皮質下梗塞と白質脳症を伴う常染色体優性脳動脈症

PURPOSE: To develop and validate an explainable deep learning-guided workflow to localize and quantify focal retinal luminal pathology on fundus fluorescein angiography (FFA) in NOTCH3 variant knock-in mouse models of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. DESIGN: Cross-sectional experimental imaging and computational analysis. SUBJECTS: Thirty-two mice (wild-type [WT] n = 12; NOTCH3C455R [C455R] n = 12; NOTCH3R1031C [R1031C] n = 8) yielding 1670 analyzable FFA images. METHODS INTERVENTION OR TESTING: Two ImageNet-pretrained VGG16 classifiers (WT vs. each mutant line) were trained with subject-grouped splitting. Grad-CAM++ and occlusion sensitivity maps defined class-discriminative regions of interest (ROIs). A centerline-based morphometry pipeline sampled luminal diameter along ordered vessel centerlines to compute mean and maximum diameter, diameter coefficient of variation, and tortuosity. A fast Fourier transform-derived vessel beading index (VBI) quantified periodic diameter oscillations using normalized, band-limited spectral power. Metrics were computed for large-vessel and small-vessel masks in both whole-field and ROI-restricted domains. Additional robustness analyses assessed hold-out testing, out-of-sample saliency, ROI-threshold sensitivity, alternative VBI spatial-period bands, and repeated balanced retraining. MAIN OUTCOME MEASURES: Primary biological outcomes were large-vessel mean diameter, maximum diameter, and VBI in whole-field and ROI-restricted analyses; classifier discrimination (area under the curve) was reported as supportive performance of the localization framework. RESULTS: Whole-field morphometry detected generalized large-vessel dilation in both mutants versus WT (mean diameter: WT 27.82 μm; C455R 30.94 μm; R1031C 32.03 μm; P ≤ 0.001) with reduced tortuosity (P < 0.001), whereas whole-field maximum diameter and VBI increased only directionally. ROI-restricted analysis amplified focal pathology: within Grad-CAM++ ROIs, large-vessel maximum diameter increased (WT 37.62 μm; C455R 48.46 μm; R1031C 45.66 μm; P < 0.001) and VBI increased (WT 1.75; C455R 3.04; R1031C 2.93; P ≤ 0.001). Occlusion ROIs showed concordant VBI increases (WT 2.11; C455R 3.84; R1031C 4.90; P < 0.001). Small-vessel ROI differences were minimal. The principal large-vessel ROI-restricted phenotype remained directionally stable across robustness analyses, and hold-out testing confirmed high classifier discrimination in both genotype comparisons. CONCLUSIONS: Explainable deep learning-guided localization on FFA identifies disease-informative vessel segments and enables sensitive quantification of focal luminal dilation and periodic beading that are diluted by whole-field averages. This framework may support development of retinal biomarkers and longitudinal monitoring in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The extent to which the cerebrovasculature is affected in various brain disorders is still not well understood. To address this, we established a transcriptomic repository of major vascular cell types and microglia to compare the global transcriptomic response in mouse models of three human brain disorders linked to neuroinflammation and associated vascular reactivity: Alzheimer's disease (AD), traumatic brain injury (TBI), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Single-cell analysis of >250,000 cells at different disease stages led to identification of two previously unknown vascular cell subtypes, expanded the endothelial zonation spectrum and allowed for a detailed analysis of the cellular and molecular responses. Surprisingly, most vascular cell types lacked major transcriptomic changes across the three conditions, while microglia exhibited significant, disease-specific transcriptional changes. Notably, microglial responses converged between late-stage TBI and AD, offering insights into the predisposition for neurodegeneration following TBI.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease caused by mutations in NOTCH3 and characterized by progressive neurovascular alterations. Although magnetic resonance imaging (MRI) can detect vascular and white matter abnormalities in CADASIL, the relationship between imaging findings and underlying cellular and molecular changes remains incompletely understood. Here, we established an integrative, multi-scale framework combining ultra-high-field MRI, quantitative histology, and single-cell RNA sequencing to characterize age-dependent neurovascular phenotypes in a Notch3R170C CADASIL mouse model. We found that cerebral blood flow declined with age, with more pronounced reductions in R170C mice at later stages, whereas oxygen saturation showed relatively mild changes and vascular fraction remained stable. Regional analyses further revealed region-specific perfusion changes across brain regions. Histological analyses showed age-dependent changes in vascular and glial markers, together with mild corpus callosum vacuolation at 16 months, whereas neuronal and oligodendrocyte-associated alterations were comparatively limited. Single-cell transcriptomic analysis revealed subtle but coordinated cell type-specific transcriptional profiles, particularly in vascular and glial populations. Together, this study provides an integrated and age-resolved characterization of neurovascular phenotypes in a Notch3R170C CADASIL mouse model, linking in vivo resting cerebral perfusion imaging with histological and molecular alterations. These findings highlight the value of multimodal approaches for characterizing experimental CADASIL.

Alzheimer's disease (AD) and cerebrovascular pathology are the two most common causes of dementia, frequently co-occurring in older people. Community-based neuropathology studies indicate that vascular disease accounts for approximately one third of the population attributable risk of dementia, controlling for other pathologies (including AD). The proportion with vascular disease as co-pathology is likely to be higher (50-70%).The most common vascular substrate is cerebral small vessel disease, which includes small artery fibrosis (arteriolosclerosis), vascular amyloid deposits (cerebral amyloid angiopathy) and monogenic forms of small vessel disease, the commonest being Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Post-stroke cognitive impairment following both ischaemic stroke and intracerebral haemorrhage also contribute. In this World Stroke Organisation (WSO) scientific statement we assembled a multi-disciplinary international group of experts to review the vascular contribution to dementia, encompassing both vascular and neurodegenerative dementia. This statement has been reviewed and approved by the WSO executive.We summarize the epidemiology, neuropathology, cognitive profile, clinical impact and management of vascular disease in dementia, and discuss the recent VasCog-2-WSO diagnostic criteria. We consider the substantial overlap with clinical stroke and with AD dementia. We catalogue transcriptomic and proteomic studies that have revealed novel candidate molecules (COL4A1/4A2, HTRA1, TRIM47, FOXF2) as possible treatment targets. We appraise imaging-based biomarkers relevant to vascular disease, and potential biochemical markers (VEGF-A, PLGF, IL-6, MMP9, CTSB). We highlight the potential for vascular interventions to treat not only vascular dementia, but also the vascular component of neurodegenerative dementia. We review recent clinical trials targeting multiple pathways, including nitric oxide signalling, high blood pressure, the GABAergic system, angiogenic activity, microglial inhibition, PDE3 and PDE5 inhibition, as well as dietary supplementation with omega-3-fatty acid, s-equol and vitamin E. Finally, we consider upcoming opportunities and challenges relevant to vascular disease in dementia.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by NOTCH3 variants, and is the leading hereditary cerebral small-vessel disease (SVD). Temporopolar white-matter hyperintensities (WMH) are characteristic imaging features of CADASIL, but their diagnostic accuracy across different NOTCH3 variants and their relationship with the disease severity remain uncertain. METHODS: We analyzed 385 CADASIL patients and 191 sporadic SVD patients in whom no pathogenic mutations were identified in the next-generation sequencing of 183 genes. CADASIL patients were stratified into high-, medium-, and low-risk epidermal growth factor-like repeat (HR-, MR-, and LR-EGFr) categories according to the variant locations. The severity of temporopolar WMH was scored using Scheltens' scale, and disability was assessed using the modified Rankin Scale (mRS). Logistic and ordinal regression models were used to evaluate the associations between temporopolar WMH, clinical severity, and neuroimaging markers. RESULTS: Temporopolar WMH were detected in 94.7%, 54.4%, and 33.3% of CADASIL patients carrying HR-, MR-, and LR-EGFr variants, respectively, compared with in 31.9% of the sporadic SVD patients. The sensitivity for distinguishing HR-EGFr carriers from sporadic SVD was high (95%), but lower for MR-EGFr (54%) and LR-EGFr (33%) carriers. In the CADASIL patients, temporopolar WMH independently predicted greater disability (mRS score >3), and they were correlated in a dose-dependent manner with the total WMH volume, Fazekas scores, and number of lacunes. Similar associations were observed in sporadic SVD. CONCLUSIONS: The diagnostic accuracy of temporopolar WMH varies with the NOTCH3 risk category and warrants cautious interpretations, particularly in Asian populations in whom MR-EGFr founder variants are prevalent. The temporopolar WMH severity is associated with the functional status and radiological burden across hereditary and sporadic SVD.