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Background and Objectives: NOTCH3 pathologic variants cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which presents with stroke and dementia and is characterized by white matter hyperintensities (WMHs) on brain MRI. The R544C variant is a common pathologic variant in Taiwan, but not all carriers exhibit significant symptoms. We investigated whether WMHs occur before clinical symptoms in carriers with pathogenic variants, examined factors associated with WMHs, and explored their relationship with cognitive functions., Methods: We enrolled 63 R544C carriers without overt clinical disease (WOCD) and 37 age-matched and sex-matched noncarriers as controls from the Taiwan Precision Medicine Initiative data set. All participants underwent clinical interviews, comprehensive neuropsychological assessments, and brain MRI. We calculated total and regional WMH volumes, determined the age at which WMHs began increasing in carriers, and examined the relationship between WMHs and neuropsychological performance. Factors associated with WMH volumes were analyzed using multivariable linear regression models., Results: Compared with controls, R544C carriers WOCD had increased WMH volume, except in the occipital and midbrain areas, and showed a rapid increase in WMHs starting at age 48. They scored lower on the Mini-Mental State Examination (median = 28.4 vs 29.0, p = 0.048), Montreal Cognitive Assessment (MoCA) (median = 28.3 vs 29.0, p = 0.013), and memory and executive function tests than controls. After adjusting for age, sex, and education, MoCA scores were associated with whole-brain (r = -0.387, p adj = 0.008) and regional WMHs (all p adj < 0.05) except in the midbrain area. Age (β = 0.034, 95% CI 0.021-0.046, p < 0.001), hypercholesterolemia (β = 0.375, 95% CI 0.097-0.653, p = 0.009), and the vascular risk factor (VRF) index (β = 0.132, 95% CI 0.032-0.242, p = 0.019) were associated with the WMH severity in carriers., Discussion: Our study revealed that WMHs are extensively distributed in R544C carriers WOCD. They exhibited a rapid increase in WMHs beginning at age 48, approximately 7 years earlier than the reported age at symptomatic onset. Age was the strongest predictive factor of WMHs, and VRF, particularly hypercholesterolemia, might be modifying factors of WMHs.

Background and Objectives: Pathogenic variants in NOTCH3 are the main cause of hereditary cerebral small vessel disease (SVD). SVD-associated NOTCH3 variants have recently been categorized into high risk (HR), moderate risk (MR), or low risk (LR) for developing early-onset severe SVD. The most severe NOTCH3-associated SVD phenotype is also known as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to investigate whether NOTCH3 variant risk category is associated with 2-year progression rate of SVD clinical and neuroimaging outcomes in CADASIL., Methods: A single-center prospective 2-year follow-up study was performed of patients with CADASIL. Clinical outcomes were incident stroke, disability (modified Rankin Scale), and executive function (Trail Making Test B given A t -scores). Neuroimaging outcomes were mean skeletonized mean diffusivity (MSMD), normalized white matter hyperintensity volume (nWMHv), normalized lacune volume (nLV), and brain parenchymal fraction (BPF). Cox regression and mixed-effect models, adjusted for age, sex, and cardiovascular risk factors, were used to study 2-year changes in outcomes and differences in disease progression between patients with HR- NOTCH3 and MR- NOTCH3 variants., Results: One hundred sixty-two patients with HR (n = 90), MR (n = 67), and LR (n = 5) NOTCH3 variants were included. For the entire cohort, there was 2-year mean progression for MSMD (β = 0.20, 95% CI 0.17-0.23, p = 7.0 × 10 -24 ), nLV (β = 0.13, 95% CI 0.080-0.19, p = 2.1 × 10 -6 ), nWMHv (β = 0.092, 95% CI 0.075-0.11, p = 8.8 × 10 -20 ), and BPF (β = -0.22, 95% CI -0.26 to -0.19, p = 3.2 × 10 -22 ), as well as an increase in disability ( p = 0.002) and decline of executive function (β = -0.15, 95% CI -0.30 to -3.4 × 10 -5 , p = 0.05). The HR-NOTCH3 group had a higher probability of 2-year incident stroke (hazard ratio 4.3, 95% CI 1.4-13.5, p = 0.011), and a higher increase in MSMD (β = 0.074, 95% CI 0.013-0.14, p = 0.017) and nLV (β = 0.14, 95% CI 0.034-0.24, p = 0.0089) than the MR-NOTCH3 group. Subgroup analyses showed significant 2-year progression of MSMD in young (n = 17, β = 0.014, 95% CI 0.0093-0.019, p = 1.4 × 10 -5 ) and premanifest (n = 24, β = 0.012, 95% CI 0.0082-0.016, p = 1.1 × 10 -6 ) individuals., Discussion: In a trial-sensitive time span of 2 years, we found that patients with HR- NOTCH3 variants have a significantly faster progression of major clinical and neuroimaging outcomes, compared with patients with MR- NOTCH3 variants. This has important implications for clinical trial design and disease prediction and monitoring in the clinic. Moreover, we show that MSMD is a promising outcome measure for trials enrolling premanifest individuals.

Competing Interests: Disclosures None.

Background: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic small-vessel disease that is characterized by a wide range of neurologic and neuropsychological impairments. Constructional impairments have been reported in some cases but have never been assessed systematically., Objective: To evaluate constructional abilities and their cognitive and neural correlates in nondemented individuals with CADASIL., Method: Thirty individuals with CADASIL who were not affected by clinically relevant cognitive deterioration and 30 healthy controls (HC) underwent an extensive cognitive assessment and paper-and-pencil visuoconstructional tasks in order to detect constructional impairments. Performance on the visuoconstructional tasks was correlated with the cognitive assessment scores and with quantitative indices of regional gray matter atrophy (obtained via FreeSurfer image analysis) and white matter involvement., Results: The individuals with CADASIL achieved significantly lower scores on the cognitive assessment compared with the HC. Poor visuoconstructional abilities were observed in seven (23.3%) of the individuals with CADASIL when performing the copy drawing task and in nine (30%) when performing the Rey Complex Figure Test. Logistic regression revealed that visuoconstructional impairments were significantly associated with scores on the Frontal Assessment Battery and the Attentional Matrices Test. Morphometric results revealed that scores on the visuoconstructional tasks were related to gray matter atrophy of the left frontal lobe and right parietal lobe., Conclusion: Impairments on visuoconstructional tasks are quite common in individuals with CADASIL, even in the lack of clinically relevant cognitive deterioration, and are critically related to frontal and parietal atrophy., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: A retrospective study has shown that EGFr (epidermal growth factor-like repeat) group in the NOTCH3 gene is an important cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) disease modifier of age at first stroke and white matter hyperintensity (WMH) volume. No study has yet assessed the effect of other known CADASIL modifiers, that is, cardiovascular risk factors and sex, in the context of NOTCH3 EGFr group. In this study, we determined the relative disease-modifying effects of NOTCH3 EGFr group, sex and cardiovascular risk factor on disease severity in the first genotype-driven, large prospective CADASIL cohort study, using a comprehensive battery of CADASIL clinical outcomes and neuroimaging markers., Methods: Patients with CADASIL participated in a single-center, prospective cohort study (DiViNAS [Disease Variability in NOTCH3 Associated Small Vessel Disease]) between 2017 and 2020. The study protocol included a clinical assessment, neuropsychological test battery and brain magnetic resonance imaging on a single research day. Multivariable linear, logistic and Cox regression models were used to cross-sectionally assess the effect of CADASIL modifiers on clinical severity (stroke, disability, processing speed) and neuroimaging markers (WMH volume, peak width of skeletonized mean diffusivity, lacune volume, brain volume, cerebral microbleed count)., Results: Two hundred patients with CADASIL participated, of which 103 harbored a NOTCH3 EGFr 1-6 variant and 97 an EGFr 7-34 variant. NOTCH3 EGFr 1-6 group was the most important modifier of age at first stroke (hazard ratio, 2.45 [95% CI, 1.39-4.31]; P =0.002), lacune volume (odds ratio, 4.31 [95% CI, 2.31-8.04]; P =4.0×10 -6 ), WMH volume (B=0.81 [95% CI, 0.60-1.02]; P =1.1×10 -12 ), and peak width of skeletonized mean diffusivity (B=0.65 [95% CI, 0.44-0.87]; P =1.6×10 -8 ). EGFr 1-6 patients had a significantly higher WMH volume in the anterior temporal lobes and superior frontal gyri and a higher burden of enlarged perivascular spaces. After NOTCH3 EGFr group, male sex and hypertension were the next most important modifiers of clinical outcomes and neuroimaging markers., Conclusions: NOTCH3 EGFr group is the most important CADASIL disease modifier not only for age at first stroke and WMH volume but also strikingly so for a whole battery of clinically relevant disease measures such as lacune volume and peak width of skeletonized mean diffusivity. NOTCH3 EGFr group is followed in importance by sex, hypertension, diabetes, and smoking.

Background and Objectives: The course and pattern of cognitive decline in ischemic cerebral small vessel disease remain poorly characterized. We analyzed the trajectory pattern of cognitive decline from age 25 to 75 years in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)., Methods: We applied latent process mixed models to data obtained from patients with CADASIL who were repeatedly scored during their follow-up using 16 selected clinical scales or cognitive tests., Results: The modeled evolutions of these scores obtained from 1,243 observations in 265 patients recruited at the French National Referral Centre (50.1 years on average and 45.3% men) showed wide and heterogeneous variations in amplitude along the age-related progression of the disease. Although the Backward Digit Span remained essentially stable, a linear deterioration of scores obtained using the Symbol Digit Numbers or Number of Errors of Trail Making Test B was detected from 25 to 75 years. By contrast, the largest score changes were observed at midlife using the Digit Cancellation Task. All other tests related to executive functions, memory performances, or global cognitive efficiency showed a rate of change accelerating especially at the advanced stage of the disease. Male gender and the presence of gait disorders or of some disability at baseline were found to predict earlier or large changes of 4 scores (Index of Sensitivity to Cueing, Delayed Total Recall, Initiation/Perseveration, and Barthel Index) in a subgroup of individuals distinct from the rest of the sample., Discussion: Cognitive alterations develop heterogeneously during the progression of CADASIL and vary largely according to the stage of the disease. These results suggest that not only the target population and study duration but also the stage of disease progression should be considered in preparing future clinical trials aimed at reducing cognitive decline in any such condition., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: This study investigated the cutaneous small fiber pathology of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and its clinical significance, that is, the NOTCH3 deposition in cutaneous vasculatures and CNS neurodegeneration focusing on cognitive impairment., Methods: Thirty-seven patients with CADASIL and 59 age-matched healthy controls were enrolled to evaluate cutaneous small fiber pathology by quantitative measures of intraepidermal nerve fiber density (IENFD), sweat gland innervation, and vascular innervation. Cognitive performance of patients with CADASIL was evaluated by a comprehensive neuropsychological assessment, and its association with small fiber pathology was tested using multivariable linear regression analysis adjusted for age and diabetes mellitus. We further assessed the relationships of IENFD with cutaneous vascular NOTCH3 ectodomain (NOTCH3ECD) deposition and biomarkers of neurodegeneration including structural brain MRI measures, serum neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin carboxy-terminal hydrolase L1., Results: Patients with CADASIL showed reduced IENFD (5.22 ± 2.42 vs 7.88 ± 2.89 fibers/mm, p = 0.0001) and reduced sweat gland ( p < 0.0001) and vascular ( p < 0.0001) innervations compared with age-matched controls. Reduced IENFD was associated with impaired global cognition measured by Mini-Mental State Examination ( B = 1.062, 95% CI = 0.370-1.753, p = 0.004), and this association remained after adjustment for age and diabetes mellitus ( p = 0.043). In addition, IENFD in patients with CADASIL was associated with mean cortical thickness (Pearson r = 0.565, p = 0.0023) but not white matter hyperintensity volume, total lacune count, or total microbleed count. Reduced IENFD was associated with cutaneous vascular NOTCH3ECD deposition amount among patients harboring pathogenic variants in exon 11 (mainly p.R544C) ( B = -0.092, 95% CI = -0.175 to -0.009, p = 0.031). Compared with those with normal cognition, patients with CADASIL with cognitive impairment had an elevated plasma NfL level regardless of concurrent small fiber denervation, whereas only patients with both cognitive impairment and small fiber denervation showed an elevated plasma GFAP level., Discussion: Cutaneous small fiber pathology correlates with cognitive impairment and CNS neurodegeneration in patients with CADASIL, indicating a peripheral neurodegenerative process related to NOTCH3ECD aggregation., (© 2022 American Academy of Neurology.)

Background and Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke and early-onset dementia. We determined the prevalence of vascular cognitive impairment (VCI) in a group of patients with CADASIL and investigated which factors were associated with VCI risk, including clinical, genetic, and MRI parameters., Methods: Cognition was assessed in patients with genetically confirmed CADASIL (n = 176) and healthy controls (n = 265) (mean [SD] age 50.95 [11.35] vs 52.37 [7.93] years) using the Brief Memory and Executive Test (BMET) and the Montreal Cognitive Assessment (MoCA). VCI was defined according to previously validated cutoffs. We determined the prevalence of VCI and its associations with clinical risk factors, mutation location (epidermal growth factor-like repeats [EGFr] 1-6 vs EGFr 7-34), and MRI markers of small vessel disease., Results: VCI was more common in patients with CADASIL than in controls; 39.8 vs 10.2% on the BMET and 47.7% vs 19.6% on the MOCA. Patients with CADASIL had worse performance across all cognitive domains. A history of stroke was associated with VCI on the BMET (OR 2.12, 95% CI [1.05, 4.27] p = 0.04) and MoCA (OR 2.55 [1.21, 5.41] p = 0.01), after controlling for age and sex. There was no association of VCI with mutation site. Lacune count was the only MRI parameter independently associated with VCI on the BMET (OR: 1.63, 95% CI [1.10, 2.41], p = 0.014), after controlling for other MRI parameters. These associations persisted after controlling for education in the sensitivity analyses., Discussion: VCI is present in almost half of the patients with CADASIL with a mean age of 50 years. Stroke and lacune count on MRI were both independent predictors of VCI on the BMET., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: Magnetic resonance susceptibility-weighted imaging (SWI) can identify small brain blood vessels that contain deoxygenated blood due to its induced magnetic field disturbance. We observed focal clusters of possible dilated small vessels on SWI in white matter in severe small vessel disease (SVD). We assessed their prevalence, associations with SVD lesions, and vascular reactivity in patients with sporadic SVD and in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)., Methods: Secondary cross-sectional analysis of a prospective multicenter observational study of patients with either sporadic SVD or CADASIL (INVESTIGATE-SVD) studied with 3 Tesla MRI including blood-oxygen-level-dependent MRI cerebrovascular reactivity (CVR). Two independent raters evaluated SWI sequences to identify "vessel-clusters" in white matter as focal low-signal dots/lines with small vessel appearance (interrater agreement, kappa statistic = 0.66). We assessed per-patient and per-cluster associations with SVD lesion type and severity on structural MRI sequences. We also assessed CVR within and at 2-voxel concentric intervals around the vessel-clusters using contralateral volumes as a reference., Results: Among the 77 patients enrolled, 76 had usable SWI sequences, 45 with sporadic SVD (mean age 64 years [SD 11], 26 men [58%]) and 31 with CADASIL (53 years [11], 15 men [48%]). We identified 94 vessel-clusters in 36 of the 76 patients (15/45 sporadic SVD, 21/31 CADASIL). In covariate-adjusted analysis, patients with vessel-clusters had more lacunes (OR, 95% CI) (1.30, 1.05-1.62), higher white matter hyperintensity (WMH) volume (per-log10 increase, 1.92, 1.04-3.56), and lower CVR in normal appearing white matter (per %/mm Hg, 0.77, 0.60-0.99), compared with patients without vessel-clusters. Fifty-seven of the 94 vessel-clusters (61%) corresponded to noncavitated or partially cavitated WMH on fluid-attenuated inversion recovery, and 37 of 94 (39%) to complete cavities. CVR magnitude was lower than in the corresponding contralateral volumes (mean difference [SD], t , p ) within vessel-cluster volumes (-0.00046 [0.00088], -3.021, 0.005) and in the surrounding volume expansion shells up to 4 voxels (-0.00011 [0.00031], -2.140, 0.039; -0.00010 [0.00027], -2.295, 0.028) in vessel-clusters with complete cavities, but not in vessel-clusters without complete cavitation., Discussion: Vessel-clusters might correspond to maximally dilated vessels in white matter that are approaching complete tissue injury and cavitation. The pathophysiologic significance of this new feature warrants further longitudinal investigation., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: To determine whether extremely mild small vessel disease (SVD) phenotypes can occur in NOTCH3 variant carriers from Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) pedigrees using clinical, genetic, neuroimaging, and skin biopsy findings., Methods: Individuals from CADASIL pedigrees fulfilling criteria for extremely mild NOTCH3 -associated SVD (mSVD NOTCH3 ) were selected from the cross-sectional Dutch CADASIL cohort (n=200), enrolled between 2017 and 2020. Brain magnetic resonance imaging were quantitatively assessed for SVD imaging markers. Immunohistochemistry and electron microscopy was used to quantitatively assess and compare NOTCH3 ectodomain (NOTCH3 ECD ) aggregation and granular osmiophilic material deposits in the skin vasculature of mSVD NOTCH3 cases and symptomatic CADASIL patients., Results: Seven cases were identified that fulfilled the mSVD NOTCH3 criteria, with a mean age of 56.6 years (range, 50-72). All of these individuals harbored a NOTCH3 variant located in one of EGFr domains 7-34 and had a normal brain magnetic resonance imaging, except the oldest individual, aged 72, who had beginning confluence of WMH (Fazekas score 2) and 1 cerebral microbleed. mSVD NOTCH3 cases had very low levels of NOTCH3 ECD aggregation in skin vasculature, which was significantly less than in symptomatic EGFr 7-34 CADASIL patients ( P =0.01). Six mSVD NOTCH3 cases had absence of granular osmiophilic material deposits., Conclusions: Our findings demonstrate that extremely mild SVD phenotypes can occur in individuals from CADASIL pedigrees harboring NOTCH3 EGFr 7-34 variants with normal brain magnetic resonance imaging up to age 58 years. Our study has important implications for CADASIL diagnosis, disease prediction, and the counseling of individuals from EGFr 7-34 CADASIL pedigrees.

Rationale: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of familial cerebral small vessel disease in adults, and is caused by NOTCH3 mutations. However, individual symptom types, onset, and disease severity span a wide range., Patient Concerns: Herein, we report a case of chronic neurological symptoms including slurring of speech, recurrent weakness in both limbs and legs, and progressive memory loss. Cranial magnetic resonance imaging revealed recurrent acute lacunar subcortical infarction and extensive white matter hyperintensities. Skin biopsy revealed granular osmiophilic materials close to the cell surface of smooth muscle cells in an arteriolar vessel. The patient's genomic DNA showed a mutation c.635G>C[p.(Cys212Ser)] in exon 4., Diagnosis: The patient was finally diagnosed with CADASIL., Interventions: The patient was treated with antiplatelet therapy and extremity rehabilitation., Outcomes: There was no improvement in speech, extremity function, or memory., Lessons: Accurate early diagnosis and appropriate treatment are crucial to improve the prognosis of patients with CADASIL., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial arteriopathy characterized by recurrent lacunar stroke, migraine, and depression. The mechanism of cognitive dysfunction in CADASIL is still uncertain. The aim of this study was to use tract-based spatial statistics (TBSS) to map voxelwise the spatial distribution of brain microstructural change revealed by DTI-derived indices in patients with CADASIL to further study the underlying neuropsychopathological mechanism of CADASIL., Method: Twelve patients with CADASIL and 11 age-, sex-matched healthy controls underwent magnetic resonance imaging at 3 T. Then we evaluated DTI-derived indices (fractional anisotropy [FA], mode of anisotropy [MO], mean diffusivity [MD], axial diffusivity [AD] and radial diffusivity [RD]) of brain white matter (WM) between CADASIL patients and healthy subjects through TBSS., Results: Compared with healthy controls, patients with CADASIL showed extensive decreased FA, MO and increased RD, AD, and MD throughout the entire brain (mainly the WM of the temporal poles, inferior and superior longitudinal fasciculus, inferior fronto-occipital fasciculus, corpus callosum, uncinate fasciculus, internal capsule, external capsule, corona radiata, thalamic radiation, and cingulum). Furthermore, these WM microstructural alterations were significantly correlated with cognitive scores and Scheltens scores. Decreased FA values and MO values were positively correlated with Montreal Cognitive Assessment scores in CADASIL patients. Increased AD, RD, and MD values were significantly negatively correlated with Montreal Cognitive Assessment scores., Conclusions: Widespread WM abnormalities were clearly shown in CADASIL by using TBSS. Severity of microstructural changes correlates significantly with extension of T2 hyperintensity. Moreover, WM microstructural damage and cognitive impairment were significantly correlated. This study indicated that WM tract damage plays an important role in cognitive impairment in CADASIL., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To test the hypothesis that multi-shell diffusion models improve the characterization of microstructural alterations in cerebral small vessel disease (SVD), we assessed associations with processing speed performance, longitudinal change, and reproducibility of diffusion metrics., Methods: We included 50 patients with sporadic and 59 patients with genetically defined SVD (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) with cognitive testing and standardized 3T MRI, including multi-shell diffusion imaging. We applied the simple diffusion tensor imaging (DTI) model and 2 advanced models: diffusion kurtosis imaging (DKI) and neurite orientation dispersion and density imaging (NODDI). Linear regression and multivariable random forest regression (including conventional SVD markers) were used to determine associations between diffusion metrics and processing speed performance. The detection of short-term disease progression was assessed by linear mixed models in 49 patients with sporadic SVD with longitudinal high-frequency imaging (in total 459 MRIs). Intersite reproducibility was determined in 10 patients with CADASIL scanned back-to-back on 2 different 3T MRI scanners., Results: Metrics from DKI showed the strongest associations with processing speed performance ( R 2 up to 21%) and the largest added benefit on top of conventional SVD imaging markers in patients with sporadic SVD and patients with CADASIL with lower SVD burden. Several metrics from DTI and DKI performed similarly in detecting disease progression. Reproducibility was excellent (intraclass correlation coefficient >0.93) for DTI and DKI metrics. NODDI metrics were less reproducible., Conclusion: Multi-shell diffusion imaging and DKI improve the detection and characterization of cognitively relevant microstructural white matter alterations in SVD. Excellent reproducibility of diffusion metrics endorses their use as SVD markers in research and clinical care. Our publicly available intersite dataset facilitates future studies., Classification of Evidence: This study provides Class I evidence that in patients with SVD, diffusion MRI metrics are associated with processing speed performance., (© 2020 American Academy of Neurology.)

Objective: To assess the relationship among iron accumulation, blood-brain barrier (BBB) damage, and cognitive function in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)., Methods: We enrolled 21 patients with NOTCH3 mutations and 21 age-matched healthy controls in this cross-sectional study. All participants underwent global physical and cognitive assessments and brain MRI using voxel-based quantitative susceptibility mapping (QSM; iron deposition measure) and dynamic contrast-enhanced MRI (BBB permeability measure). We compared behavioral and imaging data between the groups and analyzed the correlations in each group., Results: Among 21 NOTCH3 mutation carriers, 10 were symptomatic and 11 asymptomatic. Montreal Cognitive Assessment scores were significantly different among the groups (symptomatic < asymptomatic < control participants). Voxel-based QSM analysis revealed that the symptomatic group had higher QSM values than did the asymptomatic group in the putamen, caudate nucleus, temporal pole, and centrum semiovale. These QSM values were positively correlated with regional BBB permeabilities (putamen: r = 0.57, p = 0.006; caudate nucleus: r = 0.51, p = 0.019; temporal pole: r = 0.48, p = 0.030; centrum semiovale: r = 0.45, p = 0.044) and negatively correlated with Montreal Cognitive Assessment scores (caudate nucleus: r = -0.53, p = 0.012; temporal pole: r = -0.56, p = 0.008)., Conclusions: This study showed that cerebral iron burden was associated with regional BBB permeability and cognitive dysfunction in patients with CADASIL, highlighting the potential of these imaging techniques as auxiliary biomarkers to monitor the course of small vessel disease., (© 2020 American Academy of Neurology.)

Objective: To test the hypothesis that the prevalence and clinical effect of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have been underestimated in Asian populations., Methods: The Taiwan Biobank, containing 1,517 Taiwanese genome sequences, was queried for pathogenic NOTCH3 cysteine-altering mutations. NOTCH3 mutations identified in the reference population were genotyped in 7,038 stroke- and dementia-free individuals and 800 patients with ischemic stroke. NOTCH3 genotyping, clinical manifestations, and the severity of white matter lesions on MRI were compared between the 2 groups., Results: Three cysteine-altering NOTCH3 variants (p.R544C, p.C853Y, and p.C884Y) were identified from the Taiwan Biobank. We confirmed that the NOTCH3 p.R544C mutation was present in a significant number of individuals in Taiwan, including 60 of the 7,038 healthy controls (0.9%), 17 of the 800 patients with ischemic stroke (2.1%), and 16 of the 245 patients with small vessel occlusion (SVO) stroke (6.5%). The other 2 cysteine-altering mutations were rarely detected. After adjusting for vascular risk factors, harboring the p.R544C variant resulted in a 3.40-fold increased risk for overall stroke and an 11.05-fold increased risk for SVO stroke ( p = 0.0001 and 3.9 × 10 -10 , respectively). Three symptom-free individuals carrying the p.R544C mutation had extensive leukoencephalopathy typical of CADASIL at age 59, 66, and 67, suggesting that p.R544C-related CADASIL could remain subclinical at advanced age., Conclusion: The NOTCH3 p.R544C variant is an important risk factor for SVO stroke in Taiwan. Phenotypic variation among individuals carrying a NOTCH3 mutation indicates the existence of disease-modifying factors in CADASIL., (© 2019 American Academy of Neurology.)

Background and Purpose- Accumulating evidence has demonstrated hemodynamic abnormalities and cerebral hypoperfusion in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Increased venous susceptibility assessed by susceptibility weighted imaging and mapping has been shown to indicate a decrease in venous oxygen saturation. This study aimed to investigate whether altered venous oxygen saturation is related to clinical phenotypes of CADASIL patients. Methods- Using 7.0-T susceptibility weighted imaging and mapping, we compared venous susceptibility of cortical veins between 41 CADASIL patients and 43 age- and sex-matched healthy controls. The magnetic resonance imaging lesion load, mini-mental state examination score, Barthel Index, and modified Rankin Scale were examined in the patient group, and the correlations between venous susceptibility and clinical characteristics were analyzed. Results- Venous susceptibility increased with age ( r =0.508, P =0.001) and was higher in CADASIL patients than in healthy controls ( t =-4.673; P <0.001). We found a positive association between venous susceptibility and the age-related white matter change scores ( r =0.364; P =0.019), number of lacunar infarctions ( r =0.520; P <0.001), number of cerebral microbleeds ( ρ =0.445; P =0.004), and small-vessel disease scores ( ρ =0.465; P =0.002) in CADASIL patients. Moreover, increased venous susceptibility was associated with higher modified Rankin Scale scores in CADASIL patients after adjustment for age- and small-vessel disease scores (odds ratio=3.178; 95% CI, 1.101-9.179; P =0.033). Conclusions- Our findings indicate that extensive cerebral hypoperfusion may induce central nervous system impairment in CADASIL, and susceptibility weighted imaging and mapping could be used clinically to assess the condition of CADASIL patients.

The main clinical manifestations of Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are migraine with aura, ischemic strokes, and progressive cognitive decline. Intracerebral hemorrhage (ICH) has been described in CADASIL, but is not widely recognized. Here we report a case with CADASIL that presented with fatal ICH. A 57-year-old right-handed man of Pakistani descent with history of genetically confirmed CADASIL, hypertension, and mood disorder presented to the emergency department via Emergency Medical Services (EMSs) after he was found down. Initial neurological examination showed a Glasgow Coma Scale (GCS) of 7 (E2, V1, M4), left gaze deviation, pinpoint pupils, and left hemiplegia. His medications included antihypertensive agents and aspirin. He was intubated in the emergency department due to inability to protect his airway. Computed tomographic scan of the head revealed acute hemorrhage in the right pons (ICH score 2) with extension into the right cerebral peduncle, as well as enlargement of the third and lateral ventricles suggesting early obstructive hydrocephalus that required an external ventricular drain placement. He had no improvement of his clinical status, and eventually extubation and comfort care were pursued. He died 6 days after presentation. CADASIL vasculopathy, cerebral microbleeds, hypertension, and antithrombotic agents are factors that could be related to ICH in patients with CADASIL. This case highlights the importance of adequate blood pressure control, magnetic resonance imaging assessment of cerebral microbleed, and careful discussion of the risk and benefits of antiplatelet agents when evaluating and treating patients with CADASIL.

CNS small vessel disease (CSVD) causes 25% of strokes and contributes to 45% of dementia cases. Prevalence increases with age, affecting about 5% of people aged 50 years to almost 100% of people older than 90 years. Known causes and risk factors include age, hypertension, branch atheromatous disease, cerebral amyloid angiopathy, radiation exposure, immune-mediated vasculitides, certain infections, and several genetic diseases. CSVD can be asymptomatic; however, depending on location, lesions can cause mild cognitive dysfunction, dementia, mood disorders, motor and gait dysfunction, and urinary incontinence. CSVD is diagnosed on the basis of brain imaging biomarkers, including recent small subcortical infarcts, white matter hyperintensities, lacunes, cerebral microbleeds, enlarged perivascular spaces, and cerebral atrophy. Advanced imaging modalities can detect signs of disease even earlier than current standard imaging techniques. Diffusion tensor imaging can identify altered white matter connectivity, and blood oxygenation level-dependent imaging can identify decreased vascular reactivity. Pathogenesis is thought to begin with an etiologically specific insult, with or without genetic predisposition, which results in dysfunction of the neurovascular unit. Uncertainties regarding pathogenesis have delayed development of effective treatment. The most widely accepted approach to treatment is to intensively control well-established vascular risk factors, of which hypertension is the most important. With better understanding of pathogenesis, specific therapies may emerge. Early identification of pathologic characteristics with advanced imaging provides an opportunity to forestall progression before emergence of symptoms., (© 2019 American Academy of Neurology.)

Background and Purpose- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke usually presenting with migraine with aura, lacunar infarcts, and cognitive impairment. Acute encephalopathy is a less recognized presentation of the disease. Methods- Data collected prospectively from 340 consecutively recruited symptomatic patients with diagnosis of CADASIL seen in a British National CADASIL clinic was retrospectively reviewed and original clinical records and imaging obtained. An encephalopathic event was defined as an acute event of an altered state of consciousness in a patient with CADASIL, manifesting with signs of brain dysfunction, which warranted hospital admission in the absence of any other cause. Clinical characteristics, risk factors, and outcome of encephalopathic presentations were studied. Results- A total of 35 of 340 (10.3%) participants had a history of 50 encephalopathic events which was the first hospital presentation of CADASIL in 33 (94.3%) patients. Most commonly reported features during episodes were visual hallucinations (44%), seizures (22%), and focal neurological deficits (60%).Complete recovery within 3 months was reported in 48(96%) episodes. In 62% of episodes, there was a history of migraine or migraine aura directly preceding the encephalopathy. In 2 out of 15 cases where magnetic resonance imaging during episodes was available, unilateral focal cortical swelling was seen. A past history of migraine was independently associated with encephalopathy (odds ratio=12.3 [95% CI, 1.6-93.7]; P=0.015). Conclusions- In up to 10% of CADASIL patients, a reversible encephalopathy is the first presentation leading to diagnosis. The strong association with migraine suggests a shared pathogenesis. Focal cortical swelling may be seen on magnetic resonance imaging during the acute episode.

Background and Purpose- In cerebral small vessel diseases, small subcortical ischemic lesions (SSIL) on diffusion imaging are responsible for stroke manifestations but can also be occasionally observed in the absence of overt neurological symptoms. We aimed to determine, in a large cohort of young patients with CADASIL (Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy), a severe monogenic condition leading to SSIL in young patients, the characteristics of SSIL and of surrounding cerebral tissue associated with the presence of stroke symptoms. Methods- Among a cohort of 323 genetically confirmed CADASIL patients who were systematically evaluated every 18 months clinically and with magnetic resonance imaging, we studied all visible SSIL and documented ischemic stroke events with available magnetic resonance imaging data. We used mixed-effect logistic regression models to determine whether the presence of stroke symptoms was associated with age, sex, the volume of SSIL, their location with respect to preexisting white matter hyperintensities and with the load of the different magnetic resonance imaging markers of small vessel disease. Results- We identified 73 SSIL (30 with stroke symptoms and 43 without) in 55 patients. In multivariable models, stroke symptoms were more frequent in male patients (estimate=1.94; SE=0.82; P=0.03) and less frequent when SSIL appeared in contact to preexisting white matter hyperintensities (estimate=-2.12; SE=0.83; P=0.01). Within pyramidal tracts, stroke symptoms were more frequent in patients with extensive white matter hyperintensities (estimate=3.8×10 -5 ; SE=9.3×10 -6 ; P<10 -4 ). Conclusions- Altogether, our results suggest that when SSIL occur, the presence of stroke symptoms may depend on sex and alterations of the surrounding brain tissue rather than on the characteristics of the SSIL itself.

Background and Purpose: Cerebral microbleeds are associated with an increased risk of intracerebral hemorrhage. Recent data suggest that microbleeds may also predict the risk of incident ischemic stroke. However, these results were observed in elderly individuals undertaking various medications and for whom causes of microbleeds and ischemic stroke may differ. We aimed to test the relationship between the presence of microbleeds and incident stroke in CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy)-a severe monogenic small vessel disease known to be responsible for both highly prevalent microbleeds and a high incidence of ischemic stroke in young patients., Methods: We assessed microbleeds on baseline MRI in all 378 patients from the Paris-Munich cohort study. Incident ischemic strokes were recorded during 54 months. Survival analyses were used to test the relationship between microbleeds and incident ischemic stroke., Results: Three hundred sixty-nine patients (mean age, 51.4±11.4 years) were followed-up during a median time of 39 months (interquartile range, 19 months). The risk of incident ischemic stroke was higher in patients with microbleeds than in patients without (35.8% versus 19.6%, hazard ratio, 1.87; 95% confidence interval, 1.16-3.01; P =0.009). These results persisted after adjustment for history of ischemic stroke, age, sex, vascular risk factors, and antiplatelet agents use (hazard ratio, 1.89; 95% confidence interval, 1.10-3.26; P =0.02)., Conclusions: The presence of microbleeds is an independent risk marker of incident ischemic stroke in CADASIL, emphasizing the need to carefully interpret MRI data., (© 2017 American Heart Association, Inc.)

Background and Purpose: Cortical microinfarcts and secondary cortical degeneration have been demonstrated in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a severe monogenic cerebral small vessel disease. The aim of this study was to determine whether focal macroscopic cortical lesions can be detected using a specific in vivo magnetic resonance imaging approach., Methods: Three-dimensional T1 magnetic resonance imaging scans were obtained in 28 nondemented nondisabled CADASIL patients and 29 age- and sex-matched controls. The cortical mantle of patients and controls were extracted using Brainvisa by an experienced user and then evaluated during a dedicated reading session by a second reader after removing the white matter to stay blind to the clinical status. Thereafter, confirmed focal macroscopic cortical lesions were characterized using all available imaging data, including 7-T magnetic resonance imaging in some patients., Results: Three focal macroscopic cortical lesions were confirmed in 3 of 28 patients (11%) but none in controls. All lesions were observed in the close vicinity of severe signal changes in the underlying white matter., Conclusions: Focal macroscopic cortical lesions can be detected using specific magnetic resonance imaging approaches in CADASIL patients long before the end stage of the disorder. The underlying mechanisms and precise clinical consequences of these cortical changes still need to be determined., (© 2017 American Heart Association, Inc.)

Background and Purpose: Cortical superficial siderosis (cSS) has emerged as a clinically relevant imaging feature of cerebral amyloid angiopathy (CAA). However, it remains unknown whether cSS is also present in nonamyloid-associated small vessel disease and whether patients with cSS differ in terms of other small vessel disease imaging features., Methods: Three hundred sixty-four CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) patients, 372 population-based controls, and 100 CAA patients with cSS (fulfilling the modified Boston criteria for possible/probable CAA) were included. cSS and cerebral microbleeds were visually rated on T2*-weighted magnetic resonance imaging. White matter hyperintensities were segmented on fluid-attenauted inversion recovery images, and their spatial distribution was compared between groups using colocalization analysis. Cerebral microbleeds location was determined in an observer-independent way using an atlas in standard space., Results: cSS was absent in CADASIL and present in only 2 population-based controls (0.5%). Cerebral microbleeds were present in 64% of CAA patients with cSS, 34% of patients with CADASIL, and 12% of population-based controls. Among patients with cerebral microbleeds, lobar location was found in 95% of CAA patients with cSS, 48% of CADASIL patients, and 69% of population-based controls. The spatial distribution of white matter hyperintensities was comparable between CAA with cSS and CADASIL as indicated by high colocalization coefficients., Conclusions: cSS was absent in CADASIL, whereas other small vessel disease imaging features were similar to CAA patients with cSS. Our findings suggest that cSS in combination with other small vessel disease imaging markers is highly indicative of CAA., (© 2017 American Heart Association, Inc.)

Objective: To underline the importance of blood pressure regulation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and to describe changes that occur in the veins in this condition, specifically venous collagenosis associated with leukoaraiosis., Methods: Case report with neuroimaging and pathologic data., Results: A 61-year-old man with genetically confirmed CADASIL was initially lucid following a motor vehicle accident but subsequently became hypotensive (60/40 mm Hg) due to an open femur fracture and required intubation. Multiple new white matter infarcts appeared on brain imaging. A second hypotensive episode days later was associated with new coin-sized infarcts in the bilateral corona radiata and cerebellar peduncles, and resulted in quadriplegia. No embolic source was found on cardiac or vascular imaging. He died 5 weeks post trauma. Autopsy revealed extensive subcortical and periventricular leukoencephalopathy and multiple cavitations involving deep subcortical gray and white matter. Small arteries had thickened walls, disruption of the muscularis, and intimal periodic acid-Schiff (PAS)-positive material. Both larger periventricular and small caliber veins had thickened walls that were PAS-negative and trichrome-positive, consistent with venous collagenosis. There was no pathologic evidence of global hypoxia or diffuse axonal injury., Conclusions: The findings suggest rapid acceleration of CADASIL pathology from acute hypotension in the setting of impaired vasoreactivity. In addition, collagenosis of veins in the affected white matter regions suggests that the veins may play an important, though largely overlooked, role in maintaining white matter integrity., (© 2017 American Academy of Neurology.)

Background and Purpose: Previous studies in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy showed that accumulation of lacunes strongly relate to clinical severity. However, the potential predictors of incident lacunes and their clinical consequences over a short time frame have not been investigated. This study aimed to determine the predictors and clinical impact of such lesions in a large cohort of patients., Methods: Two hundred and six NOTCH3 mutation carriers (mean age, 49.5±10.6 years) were followed up over 3 years. Incident lacunes were identified using difference imaging from 3-dimensional T1 images. Clinical events and change in different clinical scores such as the Mattis Dementia Rating Scale, Modified Rankin Scale, Barthel index, and time to complete part A and part B of Trail Making Test were recorded. Associations were analyzed with multivariable logistic regression analysis and ANCOVA., Results: Over a mean period of 3.4±0.7 years, incident lacunes occurred in 51 of 206 patients. Both the number of lacunes (P<0.0001) and systolic blood pressure at baseline (P<0.01) were independent predictors of incident lacunes during follow-up. The results were still significant after excluding patients with systolic blood pressure >140 mm Hg. Incident lacunes were also associated with incident stroke and with change in time to complete Trail Making Test part B, initiation/perseveration subscale of the Mattis Dementia Rating Scale and Barthel Index over the study period., Conclusions: Systolic blood pressure and the number of prevalent lacunes are independent predictors of incident lacunes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. These lesions mainly impact executive performances and functional independence over 3 years., (© 2016 American Heart Association, Inc.)

Background and Purpose: Lacunes are a major manifestation of cerebral small vessel disease. Although still debated, the morphological features of lacunes may offer mechanistic insights. We systematically analyzed the shape of incident lacunes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, a genetically defined small vessel disease., Methods: A total of 88 incident lacunes from 57 patients were segmented from 3-dimensional T1 magnetic resonance images and 3 dimensionally reconstructed. Anatomic location, diameter, volume, surface area, and compactness of lacunes were assessed. The shape was analyzed using a size, orientation, and position invariant spectral shape descriptor. We further investigated the relationship with perforating arteries and fiber tracts., Results: Lacunes were most abundant in the centrum semiovale and the basal ganglia. Diameter, volume, and surface area of lacunes in the basal ganglia and centrum semiovale were larger than in other brain regions. The spectral shape descriptor revealed a continuum of shapes with no evidence for distinct classes of lacunes. Shapes varied mostly in elongation and planarity. The main axis and plane of lacunes were found to align with the orientation of perforating arteries but not with fiber tracts., Conclusions: Elongation and planarity are the primary shape principles of lacunes. Their main axis and plane align with perforating arteries. Our findings add to current concepts on the mechanisms of lacunes., (© 2016 American Heart Association, Inc.)

Background and Purpose: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary arteriopathy, which mainly involves the brain causing stroke and dementia. Mice expressing the mutated protein display early dysfunction in vasoreactivity in resistance arteries, but studies of patients have been inconclusive so far., Methods: We examined peripheral endothelium-dependent vasodilatation in 10 CADASIL-patients and 20 controls using 3 methods: venous occlusion plethysmography of forearm blood flow with intraarterial acetylcholine and sodium nitroprusside infusions for evaluation of resistance arteries, ultrasound with flow mediated vasodilatation (FMD) of the brachial artery for evaluation of a conduit artery, and the pulse wave method with measurements before and after terbutaline for evaluation of systemic endothelium-dependent vasodilation., Results: The CADASIL patients displayed reductions in both basal (P=0.034) and stimulated blood flow (P=0.023 for the highest dose of acetylcholine) and an impaired endothelium-dependent vasodilation when investigated in forearm resistance arteries (P=0.019). The FMD and the pulse wave method did not show any reduction in endothelium-dependent vasodilation in the patients., Conclusions: Endothelium-dependent vasodilation was impaired in resistance arteries, but not in a conduit artery, in the forearm of CADASIL patients.