Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts And Leukoencephalopathy Patients Research Articles

ER stress and Rho kinase activation underlie the vasculopathy of CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) leads to premature stroke and vascular dementia. Mechanism-specific therapies for this aggressive cerebral small vessel disease are lacking. CADASIL is caused by NOTCH3 mutations that influence vascular smooth muscle cell (VSMC) function through unknown processes. We investigated molecular mechanisms underlying the vasculopathy in CADASIL focusing on endoplasmic reticulum (ER) stress and RhoA/Rho kinase (ROCK). Peripheral small arteries and VSMCs were isolated from gluteal biopsies of CADASIL patients and mesentery of TgNotch3R169C mice (CADASIL model). CADASIL vessels exhibited impaired vasorelaxation, blunted vasoconstriction, and hypertrophic remodeling. Expression of NOTCH3 and ER stress target genes was amplified and ER stress response, Rho kinase activity, superoxide production, and cytoskeleton-associated protein phosphorylation were increased in CADASIL, processes associated with Nox5 upregulation. Aberrant vascular responses and signaling in CADASIL were ameliorated by inhibitors of Notch3 (γ-secretase inhibitor), Nox5 (mellitin), ER stress (4-phenylbutyric acid), and ROCK (fasudil). Observations in human CADASIL were recapitulated in TgNotch3R169C mice. These findings indicate that vascular dysfunction in CADASIL involves ER stress/ROCK interplay driven by Notch3-induced Nox5 activation and that NOTCH3 mutation–associated vascular pathology, typical in cerebral vessels, also manifests peripherally. We define Notch3-Nox5/ER stress/ROCK signaling as a putative mechanism-specific target and suggest that peripheral artery responses may be an accessible biomarker in CADASIL.

Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic paradigm of small vessel disease (SVD) caused by NOTCH3 mutations that stereotypically lead to the vascular accumulation of NOTCH3 around smooth muscle cells and pericytes. White matter (WM) lesions (WMLs) are the earliest and most frequent abnormalities, and can be associated with lacunar infarcts and enlarged perivascular spaces (ePVS). The prevailing view is that blood brain barrier (BBB) leakage, possibly mediated by pericyte deficiency, plays a pivotal role in the formation of WMLs. Herein, we investigated the involvement of BBB leakage and pericyte loss in CADASIL WMLs. Using post-mortem brain tissue from 12 CADASIL patients and 10 age-matched controls, we found that WMLs are heterogeneous, and that BBB leakage reflects the heterogeneity. Specifically, while fibrinogen extravasation was significantly increased in WMLs surrounding ePVS and lacunes, levels of fibrinogen leakage were comparable in WMLs without other pathology (“pure” WMLs) to those seen in the normal appearing WM of patients and controls. In a mouse model of CADASIL, which develops WMLs but no lacunes or ePVS, we detected no extravasation of endogenous fibrinogen, nor of injected small or large tracers in WMLs. Moreover, there was no evidence of pericyte coverage modification in any type of WML in either CADASIL patients or mice. These data together indicate that WMLs in CADASIL encompass distinct classes of WM changes and argue against the prevailing hypothesis that pericyte coverage loss and BBB leakage are the primary drivers of WMLs. Our results also have important implications for the interpretation of studies on the BBB in living patients, which may misinterpret evidence of BBB leakage within WM hyperintensities as suggesting a BBB related mechanism for all WMLs, when in fact this may only apply to a subset of these lesions.

Clinical Features of 4 Novel NOTCH3 Mutations of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy in China.

BackgroundThis study aimed to identify NOTCH3 mutations and describe the genetic and clinical features and magnetic resonance imaging results in 11 unrelated patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) from Henan province in China.Material/MethodsNOTCH3 was directly sequenced in 11 unrelated patients of Chinese descent. The clinical presentations and magnetic resonance imaging features were retrospectively analyzed in the 11 index patients with a definite diagnosis.ResultsSeven different mutations were identified in 11 unrelated patients, including 4 novel mutations (p.P167S, p.P652S, p.C709R, and p.R1100H) in China and 3 reported mutations (p.C117R, p.R578C, and p.R607C). Four novel mutations (p.P167S, p.P652S, p.C709R, and p.R1100H) were predicted to be probably pathogenic using an online pathogenicity prediction program through comprehensive analysis. Clinical presentations in symptomatic patients included stroke, cognitive decline, psychiatric disturbances, and migraine. Multiple lacunars infarcts and leukoaraiosis were detected on MRI in most symptomatic patients, while white-matter lesions were identified in the temporal pole or the external capsule in all affected patients.ConclusionsThe mutation spectrum of CADASIL patients from Henan province in China displayed some differences from that of those reported previously. DNA sequencing was used to diagnose all 11 patients as having CADASIL, and we found 4 novel mutations. The present results further contribute to the enrichment of NOTCH3 mutation databases.

Novel Characteristics of Race-Specific Genetic Functions in Korean CADASIL.

Background and Objectives: Previous studies found differences in the characteristics of NOTCH3 mutations in Caucasians and Asians with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Therefore, we sought to investigate the correlations between genetic and clinical/radiological findings in Korean CADASIL patients including some variants of unknown significance (VUS). Materials and Methods: We screened 198 patients with a suspected diagnosis of CADASIL between 2005 and 2015 via Sanger sequencing. Results: A total of 34 subjects (52.5 ± 9.5 years) were included. The majority of the mutations were in exon 3 and exon 11. R75P mutations (n = 5), followed by Y465C and R544C mutations (n = 4) were the most prevalent. Patients with those mutations exhibited less frequent anterior temporal (AT) or external capsular (EC) hyperintensities compared to patients with other locus mutations. Hemorrhagic stroke (HS) was found to be associated with mutations in exon 3 (R75P), exon 9 (Y465C), exon 11 (R587C), and exon 22 (R1175W variants), which were common locations in our study. Although it is unclear that genetic differences might affect the phenotypes in ethnicities, Asian population shows less migraine or seizure, but more intracerebral hemorrhage. Unlike in westernized countries, typical AT or EC hyperintensities may not be significant MRI markers, at least in Korean CADASIL patients. Furthermore, similar to R75P phenotypes, it is a novel finding that patients with Y465C and R1175W VUS have less frequent AT involvement than Caucasians. Conclusion: The associations between HS and common genetic locations account for the increased development of intracerebral hemorrhage in Koreans rather than Caucasians. We suggest that some CADASIL mutations appear to impart novel region-specific characteristics.

Lenticulostriate Arteries and Basal Ganglia Changes in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy, a High-Field MRI Study.

Background and Purpose: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) mainly affects the cerebral small arteries. We aimed to analyze changes in the lenticulostriate arteries (LSAs) and the basal ganglia in patients with CADASIL using high-field magnetic resonance imaging (7.0-T MRI).Methods: We examined 46 patients with CADASIL and 46 sex- and age-matched healthy individuals using 7.0-T MRI. The number and length of the LSAs, and the proportion of discontinuous LSAs were compared between the two groups. The Mini-Mental State Examination score, the modified Rankin Scale, the Barthel Index, and the MRI lesion load of the basal ganglia were also examined in patients with CADASIL. We analyzed the association between LSA measurements and the basal ganglia lesion load, as well as the association between LSA measurements and clinical phenotypes in this patient group.Results: We observed a decrease in the number of LSA branches (t = −2.591, P = 0.011), and an increase in the proportion of discontinuous LSAs (z = −1.991, P = 0.047) in patients with CADASIL when compared with healthy controls. However, there was no significant difference in the total length of LSAs between CADASIL patients and healthy individuals (t = −0.412, P = 0.682). There was a positive association between the number of LSA branches and the Mini-Mental State Examination scores of CADASIL patients after adjusting for age and educational level (β = 0.438; 95% CI: 0.093, 0.782; P = 0.014). However, there was no association between LSA measurements and the basal ganglia lesion load among CADASIL patients.Conclusions: 7.0-T MRI provides a promising and non-invasive method for the study of small artery damage in CADASIL. The abnormalities of small arteries may be related to some clinical symptoms of CADASIL patients such as cognitive impairment. The lack of association between LSA measurements and the basal ganglia lesion load among the patients suggests that changes in the basal ganglia due to CADASIL are caused by mechanisms other than anatomic narrowing of the vessel lumen.

Altered Brain Glucose Metabolism Assessed by 18F-FDG PET Imaging Is Associated with the Cognitive Impairment of CADASIL

Recurrent stroke and cognitive impairment are the primary features of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The cognitive deficits in these patients are known to be correlated with structural brain changes, such as white matter lesions and lacunae, and resting-state functional connectivity in brain networks. However, the associations between changes in brain glucose metabolism based on 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET) imaging and cognitive scores in CADASIL patients remain unclear. In the present study, 24 CADASIL patients and 24 matched healthy controls underwent 18F-FDG PET imaging. Brain glucose metabolism was measured in all subjects and Pearson's correlation analyses were performed to evaluate relationships between abnormal glucose metabolism in various brain areas and cognitive scores. Compared to controls, CADASIL patients exhibited significantly lower metabolism in the right cerebellar posterior lobe, left cerebellar anterior lobe, bilateral thalamus and left limbic lobe. Additionally, hypermetabolism was observed in the left precentral and postcentral gyri. Importantly, glucose metabolism in the left limbic lobe was positively associated with cognitive scores on the Mini-Mental State Examination (MMSE). Furthermore, glucose metabolism in the left precentral gyri was negatively correlated with cognitive scores on the Montreal Cognitive Assessment (MoCA). The present findings provide strong support for the presence of altered brain glucose metabolism in CADASIL patients as well as the associations between abnormal metabolism and cognitive scales in this population. The present findings suggest that patterns of brain glucose metabolism may become useful markers of cognitive impairment in CADASIL patients.

Automated lesion segmentation with BIANCA: Impact of population-level features, classification algorithm and locally adaptive thresholding

White matter hyperintensities (WMH) or white matter lesions exhibit high variability in their characteristics both at population- and subject-level, making their detection a challenging task. Population-level factors such as age, vascular risk factors and neurodegenerative diseases affect lesion load and spatial distribution. At the individual level, WMH vary in contrast, amount and distribution in different white matter regions.In this work, we aimed to improve BIANCA, the FSL tool for WMH segmentation, in order to better deal with these sources of variability. We worked on two stages of BIANCA by improving the lesion probability map estimation (classification stage) and making the lesion probability map thresholding stage automated and adaptive to local lesion probabilities. Firstly, in order to take into account the effect of population-level factors, we included population-level lesion probabilities, modelled with respect to a parametric factor (e.g. age), in the classification stage. Secondly, we tested BIANCA performance when using four alternative classifiers commonly used in the literature with respect to K-nearest neighbour algorithm (currently used for lesion probability map estimation in BIANCA). Finally, we propose LOCally Adaptive Threshold Estimation (LOCATE), a supervised method for determining optimal local thresholds to apply to the estimated lesion probability map, as an alternative option to global thresholding (i.e. applying the same threshold to the entire lesion probability map). For these experiments we used data from a neurodegenerative cohort, a vascular cohort and the cohorts available publicly as a part of a segmentation challenge.We observed that including population-level parametric lesion probabilities with respect to age and using alternative machine learning techniques provided negligible improvement. However, LOCATE provided a substantial improvement in the lesion segmentation performance, when compared to the global thresholding. It allowed to detect more deep lesions and provided better segmentation of periventricular lesion boundaries, despite the differences in the lesion spatial distribution and load across datasets. We further validated LOCATE on a cohort of CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) patients, a genetic form of cerebral small vessel disease, and healthy controls, showing that LOCATE adapts well to wide variations in lesion load and spatial distribution.

Primary involvement of neurovascular coupling in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most frequent monogenic cause of cerebral ischemia, but reliable biomarkers to monitor the disease are lacking. To evaluate cerebral autoregulation (CA), vasoreactivity (VR), and neurovascular coupling (NVC) in CADASIL patients through a battery of dynamic transcranial Doppler tests. We screened our database for all pre-dementia CADASIL cases. We monitored cerebral blood flow velocity (CBFV) with transcranial Doppler, blood pressure, and expiratory carbon dioxide (CO2) non-invasively. CA was assessed by transfer function from the spontaneous oscillations of blood pressure to CBFV, VR with inhalation of CO2 at 5%, and hyperventilation and NVC by the CBFV response to visual stimulation. We included 27 CADASIL patients and 20 healthy controls with similar age and sexes. CA and VR were similar between groups. However, NVC was significantly affected in CADASIL patients, with lower magnitudes of CBFV upsurge (overshoot 19 ± 5 vs 26 ± 6%, p = 0.013; gain 12 ± 7 vs 17 ± 5%, p = 0.003) and altered time behavior during visual stimulation (natural frequency 0.18 ± 0.06 vs 0.24 ± 0.06Hz, p = 0.005; rate time 0.7 ± 1.7 vs 2.7 ± 3.5s, p = 0.025). Our results express a primary and selective involvement of the neurovascular unit in CADASIL rather than a generalized cerebral vasomotor disturbance. Functional cerebrovascular testing could be useful in patient evaluation and monitoring.

The CADASIL Scale-J, A Modified Scale to Prioritize Access to Genetic Testing for Japanese CADASIL-Suspected Patients

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is definitely diagnosed by genetic testing. Such testing involves the analysis of exons 2-24 of NOTCH3, which encode the epidermal growth factor-like repeat domain, where CADASIL mutations are localized. We previously reported clinical diagnostic criteria for screening CADASIL-suspected Japanese patients prior to genetic testing. Because of its high sensitivity but low specificity, most patients need to undergo genetic testing. In this study, we aimed to develop the CADASIL scale-J, a modified scale to prioritize access to genetic testing for CADASIL-suspected Japanese patients. Methods: We modified the CADASIL scale reported by Pescini et al based on clinical features of 126 CADASIL patients and 53 NOTCH3-negative CADASIL-like patients diagnosed up until March 2016 (Phase 1). For validation, we recruited 69 consecutive patients for genetic testing of NOTCH3 from April 2016 to March 2017 (Phase 2). Results: We developed the CADASIL scale-J with a score ranging from 0 to 25 and the cut-off value of 16, using 8 items: hypertension, diabetes, young onset (≤50 years old), pseudobulbar palsy, stroke/TIA, family history, subcortical infarction, and temporal pole lesion. The sensitivity and specificity of the CADASIL scale-J were 78.9% and 85.7%, respectively. In Phase 2, we obtained a positive predictive value of 70.0% and a negative predictive value of 89.2%. In this study, we identified 54 mutations, 7 of which were novel. Conclusions: The CADASIL scale-J is helpful to prioritize access to genetic testing for CADASIL-suspected Japanese patients.

Abstract TP202: Risk of Incident Stroke and Dementia in Cadasil : A 6-Year Follow-Up of 85 Korean Patients

Background: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common hereditary cerebrovascular disease. The most frequent clinical manifestation is an ischemic stroke, and the risk of incident stroke was very high in Caucasian CADASIL patients. Also, two-thirds of patients with CADASIL developed dementia by age 65 in Caucasian. Although clinical manifestations of the Asian CADASIL patients have been reported to be different from those of Caucasian, little is known for clinical course and long-term prognosis. This study aimed to investigate the risk of incident stroke and dementia in Korean CADASIL patients. Methods: We retrospectively reviewed the medical records of patients who were diagnosed with CADASIL at our institution from March 2012 to February 2015. The patients were selected by the following criteria; (1) aged ≥18 years, (2) diagnosis of CADASIL by a NOTCH3 gene mutation, (3) followed for at least 36 months. Primary outcomes were (1) any stroke (ischemic or hemorrhagic), (2) dementia, and (3) death of any cause. Results: Of 102 CADASIL patients who were evaluated at baseline, 85 patients met the inclusion criteria (mean age 68.9±12.1 years). The median follow-up was 57 months (interquartile range: 50-68 months). Of the 85 patients, 46 patients (54.1%) had a history of ischemic or hemorrhagic stroke, and 17 patients (20.0%) had dementia at baseline examination. Of the 85 patients, 13 patients (15.3%) experienced a new ischemic stroke. The risk of incident ischemic strokes was significantly greater in patients with a history of stroke than in without (23.9% vs. 5.1%, P=0.016). However, vascular risk factors such as hypertension, diabetes, hyperlipidemia, and smoking were not associated with increased risk of incident stroke. Of 68 patients who had no dementia at baseline, incident dementia developed in 11 patients (16.2%). During follow-up, two patients (2.3%) died due to lung cancer and pneumonia respectively. Conclusions: The risk of incident ischemic stroke or dementia seems to be lower than expected in Korean CADASIL patients. These findings suggest that clinical course and prognosis could be rather benign in Korean patients compared with the Caucasian patients with CADASIL.

Abstract WP554: Nationwide Survey of CADASIL in Japan

Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one of the common type of hereditary small vessel disease. The clinical presentation of CADASIL has been reported as varies, and there may exist the racial gap between Asian and Caucasian people. However, the clinical features of CADASIL in Japan is still unclear. This study aimed to elucidate the epidemiological and clinical features of CADASIL based on the nationwide survey in Japan. Methods: Target subjects were patients with CADASIL who had visited the certified hospitals (totally 1, 448 hospitals) by Japanese Society of Neurology and/or Japan Stroke Society in 2016. This study consisted of two steps surveys; 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 patients with CADASIL to REDCap system. Results: Based on the Japanese criteria (Mizuta et al. 2017), 88 patients (50 males and 38 females) with definite CADASIL were reported. Mean age at symptom onset was 49.4 years. Late onset (> 60 years) patients were 15 (17.0%), episode of migraine was detected in 26 patients (29.5%), and patients who had vascular risk factor(s) were 33 (37.5%). Stroke-like episodes with neurological signs were detected in 59 patients (67%), cognitive impairment in 31 patients (35.2%), pyramidal sign in 41 patients (46.6%), and pseudobulbar palsy in 20 patients (22.7%). Abnormal deep white matter lesions (WMLs) were detected in 85 patients (96.6%), WMLs extending to anterior temporal pole in 73 patients (83.0%), and cerebral microbleeds in 41 patients (46.6%). Conclusions: Although, CADASIL is characterized by early onset of stroke and without vascular risk, there were more than a few CADASIL patients with late onset and vascular risk factors in Japan.

Multimodal imaging analyses in patients with genetic and sporadic forms of small vessel disease

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is thought to be a pure genetic form of subcortical vascular cognitive impairment (SVCI). The aim of this study was to compare white matter integrity and cortical thickness between typical CADASIL, a genetic form, and two sporadic forms of SVCI (with NOTCH3 and without NOTCH3 variants). We enrolled typical CADASIL patients (N = 11) and SVCI patients [with NOTCH3 variants (N = 15), without NOTCH3 variants (N = 101)]. To adjust the age difference, which reflects the known difference in clinical and radiologic courses between typical CADASIL patients and SVCI patients, we constructed a W-score of measurement for diffusion tensor image and cortical thickness. Typical CADASIL patients showed more frequent white matter hyperintensities in the bilateral posterior temporal region compared to SVCI patients (p < 0.001, uncorrected). We found that SVCI patients, regardless of the presence of NOTCH3 variants, showed significantly greater microstructural alterations (W-score, p < 0.05, FWE-corrected) and cortical thinning (W-score, p < 0.05, FDR-corrected) than typical CADASIL patients. In this study, typical CADASIL and SVCI showed distinct anatomic vulnerabilities in the cortical and subcortical structures. However, there was no difference between SVCI with NOTCH3 variants and SVCI without NOTCH3 variants.

Encephalopathy in a Large Cohort of British Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Patients.

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.

Analysis of gut microbiota in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a major hereditary small vessel disease caused by mutations in NOTCH3. The variations in progression and severity among patients suggest that the CADASIL phenotype is modified by some genetic and environmental factors. Recent studies have shown the potential roles of gut microbiota in human diseases. We hypothesized that gut microbiota modifies the disease phenotype. We performed gut microbial meta 16S rRNA analysis of fecal samples from 15 CADASIL patients and 16 controls. The microbial α- and β-diversities and taxonomy were compared between CADASIL patients and controls and between CADASIL patients with and without an ischemic stroke history. No significant difference in α- or β-diversity was observed in either case-control or subgroup comparisons. In the taxonomic microbial analysis, there was a significant increase in abundance of 6 genera and significant decrease in 2 genera in CADASIL patients compared with controls. There was a significant decrease in abundance of 2 genera in CADASIL patients with compared with those without stroke. This is the first study on CADASIL focusing on gut microbiota. Our findings suggest that gut microbiota modifies the onset and progression of CADASIL.

Functional Magnetic Resonance Imaging of Inhibitory Control Reveals Decreased Blood Oxygen Level Dependent Effect in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

Background and Purpose- Small-vessel damage in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is associated with impaired vascular constriction and dilation. We used a functional magnetic resonance imaging task with an event-related design of stimulus to explore the anticipated abnormally decreased blood oxygen level dependent effect in CADASIL. Methods- Twenty-one CADASIL patients and 16 healthy controls performed a Go/No-go task exploring reactive and proactive phases of inhibition control in a 3-T magnet. Results- Error number and reaction times were not different between patients and controls. Analysis of the reactive inhibition (No-go/baseline contrast) did not show clusters of lower or higher blood oxygen level dependent effect in patients or controls. Analysis of the proactive inhibition (alertness contrast) in CADASIL patients revealed a lower blood oxygen level dependent effect in the alerting network (anterior cingulate cortex and insula, thalamus), lower brain stem and left cerebellar hemisphere (crus I) that is involved in executive functions. Conclusions- In CADASIL patients, an event-related Go/No-go task reveals a lower blood oxygen level dependent effect in the alerting network and areas involved in executive functions possibly reflecting the altered hemodynamic response secondary to small-vessel changes. Our observation extends the role of MR in demonstrating one of the fundamental pathophysiological changes of CADASIL.

Autophagy-lysosomal defect in human CADASIL vascular smooth muscle cells

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial progressive degenerative disorder and is caused by mutations in NOTCH3 gene. Previous study reported that mutant NOTCH3 is more prone to form aggregates than wild-type NOTCH3 and the mutant aggregates are resistant to degradation. We hypothesized that aggregation or accumulation of NOTCH3 could be due to impaired lysosomal-autophagy machinery in VSMC.Here, we investigated the possible cause of accumulation/aggregation of NOTCH3 in CADASIL using cerebral VSMCs derived from control and CADASIL patients carrying NOTCH3R133C mutation. Thioflavin-S-staining confirmed the increased accumulation of aggregated NOTCH3 in VSMCR133C compared to VSMCWT. Increased levels of the lysosomal marker, Lamp2, were detected in VSMCR133C, which also showed co-localization with NOTCH3 using double-immunohistochemistry. Increased level of LC3-II/LC3-I ratio was observed in VSMCR133C suggesting an accumulation of autophagosomes. This was coupled with the decreased co-localization of NOTCH3 with LC3, and Lamp2 and, further, increase of p62/SQSTM1 levels in VSMCR133C compared to the VSMCWT. In addition, Western blot analysis indicated phosphorylation of p-ERK, p-S6RP, and p-P70 S6K. Altogether, these results suggested a dysfunction in the autophagy-lysosomal pathway in VSMCR133C.The present study provides an interesting avenue of the research investigating the molecular mechanism of CADASIL.

MRI Lesion Load of Cerebral Small Vessel Disease and Cognitive Impairment in Patients With CADASIL.

Background and objective: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the best known and the most common monogenic small vessel disease (SVD). Cognitive impairment is an inevitable feature of CADASIL. Total SVD score and global cortical atrophy (GCA) scale were found to be good predictors of poor cognitive performance in community-dwelling adults. We aimed to estimate the association between the total SVD score, GCA scale and the cognitive performance in patients with CADASIL.Methods: We enrolled 20 genetically confirmed CADASIL patients and 20 controls matched by age, gender, and years of education. All participants underwent cognitive assessments to rate the global cognition and individual domain of executive function, information processing speed, memory, language, and visuospatial function. The total SVD score and GCA scale were rated.Results: The CADASIL group performed worse than the controls on all cognition measures. Neither global cognition nor any separate domain of cognition was significantly different among patients grouped by total SVD score. Negative correlations between the GCA score and cognitive performance were observed. Approximately 40% of the variance was explained by the total GCA score in the domains of executive function, information processing speed, and language. The superficial atrophy score was associated with poor performance in most of the domains of cognition. Adding the superficial atrophy score decreased the prediction power of the deep atrophy score on cognitive impairment alone.Conclusions: The GCA score, not the total SVD score, was significantly associated with poor cognitive performance in patients with CADASIL. Adding the superficial atrophy score attenuated the prediction power of the deep atrophy score on cognitive impairment alone.

Stroke : Highlights of Selected Articles

<i>Stroke</i> : Highlights of Selected Articles

Why Are Only Some Subcortical Ischemic Lesions on Diffusion Magnetic Resonance Imaging Associated With Stroke Symptoms in Small Vessel Disease?

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.

Genetic analysis of adult leukoencephalopathy patients using a custom-designed gene panel.

Leukoencephalopathies encompass all clinical syndromes that predominantly affect brain white matter. Genetic diagnosis informs clinical management of these patients, but a large part of the genetic contribution to adult leukoencephalopathy remains unresolved. To examine this genetic contribution, we analyzed genomic DNA from 60 Japanese patients with adult leukoencephalopathy of unknown cause by next generation sequencing using a custom-designed gene panel. We selected 55 leukoencephalopathy-related genes for the gene panel. We identified pathogenic mutations in 8 of the 60 adult leukoencephalopathy patients (13.3%): NOTCH3 mutations were detected in 5 patients, and EIF2B2, CSF1R, and POLR3A mutations were found independently in 1 patient each. These results indicate that cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations is the most frequent adult leukoencephalopathy in our cohort. Moreover, brain imaging analysis indicates that CADASIL patients who do not present typical phenotypes may be underdiagnosed if not examined genetically.