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BACKGROUND AND OBJECTIVES: HTRA1-related cerebral small vessel disease (HRSVD) is a rare hereditary form of cerebral small vessel disease (CSVD) caused by HTRA1 pathogenic variants. Diagnosing HRSVD without genetic testing is challenging because of the lack of distinctive imaging features and clinical symptoms, and even family history can be unclear in some cases with HRSVD. This study investigates whether susceptibility-weighted imaging (SWI) can identify useful diagnostic findings for HRSVD. METHODS: This retrospective study included 8 patients with HRSVD, 12 with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and 14 with sporadic CSVD (sCSVD). Two neurologists blinded to clinical data counted the number of hypointense dots around the midbrain on SWI. Receiver operating characteristic curve analysis evaluated the optimal threshold of the number that can distinguish HRSVD and CADASIL or sCSVD. In addition, histopathologic analysis including measurement of leptomeningeal vessel diameter and type III collagen deposition was performed on autopsied brains from 3 cases each of HRSVD, CADASIL, and sCSVD and control participants. RESULTS: Patients with HRSVD exhibited a significantly higher number of hypointense dots around the midbrain on SWI compared with CADASIL and sCSVD groups. A threshold of 5 or more dots, termed the "Chocolate Chip Sign," well distinguished HRSVD from CADASIL and sCSVD (area under the curve: 0.817, 95% confidence interval: 0.624-1.00). Three-dimensional SWI reconstruction and 7T MRI confirmed these dots as dilated extraparenchymal vessels. Histopathologic analysis revealed pronounced dilation of leptomeningeal veins with type III collagen accumulation specifically, in HRSVD brains. DISCUSSION: The Chocolate Chip Sign on SWI represents a novel and promising neuroimaging biomarker for HRSVD. This finding holds significant potential for facilitating early diagnosis, prompting timely genetic testing, and appropriate family screening for this rare genetic disorder.

DOI： 10.1212/NXG.0000000000200237

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Age-related microangiopathy, also known as small vessel disease (SVD), causes damage to the brain, retina, liver, and kidney. Based on the DNA damage theory of aging, we reasoned that genomic instability may underlie an SVD caused by dominant C-terminal variants in TREX1, the most abundant 3'-5' DNA exonuclease in mammals. C-terminal TREX1 variants cause an adult-onset SVD known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S). In RVCL, an aberrant, C-terminally truncated TREX1 mislocalizes to the nucleus due to deletion of its ER-anchoring domain. Since RVCL pathology mimics that of radiation injury, we reasoned that nuclear TREX1 would cause DNA damage. Here, we show that RVCL-associated TREX1 variants trigger DNA damage in humans, mice, and Drosophila, and that cells expressing RVCL mutant TREX1 are more vulnerable to DNA damage induced by chemotherapy and cytokines that up-regulate TREX1, leading to depletion of TREX1-high cells in RVCL mice. RVCL-associated TREX1 mutants inhibit homology-directed repair (HDR), causing DNA deletions and vulnerablility to PARP inhibitors. In women with RVCL, we observe early-onset breast cancer, similar to patients with BRCA1/2 variants. Our results provide a mechanistic basis linking aberrant TREX1 activity to the DNA damage theory of aging, premature senescence, and microvascular disease.

DOI： 10.1038/s41467-024-49066-7

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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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DOI： 10.1002/acn3.51817

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White matter hyperintensities (WMHs) on brain magnetic resonance (MR) images are characteristic of hereditary cerebral small vessel disease (CSVD), including high-temperature requirement serine peptidase A1 (HTRA1)-related CSVD. Although HTRA1-related CSVD is increasingly recognized, the diagnosis is still challenging. We encountered two patients with HTRA1-related CSVD who were misdiagnosed with other diseases, including multiple sclerosis and idiopathic normal-pressure hydrocephalus. Both patients had extended WMHs in addition to multiple lacunes and microbleeds on brain MR images, which are characteristic of CSVD. If lacunes or microbleeds are found in patients with severe WMHs, genetic tests for hereditary CSVD should be considered.

DOI： 10.1016/j.clineuro.2022.107502

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