皮質下梗塞と白質脳症を伴う常染色体優性脳動脈症

Despite decades of progress in its management, ischemic stroke remains a leading cause of death and disability worldwide, with incidence rising in younger populations. Although traditional stroke risk assessment focuses on macrovascular pathology, the cerebral microcirculation plays an important but less-recognized role. This review synthesizes evidence on microvascular involvement in the pathogenesis of ischemic stroke and evaluates existing and emerging methods for microvascular assessment of ischemic stroke risk (MvASR). Epidemiological studies show that cerebral small vessel disease as measured by MRI biomarkers significantly increase stroke risk, with risk rising alongside lesion progression. Microemboli animal models reveal that even asymptomatic microemboli can disrupt the blood-brain barrier and trigger inflammatory changes that may predispose to stroke. Postischemia models demonstrate that no-reflow and prolonged microvascular inflammation compromise patency, potentially increasing recurrent stroke risk. Current MvASR modalities can be classified into direct imaging (cerebral angiography, retinal photography), indirect imaging (MRI, transcranial Doppler), and nonimaging approaches (e.g., genetic testing for CADASIL). Although more studies demonstrating clinical utility are needed, the accumulating pathophysiological and epidemiological evidence suggests that MvASR will become increasingly relevant to stroke prediction and prevention.

BACKGROUND: Calcitonin gene-related peptide (CGRP) pathway inhibitors are highly effective migraine preventives, but their long-term cerebrovascular and cardiovascular safety in patients with prior ischaemic events remains uncertain, as such individuals were largely excluded from clinical trials. METHODS: We analysed data from a prospective real-world registry of migraine patients treated with CGRP pathway inhibitors at our tertiary Headache Centre. Patients with a history of ischaemic stroke, transient cerebral ischaemic attack, or ischaemic heart disease were included. Clinical characteristics, treatment response, and vascular outcomes were assessed during follow-up. RESULTS: Among 420 consecutive migraine patients treated with CGRP pathway inhibitors in our registry, 17 (4%) had a history of cerebrovascular and/or cardiovascular disease and met the inclusion criteria. These patients (median age 54.5 years, 76% female; 82% chronic migraine) contributed a total of 31 patient-years of exposure, with follow-up up to 5 years. Median time from event to treatment initiation was 5.0 years (IQR 4.5). 13 patients (76%) achieved ≥ 50% reduction in monthly migraine days (10/14 in chronic migraine; 3/3 in episodic migraine). No recurrent cerebrovascular events or worsening of underlying cardiac disease were observed during treatment. Serial neuroimaging, available in a subset, showed no new ischaemic lesions. CONCLUSIONS: In this small real-world cohort patients with prior cerebrovascular and/or cardiovascular disease, the use of CGRP pathway inhibitors was not associated with new clinical or radiological ischaemic events over 31 patient‑years of follow‑up. These safety findings are reassuring but only exploratory and hypothesis-generating requiring further confirmation.

PURPOSE OF REVIEW: Arterial spin labeling (ASL) MRI noninvasively quantifies cerebral blood flow (CBF), but its role as a mechanistic biomarker and surrogate endpoint in trials of cognitive impairment remains undefined. This review evaluates evidence linking regional CBF to cognition across Alzheimer's disease, mild cognitive impairment (MCI), and cerebral small vessel disease (SVD), with particular emphasis on CADASIL as a mechanistically informative model. RECENT FINDINGS: Multipostlabeling-delay ASL, spatial coefficient of variation metrics, and harmonized processing pipelines have improved reproducibility. Cross-sectional and longitudinal studies consistently link reduced CBF to cognitive impairment, with baseline CBF predicting cognitive decline, MCI-to-Alzheimer's disease conversion, white matter hyperintensity progression, and vascular events. In CADASIL, CBF is independently associated with cognitive performance and predicts subcortical hyperintensity progression over 2 years. Interventional data from SPRINT MIND, PRESERVE, and pilot lecanemab studies indicate that ASL-CBF is responsive to therapy. SUMMARY: Within the FDA-NIH BEST framework, ASL-CBF appears to meet several criteria consistent with a reasonably likely surrogate endpoint, capturing upstream, potentially reversible hemodynamic dysfunction beyond established structural markers. CADASIL provides an optimal context for qualifications. Larger clinical trials linking treatment-induced CBF changes to clinical benefit, further protocol harmonization, and regulatory engagement are needed to translate ASL-CBF into a validated trial endpoint.

BACKGROUND AND OBJECTIVES: Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL), caused by pathogenic NOTCH3 variants, can be misdiagnosed as multiple sclerosis (MS) due to overlapping clinical and radiologic features. Although initially described in European cohorts, prevalence of pathogenic NOTCH3 variants may be higher among Asian populations. Misdiagnosis may delay appropriate management and expose patients to ineffective and potentially harmful therapies. This study aimed to estimate the proportion of CADASIL patients with prior MS misdiagnosis presenting to a multicenter tertiary-care cohort and to identify associated clinical and genetic features and consequences of this diagnostic error. METHODS: We conducted a retrospective cohort study to compare genetically or histopathologically confirmed CADASIL patients with and without a prior MS misdiagnosis. Patients were classified into high-risk, medium-risk, low-risk, or unknown-risk by the location of their NOTCH3 variant in the epidermal growth factor-like repeat (EGFr) domain. Prespecified logistic regression models were used to evaluate factors independently associated with MS misdiagnosis, adjusting for age, sex, race, and prior stroke history. RESULTS: Of 107 CADASIL patients (mean age 57.5 ± 13.4 years), 11 (10.2%) were misdiagnosed with MS. In prespecified adjusted logistic regression models, absence of prior stroke (adjusted odds ratio [OR] 4.60; 95% CI 1.02-20.68), Asian race (adjusted OR 20.74; 95% CI 3.21-134.18), asymmetric external capsule white matter hyperintensity (WMH) (adjusted OR 53.34; 95% CI 4.06-701.08), and absence of infratentorial WMH (adjusted OR 12.48; 95% CI 1.90-82.01) were independently associated with misdiagnosis. The median time to diagnostic correction was 14.45 months (range 1.18-138.07), during which 5 patients (45.5%) received unnecessary MS therapies and 2 experienced documented adverse events. Medium-risk EGFr variants were more frequent among misdiagnosed patients in unadjusted comparisons but were not independently associated after adjustment. DISCUSSION: In this multicenter tertiary-care cohort, approximately 1 in 10 patients with CADASIL had been misdiagnosed as MS, an error associated with Asian race, absence of a stroke history, and atypical neuroimaging patterns leading to worse functional outcomes and inappropriate treatments. A high index of suspicion for CADASIL is critical in patients presenting with atypical or late-onset demyelinating disease. Larger studies are needed to understand the role of medium-risk variants in misdiagnosis.

Missense mutations in NOTCH3, especially cysteine-altering pathogenic variants, are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. The NOTCH3 p.Arg1231Cys variant, located in EGFr domain 31, is classified as low-risk under the three-tiered EGFr domain risk stratification system. We report two cases of p.Arg1231Cys heterozygosity presenting with early-onset dementia, strokes, and extensive leukoencephalopathy. These cases highlight the potential contributing factors to increasing penetrance of p.Arg1231Cys variant, and the need for functional evaluation to improve the clinical utility of genetic testing in hereditary small vessel disease.