000000000292

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-ELSEVIER  

Background: Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma. Early-stage MF patches or plaques often resemble inflammatory skin disorders (ISDs), including psoriasis and atopic dermatitis. Cell adhesion molecule 1 gene (CADM1), which was initially identified as a tumor suppressor gene in human non-small cell lung cancer, has been reported as a diagnostic marker for adult T-cell leukemia/lymphoma.Objective: We investigated CADM1 expression in MF neoplastic cells, especially during early stages, and evaluated its usefulness as a diagnostic marker for MF.Methods: We conducted a retrospective study by using immunohistochemical staining and confirmed the expression of CADM1 in MF. In addition, we compared CADM1 messenger RNA expression in microdissected MF samples and ISD samples.Results: In the overall study period, 55 of 58 MF samples (94.8%) stained positive for CADM1. None of the 50 ISD samples showed positive reactivity (P < .0001). We found CADM1 messenger RNA expression in the intradermal lymphocytes of patients with MF but not in those of patients with an ISD.Limitations: We did not conduct a validation study for MF cases in other institutions.Conclusions: CADM1-positive cells can be identified in early stages with fewer infiltrating cells and may be useful as a diagnostic marker for early-stage MF.

DOI： 10.1016/j.jaad.2018.06.025

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Language：Japanese   Publisher：(一社)日本神経学会  

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We report the clinicopathologic features of 2 unrelated patients with sporadic amyotrophic lateral sclerosis (SALS) supported by tracheostomy and invasive ventilation (TIV) who were able to maintain communication ability for more than 30 years after disease onset. In both cases, the age at onset was younger than the mean, initially the progression of muscle weakness was consistent with that in the majority of SALS patients, and TIV became necessary several years after disease onset. Thereafter, however, their neurologic deterioration slowed and the patients were able to operate computers by facial movements for several decades. At autopsy, neuronal loss appeared to be confined to the motor neuron system. Furthermore, while Betz cells and lower motor neurons in the spinal anterior horns and hypoglossal nucleus were severely depleted, other pyramidal neurons in the motor cortex, and lower motor neurons in the other brainstem motor nuclei were retained. Neuronal and glial cytoplasmic inclusions immunoreactive for phosphorylated 43-kDa TAR DNA-binding protein (TDP-43) were evident in the CNS, but in extremely small numbers. The present patients may represent a distinct subgroup of patients with SALS who are able to maintain communication ability for an extremely long period, accompanied by very mild TDP-43 pathology.

DOI： 10.1093/jnen/nly082

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OBJECTIVE: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is caused by mutations in CSF1R. Pathogenic mutations in exons 12-22 including coding sequence of the tyrosine kinase domain (TKD) of CSF1R were previously identified. We aimed to identify CSF1R mutations in patients who were clinically suspected of having ALSP and to determine the pathogenicity of novel CSF1R variants. METHODS: Sixty-one patients who fulfilled the diagnostic criteria of ALSP were included in this study. Genetic analysis of CSF1R was performed for all the coding exons. The haploinsufficiency of CSF1R was examined for frameshift mutations by RT-PCR. Ligand-dependent autophosphorylation of CSF1R was examined in cells expressing CSF1R mutants. RESULTS: We identified ten variants in CSF1R including two novel frameshift, five novel missense, and two known missense mutations as well as one known missense variant. Eight mutations were located in TKD. One frameshift mutation (p.Pro104LeufsTer8) and one missense variant (p.His362Arg) were located in the extracellular domain. RT-PCR analysis revealed that the frameshift mutation of p.Pro104LeufsTer8 caused nonsense-mediated mRNA decay. Functional assay revealed that none of the mutations within TKD showed autophosphorylation of CSF1R. The p.His362Arg variant located in the extracellular domain showed comparable autophosphorylation of CSF1R to the wild type, suggesting that this variant is not likely pathogenic. CONCLUSIONS: The detection of the CSF1R mutation outside of the region-encoding TKD may extend the genetic spectrum of ALSP with CSF1R mutations. Mutational analysis of all the coding exons of CSF1R should be considered for patients clinically suspected of having ALSP.

DOI： 10.1007/s00415-018-9017-2

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary cerebral small vessel disease (CSVD) caused by homozygous or compound heterozygous mutations of the high temperature requirement A serine peptidase 1 gene (HTRA1). Affected patients suffer from cognitive impairment, recurrent strokes, lumbago and alopecia. Recently, clinical studies have indicated that some patients with heterozygous mutations in HTRA1 may also suffer CSVD. Here, we report the histopathologic features of an autopsied 55-year-old male patient who had shown cognitive impairment and multiple cerebral infarcts, and was found to have a heterozygous missense mutation (p.R302Q) in the HTRA1 gene. Histologically, small vessels in the brain and spinal cord showed intimal proliferation, splitting of the internal elastic lamina, and degeneration of smooth muscle cells in the tunica media. Thus, although less severe, the features were quite similar to those of patients with CARASIL, indicating that patients with heterozygous mutations develop CSVD through underlying pathomechanisms similar to those of CARASIL.

DOI： 10.1111/neup.12473

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OBJECTIVE: To determine predictors of cognitive impairment and frontal dysfunction in patients with multiple system atrophy (MSA). METHODS: We recruited 59 patients with MSA and determined the predictors of a decline in the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) scores. RESULTS: The MMSE scores negatively correlated with disease duration, Unified MSA Rating Scale (UMSARS) part 1 and 4 scores, and residual urine volume, and positively correlated with the coefficient of variation of electrocardiographic RR intervals. The FAB scores negatively correlated with the UMSARS part 2 score, periventricular hyperintensity grade, and deep white matter hyperintense signal grade. A significant predictor of rapidly progressive cognitive impairment was a high residual urine volume. CONCLUSIONS: Impairment of global cognitive function correlates with the long-term disease duration, global disability due to the disease, and autonomic dysfunction, whereas frontal dysfunction correlates with motor function and degeneration of cerebral white matter.

DOI： 10.1016/j.jns.2018.03.017

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We investigated whether loss of motor neurons innervating the neck muscles contributes to dropped head (DH) in multiple system atrophy (MSA). From 75 patients with autopsy-proven MSA, we retrieved 3 who had DH (MSA-DH), and examined the 4th cervical cord segments. Neurons of the medial and lateral nuclear groups (MNG and LNG) innervate the neck and shoulder muscles, respectively. We measured the area of individual neurons in the MNG and LNG, and created an area-frequency histogram. Neurons were classified as large or small based on their area, and their total numbers in the MNG and LNG were counted. In the MNG, the numbers of both total neurons and large neurons were significantly lower in MSA patients than in the controls (214.2 ± 91.4 vs 521.3 ± 74.8, p = 0.0030, and 26.2 ± 9.1 vs 88.0 ± 34.6, p = 0.020, respectively), and were significantly lower in MSA-DH than in MSA-nonDH (139.7 ± 7.6 vs 288.7 ± 74.6, p = 0.048, and 18.0 ± 4.1 vs 34.3 ± 4.1, p = 0.016, respectively). There were no differences in the LNG neuron counts between the MSA-DH and MSA-nonDH groups. Loss of cervical motor neurons may be responsible for DH in MSA.

DOI： 10.1093/jnen/nly007

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Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.

DOI： 10.1038/s41588-018-0067-2

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Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease, and the etiology of sporadic ALS is generally unknown. The TANK-binding kinase 1 (TBK1) gene was identified as an ALS gene contributing to a predisposition toward ALS. To reveal the frequency and characteristics of variants of the TBK1 gene in sporadic ALS patients in Japan, we analyzed the TBK1 gene by exome sequencing in a large Japanese cohort of 713 sporadic ALS patients and 800 controls. We identified known or potentially toxic rare variants of TBK1 gene in 9 patients (1.26%) with sporadic ALS, including 4 novel missense variants (p.V23I, p.H322R, p.R358C, and p.T478I) and 3 loss-of-function variants (p.R357X, p.P378_I379del, and p.T419_G420del). The odds ratio between sporadic ALS patients and controls was 10.2 (p = 0.008, 95% confidence interval = 1.67-62.47). These findings support the contribution of TBK1 to the etiology of sporadic ALS in Japanese patients.

DOI： 10.1016/j.neurobiolaging.2017.12.005

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We report a Japanese patient with spinocerebellar ataxia type 31 (SCA31) and sporadic Creutzfeldt-Jakob disease (sCJD). A 52-year-old man developed progressive cognitive impairment after the appearance of cerebellar symptoms. Brain MR diffusion-weighted imaging (DWI) demonstrated a slowly expanding hyperintense lesion in the cerebral cortex. The patient was finally diagnosed as having both SCA31 and sCJD by identification of genetic mutations and by real-time quaking-induced conversion (RT-QUIC) analysis of the cerebrospinal fluid (CSF), respectively. Here, we report the clinical details of this rare combined case, with particular reference to the association between prion protein and the early onset of SCA31.

DOI： 10.1080/19336896.2018.1436926

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

Background and purpose: To establish and validate diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) due to colony-stimulating factor 1 receptor (CSF1R) mutation. Methods: We developed diagnostic criteria for ALSP based on a recent analysis of the clinical characteristics of ALSP. These criteria provide ‘probable’ and ‘possible’ designations for patients who do not have a genetic diagnosis. To verify its sensitivity and specificity, we retrospectively applied our criteria to 83 ALSP cases who had CSF1R mutations (24 of these were analyzed at our institutions and the others were identified from the literature), 53 cases who had CSF1R mutation-negative leukoencephalopathies and 32 cases who had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with NOTCH3 mutations. Results: Among the CSF1R mutation-positive cases, 50 cases (60%) were diagnosed as ‘probable’ and 32 (39%) were diagnosed as ‘possible,’ leading to a sensitivity of 99% if calculated as a ratio of the combined number of cases who fulfilled ‘probable’ or ‘possible’ to the total number of cases. With regard to specificity, 22 cases (42%) with mutation-negative leukoencephalopathies and 28 (88%) with CADASIL were correctly excluded using these criteria. Conclusions: These diagnostic criteria are very sensitive for diagnosing ALSP with sufficient specificity for differentiation from CADASIL and moderate specificity for other leukoencephalopathies. Our results suggest that these criteria are useful for the clinical diagnosis of ALSP.

DOI： 10.1111/ene.13464

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

Background and purpose: To establish and validate diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) due to colony-stimulating factor 1 receptor (CSF1R) mutation. Methods: We developed diagnostic criteria for ALSP based on a recent analysis of the clinical characteristics of ALSP. These criteria provide ‘probable’ and ‘possible’ designations for patients who do not have a genetic diagnosis. To verify its sensitivity and specificity, we retrospectively applied our criteria to 83 ALSP cases who had CSF1R mutations (24 of these were analyzed at our institutions and the others were identified from the literature), 53 cases who had CSF1R mutation-negative leukoencephalopathies and 32 cases who had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with NOTCH3 mutations. Results: Among the CSF1R mutation-positive cases, 50 cases (60%) were diagnosed as ‘probable’ and 32 (39%) were diagnosed as ‘possible,’ leading to a sensitivity of 99% if calculated as a ratio of the combined number of cases who fulfilled ‘probable’ or ‘possible’ to the total number of cases. With regard to specificity, 22 cases (42%) with mutation-negative leukoencephalopathies and 28 (88%) with CADASIL were correctly excluded using these criteria. Conclusions: These diagnostic criteria are very sensitive for diagnosing ALSP with sufficient specificity for differentiation from CADASIL and moderate specificity for other leukoencephalopathies. Our results suggest that these criteria are useful for the clinical diagnosis of ALSP.

DOI： 10.1111/ene.13464

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

A brain-computer interface (BCI) or brain-machine interface is a technology that enables the control of a computer and other external devices using signals from the brain. This technology has been tested in paralysed patients, such as those with cervical spinal cord injuries or amyotrophic lateral sclerosis, but it has not been tested systematically in Duchenne muscular dystrophy (DMD), which is a severe type of muscular dystrophy due to the loss of dystrophin and is often accompanied by progressive muscle weakness and wasting. Here, we investigated the efficacy of a P300-based BCI for patients with DMD. Eight bedridden patients with DMD and eight age-and gender-matched able-bodied controls were instructed to input hiragana characters. We used a region-based, two-step P300-based BCI with green/blue flicker stimuli. EEG data were recorded, and a linear discriminant analysis distinguished the target from other non-targets. The mean online accuracy of inputted characters (accuracy for the two-step procedure) was 71.6% for patients with DMD and 80.6% for controls, with no significant difference between the patients and controls. The P300-based BCI was operated successfully by individuals with DMD in an advanced stage and these findings suggest that this technology may be beneficial for patients with this disease.

DOI： 10.1038/s41598-018-20125-6

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DOI： 10.1212/WNL.0000000000004710

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Lippincott Williams and Wilkins  

DOI： 10.1212/WNL.0000000000004710

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DOI： 10.1016/j.jns.2017.08.604

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PURPOSE: Definite diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy (CADASIL) is mostly done by identification of NOTCH3 mutations. We aimed to develop criteria for selecting patients suspected for CADASIL to undergo genetic testing. SUBJECTS AND METHODS: All subjects were Japanese. We recruited CADASIL patients genetically diagnosed up until 2011 (n=37, Group 1) or after 2011 (n=65, Group 2), 67 young stroke patients (≤55 years old), and 53 NOTCH3-negative CADASIL-like patients. The members of Japanese research committee for hereditary cerebral small vessel disease discussed and generated the new criteria to maximize positive rate in Group 1 CADASIL patients, followed by validation of sensitivity and specificity. RESULTS: In Group 1 CADASIL patients, the ages at onset excluding migraine were distributed widely (37-74 years old) and bimodal (<55 and >55 years old). Frequencies of an autosomal dominant family history and vascular risk factor(s) were 73 and 65%, respectively. From these findings, the panel considered appropriate cut-off values and weighting for each item. In CADASIL Group 1 versus young stroke controls, the sensitivity and specificity of the new criteria were 97.3% and 80.6%, respectively. However, in CADASIL Group 2 versus NOTCH3-negative controls, the sensitivity and specificity were 96.9% and 7.5%, respectively. Forty mutations of NOTCH3 distributed in exons 2-8, 11, 14, 18, 19, and 21 were identified in this study. Ten mutations were unreported ones. CONCLUSION: We propose the new criteria of high sensitivity, which will help physicians to assess the need for genetic testing.

DOI： 10.1016/j.jns.2017.08.009

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It is thought that posterior reversible encephalopathy syndrome (PRES) is both clinically and radiologically reversible. However, its reversible nature has been challenged based on reports of permanent neurological impairments. The factors that predict the development of irreversible neurological impairment are still unclear. In the present study, we investigated clinical manifestations, laboratory findings, and neuroradiological images to identify predictors of functional outcomes in PRES. We investigated 23 PRES patients. Apparent diffusion coefficient (ADC) reduction was observed in 4 patients in the poor outcome group, whereas no patients presented ADC reduction in the favourable outcome group (p<0.01). Further studies are warranted to evaluate the association between ADC reduction and functional outcome after PRES.

DOI： 10.1016/j.jns.2017.08.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Aim: Evidence for the association between dialysis treatment and cognitive decline is limited. The present study aimed to determine whether dialysis treatment is associated with cognitive decline in adult outpatients of a general hospital in Japan.Methods: This was a cross-sectional substudy of the Project in Sado for Total Etealth (PROST). Total Etealth PROST targeted adult outpatients of a general hospital in Sado City, Niigata, Japan. Among 753 patients (mean age 68.1 11.6 years) analyzed, 66 received dialysis. Cognitive state was evaluated using the Mini-Mental State Examination, and those with a Mini-Mental State Examination score <24 were considered "cognitively declined." The prevalence of cognitive decline was compared by odds ratios calculated with multiple logistic regression analysis. Variables included in the analyses were dialysis, age, sex and self-reported histories of hypertension, diabetes, stroke and ischemic heart disease.Results: Of the 66 dialysis patients, 24 (36.4%) showed cognitive decline, whereas 172 (25.0%) of 687 non-dialysis patients showed cognitive decline. The age and sex-adjusted odds ratio for cognitive decline in dialysis patients was 2.57 (95% confidence interval 1.43-4.61), relative to non-dialysis patients. The odds ratio remained significant (odds ratio 2.69, 95% confidence interval 1.49-4.88) even after adjusting for all covariates.Conclusion: The prevalence of cognitive decline was high in dialysis patients relative to non-dialysis patients among outpatients of a general hospital in Japan..

DOI： 10.1111/ggi.12937

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

The ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase Parkin, two gene products associated with young-onset Parkinson's disease (PD), participate in mitochondrial quality control. The phosphorylation of mitochondrial polyUb by PINK1, which is activated in a mitochondrial membrane potential (Delta Psi m)-dependent manner, facilitates the mitochondrial translocation and concomitant enzymatic activation of Parkin, leading to the clearance of phospho-polyUb-tagged mitochondria via mitophagy. Thus, Ub phosphorylation is a key event in PINK1-Parkin-mediated mitophagy. Here, we examined the role of phospho-Ub signaling in the pathogenesis of PD using fly PD models, human brain tissue and dopaminergic neurons derived from induced pluripotent stem cells (iPSCs) containing Parkin or PINK1 mutations, as well as normal controls. We report that phospho-Ub signaling is highly conserved between humans and Drosophila, and that phospho-Ub signaling and the relocation of axonal mitochondria upon Delta Psi m reduction are indeed compromised in human dopaminergic neurons containing Parkin or PINK1 mutations. Moreover, phospho-Ub signaling is prominent in tyrosine hydroxylase-positive neurons compared with tyrosine hydroxylase-negative neurons, suggesting that PINK1-Parkin signaling is more required for dopaminergic neurons. These results shed light on the particular vulnerability of dopaminergic neurons to mitochondrial stress.

DOI： 10.1093/hmg/ddx201

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Language：Japanese  

Hereditary spinocerebellar degenerations (SCD) are a group of neurodegenerative disorders characterized by slowly progressive ataxia associated with non-cerebellar neurological signs and symptoms. In the Japanese population, dominantly inherited SCDs are much more common than recessively inherited or X-linked SCDs. The most common dominantly inherited SCD in Japan, as well as in many other countries, is Machado-Joseph disease, also known as spinocerebellar ataxia type 3 (MJD/SCA3). MJD/SCA3 is frequently accompanied by non-cerebellar symptoms, including progressive external ophthalmoplegia, pyramidal signs, dystonia, rigidity, dysarthria, and distal muscle atrophies. SCA6 and SCA31 represent a pure cerebellar subtype of SCD, occasionally accompanied by non-cerebellar signs. Detailed medical history and neurological examination are important for clinicians to diagnose hereditary SCDs, although genetic testing can help confirm the diagnosis. Despite increasing understanding of the molecular mechanisms underlying these fatal diseases, preventive therapies are currently lacking.

DOI： 10.11477/mf.1416200839

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Objective.-To clarify the clinical features and risk factors of cervicogenic headache (CEH; as diagnosed according to the International Classification of Headache Disorders-Third Edition beta) in patients with cervical spine disorders requiring surgery.
Background.-CEH is caused by cervical spine disorders. The pathogenic mechanism of CEH is hypothesized to involve a convergence of the upper cervical afferents from the C1, C2, and C3 spinal nerves and the trigeminal afferents in the trigeminocervical nucleus of the upper cervical cord. According to this hypothesis, functional convergence of the upper cervical and trigeminal sensory pathways allows the bidirectional (afferent and efferent) referral of pain to the occipital, frontal, temporal, and/or orbital regions. Previous prospective studies have reported an 86-88% prevalence of headache in patients with cervical myelopathy or radiculopathy requiring anterior cervical surgery; however, these studies did not diagnose headache according to the International Classification of Headache Disorders criteria. Therefore, a better understanding of the prevalence rate, clinical features, risk factors, and treatment responsiveness of CEH in patients with cervical spine disorders requiring surgery is necessary.
Methods.-We performed a single hospital-based prospective cross-sectional study and enrolled 70 consecutive patients with cervical spine disorders such as cervical spondylotic myelopathy, ossification of the posterior longitudinal ligament, cervical spondylotic radiculopathy, and cervical spondylotic myeloradiculopathy who had been scheduled to undergo anterior cervical fusion or dorsal cervical laminoplasty between June 2014 and December 2015. Headache was diagnosed preoperatively according to the International Classification of Headache Disorders-Third Edition beta. The Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire, Neck Disability Index, and a 0-100 mm visual analog scale (VAS) were used to evaluate clinical features, and scores were compared between baseline (ie, preoperatively) and 3, 6, and 12 months post-surgery.
Results.-The prevalence of CEH in our population was 15/70 (21.4%, 95% CI: 11.8% to 31.0%). The main clinical features were dull and tightening/pressing headache sensations in the occipital region. Headache severity was mild (VAS, 32611 mm) and only one patient reported use of an oral analgesic. Compared to patients without CEH, patients with CEH had higher frequencies of neck pain (86.7% vs. 50.9%; P=.017), cervical range of motion limitation (ROM) (66.7% vs. 38.2%; P=.049), and higher Neck Disability Index scores (14 vs. 3; P&lt;.001). Among the different cervical spine disorders, the prevalence of CEH was highest in cervical spondylotic myeloradiculopathy patients (60%), being &lt;= 20% for all other disorders. Surgical treatments including cervical laminoplasty to relieve abnormal pressure on the spinal cord via a posterior approach, were associated with initial improvements in headache VAS that slightly diminished by 12 months post-surgery (P&lt;.001).
Conclusions.-We report a lower prevalence of CEH in patients with cervical spinal disorders requiring surgery than that reported previously. The main clinical features of CEH were mild, dull, and tightening/pressing headache sensations in the occipital region. Potential risk factors for CEH included neck pain, limited cervical ROM, high Neck Disability Index score, and a diagnosis of cervical spondylotic myeloradiculopathy. The further accumulation of patients in a multi-institutional study may be required in order to discuss the diagnostic criteria and pathophysiology of this condition.

DOI： 10.1111/head.13123

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Language：English   Publisher：JAPAN ACAD  

Multiple system atrophy (MSA) is an adult-onset neurodegenerative disorder that has both clinical and pathological variants. Clinical examples include MSA with predominant cerebellar ataxia (MSA-C) and MSA with predominant parkinsonism (MSA-P), whereas olivopontocerebellar atrophy and striatonigral degeneration represent pathological variants. We performed systematic reviews of studies that addressed the relative frequencies of clinical or pathological variants of MSA in various populations to determine the clinicopathological characteristics in Japanese MSA. The results revealed that the majority of Japanese patients have MSA-C, while the majority of patients in Europe and North America have MSA-P. A comparative study of MSA pathology showed that the olivopontocerebellar-predominant pathology was more frequent in Japanese MSA than in British MSA. Demonstrated differences in pathological subtype thus appear consistent with differences in the clinical subtype of MSA demonstrated between Japan and European populations. We concluded that olivopontocerebellar-predominant pathology and MSA-C may represent clinicopathological characteristics in Japanese MSA. Factors determining predominant involvement of olivopontocerebellar regions in MSA should therefore be explored.

DOI： 10.2183/pjab.93.016

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Posterior reversible encephalopathy syndrome (PRES) is suggested in patients with acute neurological symptoms in the appropriate clinical context, including acute hypertension, blood pressure fluctuations, renal failure, blood transfusion, immunosuppression, autoimmune disorders, and eclampsia. PRES is a clinical syndrome, and refers to a disorder with reversible subcortical vasogenic brain edema caused by endothelial dysfunction, predominantly involving the bilateral parieto-occipital regions. Although the clinical course and prognosis are favorable in most cases, intracranial hemorrhage and/or restricted diffusion similar to acute infarction could be seen in some lesions on brain magnetic resonance imaging (MRI). The spinal cord may be involved in some patients with posterior fossa lesions. Understanding the pathophysiology of PRES is helpful in making the correct early diagnosis and selecting appropriate therapies to improve its clinical course and outcome. Differentiation of PRES from strokes is critical in the setting of a neurological emergency.

DOI： 10.11477/mf.1416200653

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J04871&link_issn=&doc_id=20170217120007&doc_link_id=10.11477%2Fmf.1416200653&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1416200653&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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We previously reported familial amyotrophic lateral sclerosis (FALS) of 11years duration in a 57-year-old woman, who received artificial ventilation for 5years prior to death and exhibited widespread multisystem degeneration and neurofilamentous aggregates, so-called conglomerate inclusions (CIs). In the present study, we re-evaluated this autopsied patient (proband) with further immunohistochemical observation as well as mutational analysis of the superoxide dismutase 1 (SOD1) gene. A review of the clinical features of the proband's family revealed five affected members (including the proband) over two successive generations who showed marked variability in clinical presentation, such as the age at onset. The proband was found to harbor a heterozygous missense mutation in exon 4 (I104F) of the SOD1 gene. In the brain and spinal cord, SOD1-positive neuronal cytoplasmic inclusions (NCIs) were found to be more widely distributed than CIs, the latter being weakly positive for SOD1. No Lewy body-like hyaline inclusions were found. This is considered to be the first description of an autopsy case of FALS with an I104F SOD1 gene mutation, suggesting that combination of marked intra-familial clinical variability and multisystem degeneration with occurrence of CIs and SOD1-positive NCIs is a characteristic feature of FALS with this SOD1 gene mutation.

DOI： 10.1111/neup.12324

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Cell-therapies that invoke pleiotropic mechanisms may facilitate functional recovery in stroke patients. We hypothesized that a cell therapy using microglia preconditioned by optimal oxygen-glucose deprivation (OGD) is a therapeutic strategy for ischemic stroke because optimal ischemia induces anti-inflammatory M2 microglia. We first delineated changes in angiogenesis and axonal outgrowth in the ischemic cortex using rats. We found that slight angiogenesis without axonal outgrowth were activated at the border area within the ischemic core from 7 to 14 days after ischemia. Next, we demonstrated that administration of primary microglia preconditioned by 18 hours of OGD at 7 days prompted functional recovery at 28 days after focal cerebral ischemia compared to control therapies by marked secretion of remodelling factors such as vascular endothelial growth factor, matrix metalloproteinase-9, and transforming growth factor-beta polarized to M2 microglia in vitro/vivo. In conclusion, intravascular administration of M2 microglia preconditioned by optimal OGD may be a novel therapeutic strategy against ischemic stroke.

DOI： 10.1038/srep42582

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

Background and purpose: The clinical characteristics of colony stimulating factor 1 receptor (CSF1R) related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) have been only partially elucidated. Methods: Clinical data from CSF1R mutation carriers who had been seen at our institutions or reported elsewhere were collected and analysed using a specific investigation sheet to standardize the data. Results: In all, 122 cases from 90 families with CSF1R mutations were identified. The mean age of onset was 43 years (range 18–78 years), the mean age at death was 53 years (range 23–84 years) and the mean disease duration was 6.8 years (range 1–29 years). Women had a significantly younger age of onset than men (40 vs. 47 years, P = 0.0006, 95% confidence interval 3.158–11.177). There was an age-dependent penetrance that was significantly different between the sexes (P = 0.0013). Motor dysfunctions were the most frequent initial symptom in women whose diseases began in their 20s. Thinning of the corpus callosum, abnormal signalling in pyramidal tracts, diffusion-restricted lesions and calcifications in the white matter were characteristic imaging findings of ALSP. The calcifications were more frequently reported in our case series than in the literature (54% vs. 3%). Seventy-nine per cent of the mutations were located in the distal part of the tyrosine kinase domain of CSF1R (102 cases). There were no apparent phenotype−genotype correlations. Conclusions: The characteristics of ALSP were clarified. The phenotype of ALSP caused by CSF1R mutations is affected by sex.

DOI： 10.1111/ene.13125

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Igaku-Shoin Ltd  

Cerebral small vessel disease (CSVD) is frequently observed among the elderly and is known to cause dementia and gait disturbance associated with white matter lesions, lacunar infarcts, and cerebral hemorrhage. Molecular mechanistic studies promise to provide new insights into the pathogenesis of hereditary CSVD. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is one of the hereditary CSVDs caused by a mutation in the hightemperature requirement serine peptidase A1 (HTRA1) gene. The loss of HTRA1 protease activity increases signaling via transforming growth factor (TGF)β, thereby resulting in CARASIL. Although the CARASIL has been characterized by juvenile onset alopecia and spondylosis deformans, these features are not always observed in individuals with an HTRA1 mutation. Moreover, some HTRA1 mutations cause CSVD in heterozygous states. Therefore, the clinical features of CSVD resulting from an HTRA1 mutation extend to patients with CSVD alone or to those with dominantly inherited CSVD.

DOI： 10.11477/mf.1416200631

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Background and purpose: The clinical characteristics of colony stimulating factor 1 receptor (CSF1R) related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) have been only partially elucidated.
Methods: Clinical data from CSF1R mutation carriers who had been seen at our institutions or reported elsewhere were collected and analysed using a specific investigation sheet to standardize the data.
Results: In all, 122 cases from 90 families with CSF1R mutations were identified. The mean age of onset was 43 years (range 18-78 years), the mean age at death was 53 years (range 23-84 years) and the mean disease duration was 6.8 years (range 1-29 years). Women had a significantly younger age of onset than men (40 vs. 47 years, P = 0.0006, 95% confidence interval 3.158-11.177). There was an age-dependent penetrance that was significantly different between the sexes (P = 0.0013). Motor dysfunctions were the most frequent initial symptom in women whose diseases began in their 20s. Thinning of the corpus callosum, abnormal signalling in pyramidal tracts, diffusion-restricted lesions and calcifications in the white matter were characteristic imaging findings of ALSP. The calcifications were more frequently reported in our case series than in the literature (54% vs. 3%). Seventy-nine per cent of the mutations were located in the distal part of the tyrosine kinase domain of CSF1R (102 cases). There were no apparent phenotype similar to genotype correlations.
Conclusions: The characteristics of ALSP were clarified. The phenotype of ALSP caused by CSF1R mutations is affected by sex.

DOI： 10.1111/ene.13125

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC NEURORADIOLOGY  

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia is a rare neurodegenerative disease resulting from mutations in the colony stimulating factor 1 receptor gene. Accurate diagnosis can be difficult because the associated clinical and MR imaging findings are nonspecific. We present 9 cases with intracranial calcifications distributed in 2 brain regions: the frontal white matter adjacent to the anterior horns of the lateral ventricles and the parietal subcortical white matter. Thin-section (1-mm) CT scans are particularly helpful in detection due to the small size of the calcifications. These calcifications had a symmetric "stepping stone appearance" in the frontal pericallosal regions, which was clearly visible on reconstructed sagittal CT images. Intrafamilial variability was seen in 2 of the families, and calcifications were seen at birth in a single individual. These characteristic calcification patterns may assist in making a correct diagnosis and may contribute to understanding of the pathogenesis of leukoencephalopathy.

DOI： 10.3174/ajnr.A4938

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Language：English   Publisher：KARGER  

Objective: Reporting a novel mutation in the HTRA1 gene in a CARASIL patient from Americas. Methods: Clinical presentation and neuroimaging were consistent with CARASIL. HTRA1 DNA sequencing was performed using advanced ("next generation") sequencing technology. The results revealed a homozygous missense mutation as c.616G&gt;A (p.Gly206Arg) in the HTRA1 gene. Results: A 24-year-old man with a history of chronic back pain presented with recurrent ischemic strokes. A diagnosis of CARASIL was made with the finding of a novel homozygous missense mutation c.616G&gt;A in HTRA1 gene, resulting in change from Glycine to Arginine in the Serine Protease HTRA1. Brain imaging showed multiple lacunar infarcts with extensive abnormalities of the white matter that spared the external capsules. He also had unilateral decreased hearing with craniofacial asymmetry. None of the above features have been previously described in known CARASIL patients. Both parents of the proband were heterozygous for the same missense mutation. Conclusion: We discovered a novel missense mutation (c.616G&gt;A) associated with a phenotype of CARASIL. This is the first genetically backed case of CARASIL in the new world. The patient's craniofacial abnormalities, including asymmetry of the head, may be related to impaired modulation of transforming growth factor-beta 1, the result of loss of proteolytic activity of HTRA1. External capsules remained unaffected, despite findings of advanced changes in the rest of the cerebral white matter. Literature is briefly reviewed. The patient's history, neurological exam, neuroimaging, and genetic testing are included. (C) 2017 S. Karger AG, Basel

DOI： 10.1159/000477358

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Vibratory and joint position sensations are usually impaired simultaneously and afferents for both sensations ascend the dorsal columns. There are a few evidences that the central pathways in the spinal cord for position and vibratory sensations are not identical. In this study, we examined the clinical features of patients with sensory impairments of vibratory and joint position sensations. According to 43 evaluated patients’ results, the dissociation between an intact vibratory sensation and impaired joint position sensation may be important for the diagnosis of spinal disorders. We also report three cases of patients with spinal ataxia caused by sensory impairments and who show the dissociation between an impaired joint position sensation and an intact vibratory sensation. The combination of intact vibration sensation and impaired joint position sensation may suggest a dorsal column lesion in the spinal cord.

DOI： 10.1016/j.inat.2016.09.003

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Other Link： http://orcid.org/0000-0001-6337-8156

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Background: Human parechovirus type 3 (HPeV3) is an emerging virus that causes sepsis and meningoencephalitis in neonates and young infants. Correct diagnosis of HPeV3 infection is critical in determining appropriate management and predicting patients' clinical course. Real-time reverse transcription PCR (RT-PCR) analysis of serum and/or cerebrospinal fluid (CSF) has been used to diagnose HPeV3 infection; however, the assay detection limits have not been fully evaluated.
Objectives: We tested the hypothesis that droplet digital RT-PCR (RT-ddPCR) a novel technique that precisely quantitates low-copy target genes by diluting and partitioning samples into compartments increases the detection rate of HPeV3 RNA as compared with real-time RT-PCR.
Study design: Using samples with predetermined HPeV3 copy numbers, we evaluated one-step and two-step RT-ddPCR. Then, we tested two-step RT-ddPCR and real-time RT-PCR, using clinical samples with low copy numbers. Finally, we used two-step RT-ddPCR to evaluate clinical samples obtained from HPeV3-infected patients with positive serum but negative CSF, as determined by real-time RT-PCR.
Results: Two-step RT-ddPCR was less variable and more specific than one-step RT-ddPCR. Two-step RT-ddPCR detected HPeV3 RNA in all six CSF samples; four samples (67%) were reproducibly positive and the other two samples (33%) were positive at least once in four replicates. Finally, no nonspecific droplet was positive by two-step RT-ddPCR.
Conclusions: Two-step RT-ddPCR may enhance the rate of HPeV3 RNA detection from samples with low viral loads, thereby improving diagnosis and management of HPeV3-infected patients. (C) 2016 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jcv.2016.09.009

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Language：English   Publisher：WILEY-BLACKWELL  

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Objective: To clarify the histopathological alterations of microglia in the brains of patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) caused by mutations of the gene encoding the colony stimulating factor-1 receptor (CSF-1R).
Methods: We examined 5 autopsied brains and 1 biopsy specimen from a total of 6 patients with CSF-1R mutations. Detailed immunohistochemical, biochemical, and ultrastructural features of microglia were examined, and quantitative analyses were performed.
Results: In layers 3 to 4 of the frontal cortex in HDLS brains, microglia showed relatively uniform and delicate morphology, with thin and winding processes accompanying knotlike structures, and significantly smaller areas of Iba1 immunoreactivity and lower numbers of Iba1-positive cells were evident in comparison with control brains. On the other hand, in layers 5 to 6 and the underlying white matter, microglia were distributed unevenly; that is, in some areas they had accumulated densely, whereas in others they were scattered. Immunoblot analyses of microglia-associated proteins, including CD11b and DAP12, revealed that HDLS brains had significantly lower amounts of these proteins than diseased controls, although Ki-67-positive proliferative microglia were not reduced. Ultrastructurally, the microglial cytoplasm and processes in HDLS showed vesiculation of the rough endoplasmic reticulum and disaggregated polyribosomes, indicating depression of protein synthesis. On the other hand, macrophages were immunonegative for GLUT-5 or P2ry12, indicating that they were derived from bone marrow.
Interpretation: The pathogenesis of HDLS seems to be associated with microglial vulnerability and morphological alterations.

DOI： 10.1002/ana.24754

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

In the present study, we performed a comprehensive analysis to clarify the clinicopathological characteristics of patients with amyotrophic lateral sclerosis (ALS) that had progressed to result in a totally locked-in state (communication Stage V), in which all voluntary movements are lost and communication is impossible. In 11 patients, six had phosphorylated TAR DNA-binding protein 43 (pTDP-43)-immunoreactive (ir) neuronal cytoplasmic inclusions (NCI), two had fused in sarcoma (FUS)-ir NCI, and three had copper/zinc superoxide dismutase (SOD1)-ir NCI. The time from ALS onset to the need for tracheostomy invasive ventilation was less than 24 months in ten patients. Regardless of accumulated protein, all the patients showed common lesions in the pallido-nigro-luysian system, brainstem reticular formation, and cerebellar efferent system, in addition to motor neurons. In patients with pTDP-43-ir NCI, patients with NCI in the hippocampal dentate granule neurons (DG) showed a neuronal loss in the cerebral cortex, and patients without NCI in DG showed a preserved cerebral cortex. By contrast, in patients with FUS-ir NCI, patients with NCI in DG showed a preserved cerebral cortex and patients without NCI in DG showed marked cerebral degeneration. The cerebral cortex of patients with SOD1-ir NCI was preserved. Together, these findings suggest that lesions of the cerebrum are probably not necessary for progression to Stage V. In conclusion, patients with ALS that had progressed to result in communication Stage V showed rapidly-progressed symptoms, and their common lesions could cause the manifestations of communication Stage V.

DOI： 10.1186/s40478-016-0379-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are types of major TDP-43 (43-kDa TAR DNA-binding protein) proteinopathy. Cortical TDP-43 pathology has been analyzed in detail in cases of FTLD-TDP, but is still unclear in cases of ALS. We attempted to clarify the cortical and subcortical TDP-43 pathology in Japanese cases of sporadic ALS (n = 96) using an antibody specific to phosphorylated TDP-43 (pTDP-43). The cases were divided into two groups: those without pTDP-43-positive neuronal cytoplasmic inclusions in the hippocampal dentate granule cells (Type 1, n = 63), and those with such inclusions (Type 2, n = 33). Furthermore, the Type 2 cases were divided into two subgroups based on semi-quantitative estimation of pTDP-43-positive dystrophic neurites (DNs) in the temporal neocortex: Type 2a (accompanied by no or few DNs, n = 22) and Type 2b (accompanied by abundant DNs, n = 11). Clinico-pathologic analysis revealed that cognitive impairment was a feature in patients with Type 2a and Type 2b, but not in those with Type 1, and that importantly, Type 2b is a distinct subtype characterized by a poor prognosis despite the less severe loss of lower motor neurons, the unusual subcortical dendrospinal pTDP-43 pathology, and more prominent glial involvement in cortical pTDP-43 pathology than other two groups. Considering the patient survival time and severity of motor neuron loss in each group, transition from Type 1 to Type 2, or from Type 2a to Type 2b during the disease course appeared unlikely. Therefore, each of these three groups was regarded as an independent subtype.

DOI： 10.1186/s40478-016-0335-2

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Modulation of the intracellular calcium concentration is a ubiquitous signaling system involved in the control of numerous biological processes in a wide variety of cells. Inositol 1,4,5-trisphosphate (IP3) receptors (IP(3)Rs), which act as calcium release channels in the ER membrane, play a key role in the regulation of intracellular calcium concentration. IP3R type 1 (IP(3)R1) is the major neuronal IP3R isoform in the central nervous system and particularly abundant in cerebellar Purkinje cells. Heterozygous deletions or missense mutations in ITPR1, which encodes IP(3)R1, result in autosomal dominantly inherited spinocerebellar ataxias (SCAs), including SCA types 15 (SCA15) and 29 (SCA29). In addition, homozygous missense mutations in carbonic anhydrase-related protein VIII (CARP), which suppresses the ability of IP3 to bind to IP(3)R1, cause a recessively inherited ataxia with mild cognitive impairment with/without quadrupedal gait. Moreover, cytosolic calcium overload with excessive IP(3)R1 activity has been implicated in the pathogenesis of other SCAs, including SCA types 2 (SCA2) and 3 (SCA3). These facts indicate that dysregulation of IP3R-mediated calcium signaling is linked to the pathogenesis of SCAs. Here, we focus on the molecular basis of SCA15 and SCA29, which are caused by mutations in ITPR1. In addition, we discuss other SCAs whose pathogenesis may be linked to aberrant activation of IP3R-mediated Ca2+ signaling. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.neuint.2016.01.007

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Progressive supranuclear palsy (PSP) is a four-repeat tauopathy with tau-positive, argyrophilic tuft-shaped astrocytes (TAs). We performed a pathological and clinical investigation in 40 consecutive autopsied Japanese patients with pathological diagnoses of PSP or PSP-like disease. Unequivocal TAs were present in 22 cases, all of which were confirmed to be PSP. Such TAs were hardly detected in the other 18 cases, which instead exhibited tau-positive, argyrophilic astrocytes, appearing as comparatively small clusters with central nuclei of irregularly shaped, coarse structures (equivocal TAs). Cluster analysis of the distribution pattern of tau-related pathology for these 18 cases identified two subgroups, pallido-nigro-luysian atrophy (PNLA) Type 1 (n=9) and Type 2 (n=9), the former being distinguished from the latter by the presence of tau-related lesions in the motor cortex, pontine nucleus and cerebellar dentate nucleus in addition to the severely affected PNL system. The duration from symptom onset until becoming wheelchair-bound was significantly longer in PNLAType 1. Immunoblotting of samples from the three disease conditions revealed band patterns of low-molecular-mass tau fragments at approximate to 35kDa. These findings shed further light on the wide pathological and clinical spectrum of four-repeat tauopathy, representing PSP in the broad sense rather than classical PSP.

DOI： 10.1111/bpa.12265

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

Background/Aims: Evidence on modifiable factors associated with cognitive impairment in Japanese patients is scarce. This study aimed to determine modifiable factors for cognitive impairment in a Japanese hospital-based population. Methods: Subjects of this cross-sectional study were 1,143 patients of Sado General Hospital (Niigata, Japan) registered in the Project in Sado for Total Health (PROST) between June 2008 and September 2014. We assessed disease history, body mass index (BMI), leisure time physical activity, walking time, smoking and drinking habits, and consumption of vegetables, fruits, and green tea as predictors, with cognitive impairment defined by the Mini-Mental State Examination (score &lt
24) as an outcome. Multiple logistic regression analysis was performed to calculate odds ratios (ORs) for cognitive impairment. Results: The mean subject age was 68.9 years, and the prevalence of cognitive impairment was 21.5%. Multivariate analysis revealed that age (p &lt
0.001), low BMI (&lt
21.1
OR 1.39, 95% CI 1.12-1.72), a history of stroke (p = 0.003), a history of myocardial infarction (p = 0.038), low fruit consumption (p for trend = 0.012), and low green tea consumption (p for trend = 0.032) were independently associated with a higher prevalence of cognitive impairment. Conclusions: Modifiable factors, such as low BMI, low fruit consumption, and low green tea consumption, are associated with cognitive impairment. Longitudinal studies will be needed to confirm these findings.

DOI： 10.1159/000447963

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Background/Aims: We aimed to determine whether the concentration of serum C-reactive protein (CRP) is associated with cognitive function in an adult Japanese population. Methods: Participants of this cross-sectional study were from a subgroup of the Project in Sado for Total Health (PROST; n = 454; mean age, 70.5 years). The cognitive state was evaluated using the Mini-Mental State Examination (MMSE), and those with an MMSE score <24 were considered 'cognitively declined'. Concentrations of serum high-sensitivity CRP were measured. Multiple logistic regression analysis was used to calculate odds ratios (ORs) for cognitive decline, adjusting for the covariates of age, sex, BMI, disease history, and APOE allele. Results: Of the 454 participants, 94 (20.7%) were cognitively declined. Relative to the lowest (first) quartile of CRP concentration, adjusted ORs were 1.29 (95% CI 0.61-2.75) for the second, 1.78 (95% CI 0.82-3.86) for the third, and 3.05 (95% CI 1.45-6.42) for the highest (fourth) quartiles (p for trend = 0.018). When data were stratified by sex, the association between CRP concentration and cognitive decline was observed only in women. Conclusion: Our findings suggest an association between higher CRP concentration and lower cognitive function. Chronic inflammation may affect cognitive function in adults, in particular women. (C) 2016 The Author(s) Published by S. Karger AG, Basel

DOI： 10.1159/000442585

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Language：English   Publisher：BMJ PUBLISHING GROUP  

Recent advances in our understanding of neurophysiological functions in the cerebellar system have revealed that each region involved in degenerative ataxias contributes differently. To regulate voluntary movements, the cerebellum forms internal models within its neural circuits that mimic the behaviour of the sensorimotor system and objects in the external environment. The cerebellum forms two different internal models: forward and inverse. The forward model is formed by efference copy signals conveyed by the corticopontocerebellar system, and it derives the estimated consequences for action. The inverse model describes sequences of motor commands to accomplish an aim. During motor learning, we improve internal models by comparing the estimated consequence of an action from the forward model with the actual consequence of the action produced by the inverse model. The functions of the cerebellum encompass the formation, storage and selection of internal models. Considering the neurophysiological properties of the cerebellar system, we have classified degenerative ataxias into four types depending on which system is involved: Purkinje cells, the corticopontocerebellar system, the spinocerebellar system and the cerebellar deep nuclei. With regard to their respective contributions to the internal models, we speculate that loss of Purkinje cells leads to malformation of the internal models, whereas disturbance of the afferent system, corticopontocerebellar system or spinocerebellar system leads to mis-selection of the proper internal model. An understanding of the pathophysiological properties of ataxias in each degenerative ataxia enables the development of new methods to evaluate ataxias.

DOI： 10.1136/jnnp-2013-307225

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Objective: Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series. Methods: We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants. Results: In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 9 10(-3)). Interpretation: The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

DOI： 10.1002/acn3.185

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Publishing type：Research paper (scientific journal)   Publisher：Neurodegenerative Disorders as Systemic Diseases  

DOI： 10.1007/978-4-431-54541-5_1

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1161/STR.0000000000000044

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Language：English   Publisher：WILEY-BLACKWELL  

DOI： 10.1111/nan.12157

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy characterized by clinical and genetic heterogeneity. Although more than 30 loci harboring CMT-causing mutations have been identified, many other genes still remain to be discovered for many affected individuals. For two consanguineous families with CMT (axonal and mixed phenotypes), a parametric linkage analysis using genome-wide SNP chip identified a 4.3 Mb region on 12q24 showing a maximum multipoint LOD score of 4.23. Subsequent whole-genome sequencing study in one of the probands, followed by mutation screening in the two families, revealed a disease-specific 5 bp deletion (c.247-10_247-6de1CACTC) in a splicing element (pyrimidine tract) of intron 2 adjacent to the third exon of cytochrome c oxidase subunit VIa polypeptide 1 (COX6A1), which is a component of mitochondrial respiratory complex IV (cytochrome c oxidase [COX]), within the autozygous linkage region. Functional analysis showed that expression of COX6A1 in peripheral white blood cells from the affected individuals and COX activity in their EB-virus-transformed lymphoblastoid cell lines were significantly reduced. In addition, Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking. Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal or mixed CMT.

DOI： 10.1016/j.ajhg.2014.07.013

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Bunina bodies (BBs) are small eosinophilic neuronal cytoplasmic inclusions (NCIs) found in the remaining lower motor neurons (LMNs) of patients with sporadic amyotrophic lateral sclerosis (SALS), being a specific feature of the cellular pathology. We examined a case of SALS, unassociated with TDP-43 or C9ORF72 mutation, of 12 years duration in a 75-year-old man, who had received artificial respiratory support for 9 years, and showed widespread multisystem degeneration with TDP-43 pathology. Interestingly, in this patient, many NCIs reminiscent of BBs were observed in the oculomotor nucleus, medullary reticular formation and cerebellar dentate nucleus. As BBs in the cerebellar dentate nucleus have not been previously described, we performed ultrastructural and immunohistochemical studies of these NCIs to gain further insight into the nature of BBs. In each region, the ultrastructural features of these NCIs were shown to be identical to those of BBs previously described in LMNs. These three regions and the relatively well preserved sacral anterior horns (S1 and S2) and facial motor nucleus were immunostained with antibodies against cystatin C (CC) and TDP-43. Importantly, it was revealed that BBs exhibiting immunoreactivity for CC were a feature of LMNs, but not of non-motor neurons, and that in the cerebellar dentate nucleus, the ratio of neurons with BBs and TDP-43 inclusions/neurons with BBs was significantly lower than in other regions. These findings suggest that the occurrence of BBs with CC immunoreactivity is intrinsically associated with the particular cellular properties of LMNs, and that the mechanism responsible for the formation of BBs is distinct from that for TDP-43 inclusions.

DOI： 10.1111/neup.12105

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Aims: Mutations in the SCARB2 gene cause a rare autosomal recessive disease, progressive myoclonus epilepsy (PME) with or without renal failure, the former also being designated action myoclonus-renal failure syndrome. Although reported cases have been accumulating, only a few have described its neuropathology. We studied two Japanese patients with PME without renal failure, in whom the ages at onset and disease durations were 45 and 20 years, and 14 and 8.5 years respectively. Methods: Sequencing and restriction analysis of the SCARB2 gene and neuropathological examination with immunohistochemistry were performed. Results: Gene analyses revealed novel homozygous frameshift and nonsense mutations in the SCARB2 gene. Both cases exhibited deposition of brown pigment in the brain, especially the cerebellar and cerebral cortices. Ultrastructurally, the pigment granules were localized in astrocytes. Neuronal loss and gliosis were also evident in the brain, including the pallidoluysian and cerebello-olivary systems. The spinal cord was also affected. Such changes were less severe in one patient with late-onset disease than in the other patient with early-onset disease. In brain and kidney sections, immunostaining with an antibody against the C-terminus of human SCARB2 revealed decreased levels and no expression of the protein respectively. Conclusions: The frameshift mutation detected in the patient with late-onset disease is a hitherto undescribed, unique type of SCARB2 gene mutation. The present two patients are the first reported to have clearly demonstrated both extraneuronal brown pigment deposition and system neurodegeneration as neuropathological features of PME with SCARB2 mutations.

DOI： 10.1111/nan.12057

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Only a few prospective studies have determined which clinical symptoms and factors are associated with the disease severity of spinocerebellar ataxia type 6 (SCA6). A multicenter longitudinal cohort study was conducted to clarify both the natural history of SCA6 in Japan and the factors influencing disease progression.Methods: Patients were consecutively recruited between 2007 and 2008. Scores from the Scale for the Assessment and Rating of Ataxia (SARA) and Barthel Index (BI) were collected prospectively each year. Additionally, data from the Japan intractable diseases research (IDR) registry were collected both retrospectively, from 2003 to 2006, and prospectively, from 2007 to 2010. As a result, we were able to collect 3 years of retrospective data and 4 years of prospective data during the course of 3 yearly visits.Results: Forty-six patients were registered. The follow-up rate of the third year was 93%. The SARA scores worsened significantly each year. Over 3 years, the decline of the SARA scores was 1.33 +/- 1.40 points/year. The results of multivariate analysis of the decline of the SARA score were not significant. The IDR scores correlated well with the SARA and BI scores. Kaplan-Meier curves of 7 years of data from the IDR registry illustrated the correlation between the ability to walk and the time course of the disease.Conclusions: Information regarding the progression of ataxia and the decline in the activities of daily living (ADL) in patients with SCA6 was obtained by a 3-year cohort study and a 7-year IDR study. The decline of the SARA score of patients with SCA6 was 1.33 +/- 1.40 points/year. The results elucidate the natural history of SCA6, factors influencing disease severity, and utility of data from the IDR registry of Japan.

DOI： 10.1186/s13023-014-0118-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMJ PUBLISHING GROUP  

Background The GGGGCC-repeat expansion in C9orf72 is the most frequent mutation found in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the studies on C9orf72 have relied on repeat-primed PCR (RP-PCR) methods for detection of the expansions. To investigate the inherent limitations of this technique, we compared methods and results of 14 laboratories.
Methods The 14 laboratories genotyped DNA from 78 individuals (diagnosed with ALS or FTD) in a blinded fashion. Eleven laboratories used a combination of amplicon-length analysis and RP-PCR, whereas three laboratories used RP-PCR alone; Southern blotting techniques were used as a reference.
Results Using PCR-based techniques, 5 of the 14 laboratories got results in full accordance with the Southern blotting results. Only 50 of the 78 DNA samples got the same genotype result in all 14 laboratories. There was a high degree of false positive and false negative results, and at least one sample could not be genotyped at all in 9 of the 14 laboratories. The mean sensitivity of a combination of amplicon-length analysis and RP-PCR was 95.0% (73.9-100%), and the mean specificity was 98.0% (87.5-100%). Overall, a sensitivity and specificity of more than 95% was observed in only seven laboratories.
Conclusions Because of the wide range seen in genotyping results, we recommend using a combination of amplicon-length analysis and RP-PCR as a minimum in a research setting. We propose that Southern blotting techniques should be the gold standard, and be made obligatory in a clinical diagnostic setting.

DOI： 10.1136/jmedgenet-2014-102360

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

To explore the molecular pathogenesis of amyotrophic lateral sclerosis (ALS), the nuclear function of TAR-DNA binding protein 43kDa (TDP-43) must be elucidated. TDP-43 is a nuclear protein that colocalizes with Cajal body or Gem in cultured cells. Several recent studies have reported that the decreasing number of Gems accompanied the depletion of the causative genes for ALS, TDP-43 and FUS. Gems play an important role in the pathogenesis of spinal muscular atrophy. Gems are the sites of the maturation of spliceosomes, which are composed of uridylate-rich (U) snRNAs (small nuclear RNAs) and protein complex, small nuclear ribonuclearprotein (snRNP). Spliceosomes regulate the splicing of pre-mRNA and are classified into the major or minor classes, according to the consensus sequence of acceptor and donor sites of pre-mRNA splicing. Although the major class of spliceosomes regulates most pre-mRNA splicing, minor spliceosomes also play an important role in regulating the splicing or global speed of pre-mRNA processing. A mouse model of spinal muscular atrophy, in which the number of Gems is decreased, shows fewer subsets U snRNAs. Interestingly, in the central nervous system, U snRNAs belonging to the minor spliceosomes are markedly reduced. In ALS, the U12 snRNA is decreased only in the tissue affected by ALS and not in other tissues. Although the molecular mechanisms underlying the decreased U12 snRNA resulting in cell dysfunction and cell death in motor neuron diseases remain unclear, these findings suggest that the disturbance of nuclear bodies and minor splicing may underlie the common molecular pathogenesis of motor neuron diseases.

DOI： 10.1111/neup.12070

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Language：English   Publishing type：Part of collection (book)   Publisher：Springer Berlin Heidelberg  

Modulation of intracellular calcium concentration is a ubiquitous signaling system involved in numerous biological processes in diverse cell types. Alterations of intracellular calcium homeostasis have been implicated in age-related neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and spinocerebellar ataxias (SCAs). Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), calcium release channels in the ER membrane, play a key role in regulating intracellular calcium concentration. IP3R type 1 (IP3R1), a major neuronal type of IR3R, is expressed ubiquitously and is involved in diverse biological processes. Cerebellar Purkinje cells are mainly affected by alterations in IP3R1. Heterozygous deletion or missense mutations in ITPR1, the IP3R1 gene, result in autosomal dominantly inherited ataxias, including SCA type 15 or 29. In addition, mutations in carbonic anhydrase-related protein VIII, which suppresses the binding ability of IP3to IP3R1, cause recessively, inherited ataxia. These results indicate that IP3R1-mediated calcium signaling has an important role in maintaining the function of Purkinje cells. Moreover, cytosolic calcium overload with excessive IP3R1 activity has been implicated in pathogenesis of other neurodegenerative diseases, including SCA type 2, SCA type 3, Huntington’s disease, and Alzheimer’s disease, where dysregulation of IP3R1-mediated calcium signaling may link to the pathogenesis.

DOI： 10.1007/978-3-642-40282-1_28

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objective:To clarify the genetic, clinicopathologic, and neuroimaging characteristics of patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) with the colony stimulating factor 1 receptor (CSF-1R) mutation.Methods:We performed molecular genetic analysis of CSF-1R in patients with HDLS. Detailed clinical and neuroimaging findings were retrospectively investigated. Five patients were examined neuropathologically.Results:We found 6 different CSF-1R mutations in 7 index patients from unrelated Japanese families. The CSF-1R mutations included 3 novel mutations and 1 known missense mutation at evolutionarily conserved amino acids, and 1 novel splice-site mutation. We identified a novel frameshift mutation. Reverse transcription PCR analysis revealed that the frameshift mutation causes nonsense-mediated mRNA decay by generating a premature stop codon, suggesting that haploinsufficiency of CSF-1R is sufficient to cause HDLS. Western blot analysis revealed that the expression level of CSF-1R in the brain from the patients was lower than from control subjects. The characteristic MRI findings were the involvement of the white matter and thinning of the corpus callosum with signal alteration, and sequential analysis revealed that the white matter lesions and cerebral atrophy relentlessly progressed with disease duration. Spotty calcifications in the white matter were frequently observed by CT. Neuropathologic analysis revealed that microglia in the brains of the patients demonstrated distinct morphology and distribution.Conclusions:These findings suggest that patients with HDLS, irrespective of mutation type in CSF-1R, show characteristic clinical and neuroimaging features, and that perturbation of CSF-1R signaling by haploinsufficiency may play a role in microglial dysfunction leading to the pathogenesis of HDLS.

DOI： 10.1212/WNL.0000000000000046

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Language：Japanese   Publishing type：Research paper (international conference proceedings)   Publisher：Societas Neurologica Japonica  

TDP-43 is a nuclear protein that plays a role in RNA metabolism, and its dysfunction has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a typical adult-onset motor neuron disease. We investigated RNA metabolism in relation to TDP-43 function in neuronal tissues affected by ALS, and found a decrease in the number of nuclear GEM bodies, as well as reduced expression of minor spliceosomes, which are functional RNA-protein complexes. Similar features have been reported in spinal muscular atrophy (SMA), a motor neuron disease affecting infants. These findings, together with those reported in SMA, strongly suggest that reduction of minor spliceosomes has an important role in the pathomechanism underlying the selective degeneration of motor neurons characteristic of both ALS and SMA.

DOI： 10.5692/clinicalneurol.54.1155

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Background: Patients who develop progressive supranuclear palsy with predominant cerebellar ataxia (PSP-C) develop cerebellar ataxia as the initial and principal symptom, may be misdiagnosed as having multiple system atrophy with predominant cerebellar features (MSA-C). Therefore, we investigated the clinical signs and symptoms between PSP-C and MSA-C early in their disease course.
Methods: We reviewed the medical records of 15 consecutive patients with pathologically proven PSP-C (4) and MSA-C (11). We recorded the presence or absence of clinical features that developed within 2 years of disease onset.
Results: The age at onset of PSP-C patients was older than that of MSA-C patients (p = 0.009). The frequencies of falls were higher in PSP-C patients than in MSA-C patients (p = 0.026). Additionally, the development of supranuclear vertical gaze palsy was higher in PSP-C patients than in MSA-C patients (p = 0.011), whereas the frequency of dysautonomia was lower in PSP-C patients than in MSA-C patients (p = 0.035).
Conclusions: Older onset, early falls, and supranuclear vertical gaze palsy without dysautonomia may predict the diagnosis of PSP-C in patients with late-onset sporadic cerebellar ataxia. (C) 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.parkreldis.2013.07.019

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder characterized by the degeneration of motor neurons and typically results in death within 3-5 years from onset. Familial ALS (PALS) comprises 5%-10% of ALS cases, and the identification of genes associated with FALS is indispensable to elucidating the molecular pathogenesis. We identified a Japanese family affected by late-onset, autosomal-dominant ALS in which mutations in genes known to be associated with FALS were excluded. A whole- genome sequencing and parametric linkage analysis under the assumption of an autosomal-dominant mode of inheritance with incomplete penetrance revealed the mutation c.2780G&gt;A (p. Arg927Gln) in ERBB4. An extensive mutational analysis revealed the same mutation in a Canadian individual with familial ALS and a de novo mutation, c.3823C&gt;T (p. Arg1275Trp), in a Japanese simplex case. These amino acid substitutions involve amino acids highly conserved among species, are predicted as probably damaging, and are located within a tyrosine kinase domain (p. Arg927Gln) or a C-terminal domain (p. Arg1275Trp), both of which mediate essential functions of ErbB4 as a receptor tyrosine kinase. Functional analysis revealed that these mutations led to a reduced autophosphorylation of ErbB4 upon neuregulin-1 (NRG-1) stimulation. Clinical presentations of the individuals with mutations were characterized by the involvement of both upper and lower motor neurons, a lack of obvious cognitive dysfunction, and relatively slow progression. This study indicates that disruption of the neuregulin-ErbB4 pathway is involved in the pathogenesis of ALS and potentially paves the way for the development of innovative therapeutic strategies such using NRGs or their agonists to upregulate ErbB4 functions.

DOI： 10.1016/j.ajhg.2013.09.008

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Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance mechanism that eliminates aberrant mRNAs containing premature termination codons (PTCs). NMD inhibits the production of aberrant proteins that still retain, at least in part, wild-type function as well as dominant-negative peptides. Therefore, the selective inhibition of NMD has the potential to ameliorate NMD-exacerbated mutant phenotypes. However, we do not have sufficient knowledge of how to effectively suppress NMD with minimum cytotoxic effects. In this study, we aimed to identify NMD-related factors that can be targeted to efficiently inhibit NMD without causing significant cytotoxicity to restore the levels of truncated but partially functional proteins. We evaluated the knockdown of 15 NMD components in Ullrich congenital muscular dystrophy fibroblasts, which have a homozygous frameshift mutation causing a PTC in the collagen type VI a 2 gene. Of the 15 NMD factors tested, knockdown of SMG-8 produced the best effect for restoring defective mRNA and protein levels without affecting cell growth, cell-cycle progression, or endoplasmic reticulum stress. The efficacy of SMG-8 knockdown to improve the mutant phenotype was confirmed using another cell line, from a cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy patient who carries a PTC-containing mutation in HtrA serine peptidase 1. Our results suggest that SMG-8 is an appropriate target for inhibiting NMD to improve NMD-exacerbated mutant phenotypes. NMD inhibition by knockdown of SMG-8 may also be useful to induce synergy in combining the use of read-through drugs for patients with nonsense mutation-associated diseases.