Phenotypic variability in 446 CADASIL patients: Impact of NOTCH3 gene mutation location in addition to the effects of age, sex and vascular risk factors.

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.

Trajectory Pattern of Cognitive Decline in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

BACKGROUND AND OBJECTIVE: The course and pattern of cognitive decline in ischemic cerebral small vessel disease (cSVD) remains poorly characterized. We analysed the trajectory pattern of cognitive decline from age 25 to 75 years in CADASIL. METHODS: We applied latent process mixed models to data obtained from CADASIL patients who were repeatedly scored during follow-up using 16 selected clinical scales or cognitive tests. RESULTS: The modelled evolutions of these scores obtained from 1243 observations in 265 patients recruited at the French National Referral Centre (50.1 years on average and 45.3% males) showed wide and heterogeneous variations in amplitude along the age-related progression of the disease. While 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. In 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, 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 form 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, 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.

Vanishing White Matter Hyperintensities in CADASIL: A Case Report with Insight into Disease Mechanisms.

In a woman with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) followed for 15 years, we observed magnetic resonance imaging white matter hyperintensities that vanished in the anterior temporal poles while the brain volume decreased unexpectedly. These imaging changes were transient and detected when the patient was being treated by valproic acid for stabilizing mood disturbances. This intriguing case supports that mechanisms underlying white matter hyperintensities can vary from one brain area to another and that important modifications of water influx into the brain tissue might be involved in some imaging features of CADASIL.

Predictors of Clinical Worsening in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: Prospective Cohort Study.

BACKGROUND AND PURPOSE: Predictors of clinical worsening in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy remain unknown. This study aims to identify demographic, clinical, and magnetic resonance imaging predictors of incident strokes, incident dementia, clinical deterioration, and death in patients with this genetically proven disease. METHODS: Two hundred ninety subjects (mean age, 50.6±11.4 years) were assessed at baseline and followed up for 36 months. Incident clinical events were recorded, and clinical scores included the Mini Mental State Examination, Mattis Dementia Rating Scale, modified Rankin Scale, and Barthel index. The number of lacunes and microbleeds, the volume of white-matter hyperintensities, and brain parenchymal fraction were assessed on baseline magnetic resonance imaging. Data were analyzed by ANCOVA, multivariable logistic regression, and Cox proportional hazard models. RESULTS: Incident stroke occurred in 55 of 278 patients (19.8%). Moderate or severe disability developed in 19 of 210 (9%) nondisabled individuals, incident dementia in 49 of 231 (20%) nondemented subjects, and 4.8% of patients died. Active smoking, the number of lacunes, and brain parenchymal fraction independently predicted incident stroke during follow-up. Gait disturbance, dementia, and brain parenchymal fraction predicted progression toward moderate or severe disability. Active smoking, disability, and brain parenchymal fraction predicted incident dementia. Age was the only significant predictor of death. CONCLUSIONS: Clinical assessment and brain magnetic resonance imaging aid in predicting incident clinical events and clinical deterioration in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. There is a bidirectional relationship between dementia and moderate or severe disability in predicting each other's onset. Active smoking is a modifiable risk factor associated with clinical progression in Notch3 mutation carriers.

Prevalence and characteristics of migraine in CADASIL.

Background and objective Migraine with aura (MA) is a major symptom of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We assessed the spectrum of migraine symptoms and their potential correlates in a large prospective cohort of CADASIL individuals. Methods A standardized questionnaire was used in 378 CADASIL patients for assessing headache symptoms, trigger factors, age at first attack, frequency of attacks and associated symptoms. MRI lesions and brain atrophy were quantified. Results A total of 54.5% of individuals had a history of migraine, mostly MA in 84% of them; 62.4% of individuals with MA were women and age at onset of MA was lower in women than in men. Atypical aura symptoms were experienced by 59.3% of individuals with MA, and for 19.7% of patients with MA the aura was never accompanied by headache. MA was the inaugural manifestation in 41% of symptomatic patients and an isolated symptom in 12.1% of individuals. Slightly higher MMSE and MDRS scores and lower Rankin score were detected in the MA group. Conclusion MA is observed in almost half of all CADASIL patients. Atypical aura symptoms are reported by more than one in two of them. MA is often inaugural, can remain isolated and is not associated with the severity of the disorder.

A novel hereditary extensive vascular leukoencephalopathy mapping to chromosome 20q13.

OBJECTIVE: The detection of a leukoencephalopathy is a frequent situation in neurologic practice. In a number of cases, the etiology remains obscure despite extensive investigations. We characterized the clinical, pathologic, and genetic features of a novel hereditary vascular leukoencephalopathy. METHODS: After the observation of a similar leukoencephalopathy in 2 sisters, clinical, neuroimaging, and molecular genetics investigations were conducted in 21 of their consenting relatives. Pathologic data were obtained in one patient. RESULTS: Fourteen members presented with significant white matter lesions at MRI examination, among whom only 5 individuals were symptomatic. The main clinical manifestations included gait disturbances, transient movement disorders, stroke, and cognitive dysfunction. The 9 remaining members aged from 26 to 60 years were asymptomatic. The MRI pattern was highly stereotyped with symmetric white matter hyperintensities worsening with patient's age. We mapped the gene involved in this condition on chromosome 20q13. Neuropathologic examination suggested that this leukoencephalopathy is underlaid by a cerebral arteriolopathy affecting small preterminal arterioles, clearly distinct from amyloid angiopathy and hypertension-related small-vessel disease. CONCLUSIONS: These data establish that this family is affected by a novel autosomal dominant vascular leukoencephalopathy mapping to chromosome 20q13. This disease is characterized by a progressive and age-related hemispheric and brainstem leukoencephalopathy contrasting with the paucity and late onset of clinical symptoms in most of the cases.

Effects of gender on the phenotype of CADASIL.

BACKGROUND AND PURPOSE: In the general population, migraine, cerebrovascular diseases, and vascular dementia differ in many aspects between men and women. CADASIL is considered a unique model to investigate migraine with aura, stroke, and dementia related to ischemic small vessel disease. This study aims to evaluate the effect of gender on the main clinical and neuroimaging characteristics of CADASIL. METHODS: Cross-sectional data from 313 CADASIL patients including various clinical and cognitive scores and MRI parameters were compared between men and women, and between those younger and older than the median age of the population corresponding to the usual age of menopause (51 years). RESULTS: At younger than 51 years, migraine with aura was 50% more prevalent in women and stroke was 75% more prevalent in men. After the fifth decade, men had higher National Institutes of Health Stroke Scale and Rankin scores than women and more severe executive dysfunction, although global cognitive scores were similar. Age at first stroke, the number of stroke events, and the prevalence of dementia and psychiatric symptoms did not differ between men and women. Brain volume was lower in men with a trend for a larger volume of lacunar infarcts. CONCLUSIONS: In CADASIL, migraine with aura is more frequent in women and stroke is more frequent in men before the age of menopause. This difference seems to vanish after this age limit but may result in a higher degree of cognitive impairment and cerebral atrophy in men at the late stage of the disease. The presumable role of ovarian hormones in these gender-related differences remains to be explored.