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.

Modeling the Cognitive Trajectory in CADASIL.

BACKGROUND: For developing future clinical trials in Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), it seems crucial to study the long-term changes of cognition. OBJECTIVE: We aimed to study the global trajectory of cognition, measured by the Mini-Mental State Examination (MMSE) and the Mattis Dementia Rating Scale (MDRS), along the course of CADASIL. METHODS: Follow-up data of 185 CADASIL patients, investigated at the French National Referral center CERVCO from 2003, were considered for analysis based on strict inclusion criteria. Assuming that the MMSE and the MDRS provide imprecise measures of cognition, the trajectory of a common cognitive latent process during follow-up was delineated using a multivariate latent process mixed model. After adjustment of this model for sex and education, the sensitivities of the two scales to cognitive change were compared. RESULTS: Analysis of the cognitive trajectory over a time frame of 60 years of age showed a decrease of performances with aging, especially after age of 50 years. This decline was not altered by sex or education but patients who graduated from high school had a higher mean cognitive level at baseline. The sensitivities of MMSE and MDRS scales were similar and the two scales suffered from a ceiling effect and curvilinearity. CONCLUSION: These data support that cognitive decline is not linear and mainly occurs after the age of 50 years during the course of CADASIL. They also showed that MMSE and MDRS scales are hampered by major limitations for longitudinal studies.

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.