Prediction of 3-year clinical course in CADASIL

International audience; Objective: To obtain simple models predicting disease evolution at 3 years for a given patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Methods: Based on data obtained in a prospective study of 236 patients, we built and validated models predicting, at the individual level, 3-year changes in Mini-Mental State Examination (MMSE), Mattis Dementia Rating Scale (MDRS), Trail Making Test version B (TMTB), and modified Rankin Scale (mRS). These models were based on different sets of predictors obtained at base-line, including either clinical data (epidemiologic data and cardiovascular risk factors) or clinical data and quantitative MRI markers (volume of lacunes [LL$_V$ ], volume of white matter hyperinten-sities, normalized brain volume [BPF], number of microbleeds). The Bayesian information criterion (BIC) and the coefficient of determination (R$^2$) were used to determine models with the highest predictive ability and the lowest numbers of predictors. Results: We obtained validated models with a demonstrated ability to predict, for a given patient, 3-year changes in MMSE, MDRS, TMTB, and mRS (R$^2$ on independent samples: 0.22, 0.12, 0.09, and 0.17, respectively). In all cases, the best models according to R$^2$ and BIC values included only the baseline values of the outcome, of BPF, and of LL V. Inclusion of other potential predictors always led to a loss of generalizability. Conclusions: The prediction of 3-year changes in MMSE, MDRS, TMTB, and mRS for a given patient with CADASIL can be obtained using simple models relying only on the initial values of the considered score, BPF, and LL$_V$. GLOSSARY BIC Bayesian Information Criterion; BPF 5 brain parenchymal fraction; CADASIL 5 cerebral autosomal dominant arterio-pathy with subcortical infarcts and leukoencephalopathy; CI 5 confidence interval; LLV 5 volume of lacunes; MBN 5 number of microbleeds; MDRS 5 Mattis Dementia Rating Scale; MMSE 5 Mini-Mental State Examination; mRS 5 modified Rankin Scale; MSPE 5 mean squared prediction error; SVD 5 small vessel disease; TMTB 5 Trail Making Test part B; WMHV 5 white matter hyperintensities of presumed vascular origin. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most frequent hereditary cerebral small vessel disease (SVD), caused by mutations of the NOTCH3 gene. In CADASIL, the clinical course appears highly variable. Some patients develop dementia and become heavily disabled around their 50s while others live independently during their 80s. Age, male sex, active smoking, brain atrophy, and volume of lacunes are associated with clinical severity and with further clinical worsening, while associations between other factors, such as blood pressure, number of microbleeds, or volume of white matter hyperintensities, and clinical severity have been inconsistently observed. Among all these factors, those that actually predict disease evolution for a given patient remain undetermined. Identifying such factors would be useful for patient care and for selection of homogeneous samples in clinical trials.