Jessica Lebenberg

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small-vessel disease. The CADASIL MRI Inventory Tool summarizes individual MRI findings as simple, type-specific lesion levels. We assessed the predictive value of these levels beyond clinical information. METHODS: At baseline, CADASIL MRI Inventory Tool levels were assigned for periventricular, deep, and superficial white matter hyperintensities, lacunes, cerebral microbleeds, perivascular spaces in the centrum semiovale and basal ganglia, superficial and deep atrophy, large infarcts, and macrobleeds. Outcomes included stroke, migraine with aura (MA), moderate or severe cognitive impairment, and disability, which were assessed at baseline and during 2-year follow-up. Multivariable logistic regression was performed, with adjustment for age, sex, vascular risk factors, mutation location, and education level. RESULTS: We analyzed 743 patients from France, Germany, and Taiwan (mean age, 53±12; 55% with prior stroke; 35% with MA; 15% with disability; 18% with cognitive impairment). At baseline, higher deep white matter hyperintensities and lacune levels were associated with stroke, whereas cerebral microbleeds and superficial atrophy were inversely associated with MA. Superficial atrophy and periventricular white matter hyperintensities were higher, and superficial white matter hyperintensities were lower, among those with cognitive impairment, whereas deep atrophy and lacunes were linked to disability. Over 2 years (n=547), 11.7% experienced ischemic stroke events, 22.2% MA attacks, 6.5% developed disability, and 6.9% moderate or severe cognitive impairment. After adjustment, lacune levels independently predicted ischemic stroke events (odds ratio, 6.10 [95% CI, 2.09–26.02] for all levels combined). Superficial atrophy and higher superficial white matter hyperintensities predicted a lower risk of MA (odds ratio, 0.29 and 0.21 [95% CI, 0.12–0.68] and [0.06–0.77]). Lacunes and deep atrophy predicted disability, and lacunes with superficial atrophy predicted cognitive impairment. CONCLUSIONS: CADASIL MRI Inventory Tool lesion levels are differentially associated with CADASIL manifestations and provide independent 2-year prognostic information beyond clinical covariates. These simple measures may supplement clinical evaluation to improve short-term risk stratification and support patient selection in clinical trials.

A major hurdle to therapeutic development in cerebral small vessel diseases is the lack of in-vivo method that can be used repeatedly for evaluating directly cerebral microvessels. We hypothesised that Adaptive Optics (AO), which allows resolution images up to 1–2 μm/pixel at retinal level, could provide a biomarker for monitoring vascular changes in CADASIL, a genetic form of such condition. In 98 patients and 35 healthy individuals, the wall to lumen ratio (WLR), outer and inner diameter, wall thickness and wall cross-sectional area were measured in a parapapillary and/or paramacular retinal artery. The ratio of vessel diameters before and after light flicker stimulations was also calculated to measure vasoreactivity (VR). Multivariate mixed-model analysis showed that WLR was increased and associated with a larger wall thickness and smaller internal diameter of retinal arteries in patients. The difference was maximal at the youngest age and gradually reduced with aging. Average VR in patients was less than half of that of controls since the youngest age. Any robust association was found with clinical or imaging manifestations of the disease. Thus, AO enables the detection of early functional or structural vascular alterations in CADASIL but with no obvious link to the clinical or imaging severity.

Background: In CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy), clinical severity is not related to the total burden of white matter hyperintensities (WMHs), presumably because of heterogeneous underlying tissue alterations. We aimed to investigate whether WMHs in the corpus callosum (WMH _CC ) are due to secondary degeneration and related to clinical severity. Methods: We evaluated data from 228 CADASIL patients included in an ongoing prospective cohort with available 3-dimensional fluid-attenuated inversion recovery magnetic resonance imaging sequences. We analyzed in a blind manner WMH _CC and lacunes in presumably connected areas to determine whether WMH _CC are related to secondary degeneration. We evaluated the links between WMH _CC and the Mattis dementia rating scale and the modified Rankin Scale—widely used measures of global cognitive performances and disability, respectively. Linear regression models were adjusted for age, sex, level of education, brain volume, number of lacunes, and volume of WMH. Results: Among 228 patients, only 105 (46%) had WMH _CC while all had WMH in the rest of the white matter. In 74% of cases, WMH _CC crossed a presumably connected nearby lacune, which was significantly higher than the expected value if the spatial distributions of WMH _CC and nearby lacunes were unrelated (11%; P CC had worse Mattis dementia rating scale (median [P25–P75], 138 [122–142] versus 143 [140–143]; P P CC (estimate, −6.2 [95% CI, −11.8 to −0.1]). Conclusions: In CADASIL, WMH _CC are likely related to secondary degeneration and are independently related to clinical severity, in contrast to the total burden of WMH.

The recent discovery that the prevalence of cysteine mutations in the NOTCH3 gene responsible for CADASIL was more than 100 times higher in the general population than that estimated in patients highlighted that the mutation location in EGFr-like-domains of the NOTCH3 receptor could have a major effect on the phenotype of the disease. The exact impact of such mutations locations on the multiple facets of the disease has not been fully evaluated. We aimed to describe the phenotypic spectrum of a large population of CADASIL patients and to investigate how this mutation location influenced various clinical and imaging features of the disease. Both a supervised and a non-supervised approach were used for analysis. The results confirmed that the mutation location is strongly related to clinical severity and showed that this effect is mainly driven by a different development of the most damaging ischemic tissue lesions at cerebral level. These effects were detected in addition to those of aging, male sex, hypertension and hypercholesterolemia. The exact mechanisms relating the location of mutations along the NOTCH3 receptor, the amount or properties of the resulting NOTCH3 products accumulating in the vessel wall, and their final consequences at cerebral level remain to be determined.

BACKGROUND AND PURPOSE: By studying the evolution of brain volume across the life span in male and female patients, we aimed to understand how sex, brain volume, and the epidermal growth factor repeat domain of the mutation, the 3 major determinants of disability in CADASIL, interact in driving disease evolution. MATERIALS AND METHODS: We used validated methods to model the evolution of normalized brain volume with age in male and female patients using nonparametric regression in a large, monocentric cohort with prospectively collected clinical and high-resolution MR imaging data. We used k-means clustering to test for the presence of different clinical course profiles. RESULTS: We included 229 patients (mean age, 53 [SD, 12] years; 130 women). Brain volume was larger in women (mean size, 1024 [SD, 62] cm³ versus 979 [SD, 50] cm³; P < .001) and decreased regularly. In men, the relationship between brain volume and age unexpectedly suggested an increase in brain volume around midlife. Cluster analyses showed that this finding was related to the presence of a group of older male patients with milder symptoms and larger brain volumes, similar to findings of age-matched women. This group did not show specific epidermal growth factor repeat domain distribution. CONCLUSIONS: Our results demonstrate a detrimental effect of male sex on brain volume throughout life in CADASIL. We identified a subgroup of male patients whose brain volume and clinical outcomes were similar to those of age-matched women. They did not have a specific distribution of the epidermal growth factor repeat domain, suggesting that yet-unidentified predictors may interact with sex and brain volume in driving disease evolution.