Lacunar lesions are independently associated with disability and cognitive impairment in CADASIL

Viswanathan, Anand; Gschwendtner, Andreas; Guichard, Jean‐Pierre; Buffon, Frédérique; Cumurciuc, R.; O’Sullivan, Michael; Holtmannspötter, Markus; Pachaï, Chahin; Bousser, Marie Germaine; Dichgans, Martin; Chabriat, Hugues

doi:10.1212/01.wnl.0000265221.05610.70

Cited by 130 publications

(107 citation statements)

References 42 publications

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“…These results are in line with previous cross-sectional data that found the number of lacunes and cerebral atrophy to be the 2 main MRI markers associated with clinical severity in CADASIL. 16,20 Our findings extend previous studies by showing that the same imaging parameters also predict future clinical worsening and can thus be considered markers of active disease. Microbleeds whose clinical value remains debated in sporadic SVD 21 showed some predictive capacity in model 2 but not in the full model, suggesting that these lesions are probably less relevant for clinical risk prediction.…”

Section: Discussionsupporting

confidence: 86%

Predictors of Clinical Worsening in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Chabriat

Hervé

Duering

et al. 2016

Stroke

103

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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. The clinical and imaging characteristics of CADASIL much resemble those of the most severe forms of sporadic SVD. We, thus, reasoned that information derived from a longitudinal study in CADASIL might offer insights relevant to SVD in general. Here, we report the final results of this study obtained in a large cohort of patients followed up for 3 years. Conclusions-Clinical Methods Study CohortSubjects were prospectively recruited between September 2003 and April 2011 through 2 major referral centers for CADASIL (University Hospital Lariboisière, Paris [n=178] and Ludwig Maximilians Universität, Munich [n=112]). They were included regardless of whether they had clinical manifestations of the disease if they were at least 18 years of age, had a documented mutation in the NOTCH3 gene, and were willing to be followed up. Details of the study protocol have been reported elsewhere.11 A follow-up interval of 3 years was chosen based on previous longitudinal data showing that significant changes in clinical scores can be detected within an interval of 2 years 8 when following up patients seen at major referral centers and to obtain a sufficient number of clinical events. In brief, clinical and demographic data were collected at study entry and included age, sex, years of education, and vascular risk factors (hypertension, diabetes mellitus, hypercholesteremia, smoking, and alcohol use). Blood pressure was measured at baseline and at follow-up.A history of transient ischemic attack...

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Section: Discussionsupporting

confidence: 86%

Predictors of Clinical Worsening in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Chabriat

Hervé

Duering

et al. 2016

Stroke

103

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“…6,7 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.…”

Section: Discussionmentioning

confidence: 99%

“…2 Age, male sex, active smoking, brain atrophy, and volume of lacunes are associated with clinical severity and with further clinical worsening, [3][4][5] 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. 6,7 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.…”

mentioning

confidence: 99%

Prediction of 3-year clinical course in CADASIL

et al. 2016

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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 baseline, 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 hyperintensities, 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 . Neurology ® 2016;87:1787-1795 GLOSSARY BIC 5 Bayesian Information Criterion; BPF 5 brain parenchymal fraction; CADASIL 5 cerebral autosomal dominant arteriopathy 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.1 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.2 Age, male sex, active smoking, brain atrophy, and volume of lacunes are associated with clinical severity and with further clinical worsening, 3-5 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. 6,7 Among all these factors, those that actually predict disease evolution for a given patient...

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“…The most consistently found predictor is age 39,95,96 . The severity of MRI structural changes, extensively evaluated in volumetric, regional blood volume and anisotropy (diffusion tensor imaging) studies is also correlated to cognitive changes.…”

Section: Cognitive Decline and Dementiamentioning

confidence: 97%

“…The severity of MRI structural changes, extensively evaluated in volumetric, regional blood volume and anisotropy (diffusion tensor imaging) studies is also correlated to cognitive changes. Specifically, variables such as the specific location of white matter lesions (eg the cingulate pathway and frontal regions), the number and total volume of ischemic lesions, the degree of diffuse cortical atrophy or the presence of atrophy in specific areas such as hippocampus and thalamus, correlate (with marked variations between studies) to the evolution of cognitive impairment and progression of secondary functional limitations [95][96][97][98][99][100] . The extension of white matter lesions per se and the presence and extent of microhemorrhages exhibit lower correlation with cognitive disorders.…”

Section: Cognitive Decline and Dementiamentioning

confidence: 99%

CADASIL: pathogenesis, clinical and radiological findings and treatment

André

2010

Arq. Neuro-Psiquiatr.

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common genetic cause of ischemic strokes and a most important model for the study of subcortical vascular dementia. This unrelentlessly progressive disease affects many hundreds of families all over the world but is not well studied in Brazil. This manuscript reviews pathogenetic, clinical, radiological and therapeutic features of CADASIL. The causal mutations are now very well known, but the same can not be said about its intimate pathogenetic mechanisms. The variable clinical presentation should lead physicians to actively pursue the diagnosis in many settings and to more thouroughly investigate family history in first degree relatives. A rational approach to genetic testing is however needed. Treatment of CADASIL is still largely empiric. Highquality therapeutic studies involving medications and cognitive interventions are strongly needed in CADASIL. Key words: CADASIL, etiology, genetics, diagnosis, therapeutics.cADAsIL: patogênese, achados clínicos e radiológicos e tratamento resumo CADASIL é a causa genética mais freqüente de infartos cerebrais e constitui modelo importante de estudo de demências vasculares subcorticais. De natureza inexoravelmente progressiva, afeta milhares de pessoas em todo o mundo. Sua importância é pouco reconhecida entre nós, o que nos levou à presente revisão dos principais aspectos patogenéticos, clínicos, neuroradiológicos e terapêuticos da doença. As mutações causais são hoje bem conhecidas, mas os mecanismos patogenéticos íntimos ainda permanecem misteriosos. A apresentação clínica variável deve fazer com que os médicos considerem o diagnóstico em vários contextos clínicos e investiguem de forma mais extensa que o usual a história familial deparentes de primeiro grau. Além disso, uma abordagem racional é necessária para reduzir custos e aumentar a eficiência do diagnóstico genético. O tratamento atual de pacientes com CADASIL é basicamente empírico. Estudos clínicos sobre medicamentos e intervenções cognitivas de alto nível metodológico constituem uma necessidade urgente.

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Lacunar lesions are independently associated with disability and cognitive impairment in CADASIL

Cited by 130 publications

References 42 publications

Predictors of Clinical Worsening in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Predictors of Clinical Worsening in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Prediction of 3-year clinical course in CADASIL

CADASIL: pathogenesis, clinical and radiological findings and treatment

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