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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 −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— 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.

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 P 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.

Background and Purpose— Recently, in a mouse model of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy, a monogenic cerebral small vessel disease, intramyelinic edema was detected in the white matter (WM) early during the course of the disease. We hypothesized that if this mechanism holds true in patients, it would translate in larger WM volume. We aimed to measure WM volume in patients with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy in comparison with age- and sex-matched controls, along with the ratio of cortical surface area to the volume of brain hemispheres as an indirect measure that should be reduced in patients. Methods— Twenty patients at the early stage of the disease (Mini Mental State Examination >24 and modified Rankin scale ≤1) and 27 age- and sex-matched controls had high-quality 3-Tesla 3DT1 MRI acquisitions. Volumes of brain hemispheres and of WM were determined. The ratio of cortical surface area to the volume of brain hemispheres was evaluated as a proxy of underlying WM volume. Results— Patients had larger volumes of WM than controls (patients: 479.4±71.7; controls: 463.9±44.2; P =0.03). They presented a lower cortical surface area and cortical volume leading to a lower ratio of cortical surface area to the volume of brain hemispheres (patients: 15.7±0.7; controls: 16.1±0.5; P =0.004). Volume of WM tended to be associated with that of WM hyperintensities ( P =0.06). Conclusions— Patients with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy have larger WM volume than age- and sex-matched controls, a finding compatible with the hypothesis of intramyelinic edema as observed recently in mice.

Background and Purpose— Previous pathological studies in humans or in animal models have shown alterations of small arteries and veins within white matter lesions in cerebral small vessel disease. We aimed to evaluate in vivo, the integrity of the cerebral venous network using high-resolution MRI both within and outside white matter hyperintensities in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Methods— High-resolution T 2 *-weighted images were obtained at 7-T in 13 CADASIL patients with no or only mild symptoms and 13 age- and sex-matched controls. Macroscopic veins were automatically counted in the centrum semiovale and compared between patients and controls. In addition, T 2 * was compared between groups in the normal-appearing white matter. Results— Vein density was found lower in CADASIL patients compared with that in controls (−14.6% in patients, P 2 *, that is presumably inversely related to the venous density, was also found increased in normal-appearing white matter of patients (+7.2%, P =0.006). All results were independent from the extent of white matter hyperintensities. Conclusions— A significant reduction in the number of visible veins was observed in the centrum semiovale of CADASIL patients both within and outside white matter hyperintensities, together with an increase of T 2 * in the normal-appearing white matter. Additional studies are needed to decipher the exact implication of such vasculature changes in the appearance of white matter lesions.