Neuropsychiatric symptoms associated with cerebral small vessel disease: a systematic review and meta-analysis

Cerebral small vessel disease, a common cause of vascular dementia, is often considered clinically silent before dementia or stroke become apparent. However, some individuals have subtle symptoms associated with acute MRI lesions. We aimed to determine whether neuropsychiatric and cognitive symptoms vary according to small vessel disease burden.

In this systematic review and meta-analysis, we searched MEDLINE, EMBASE, and PsycINFO for articles published in any language from database inception to Jan 24, 2020. We searched for studies assessing anxiety, apathy, delirium, emotional lability, fatigue, personality change, psychosis, dementia-related behavioural symptoms or cognitive symptoms (including subjective memory complaints), and radiological features of cerebral small vessel disease. We extracted reported odds ratios (OR), standardised mean differences (SMD), and correlations, stratified outcomes by disease severity or symptom presence or absence, and pooled data using random-effects meta-analyses, reporting adjusted findings when possible. We assessed the bias on included studies using the Risk of Bias for Non-randomized Studies tool. This study is registered with PROSPERO, CRD42018096673.

Of 7119 papers identified, 81 studies including 79 cohorts in total were eligible for inclusion (n=21 730 participants, mean age 69·2 years). Of these 81 studies, 45 (8120 participants) reported effect estimates. We found associations between worse white matter hyperintensity (WMH) severity and apathy (OR 1·41, 95% CI 1·05-1·89) and the adjusted SMD in apathy score between WMH severities was 0·38 (95% CI 0·15-0·61). Worse WMH severity was also associated with delirium (adjusted OR 2·9, 95% CI 1·12-7·55) and fatigue (unadjusted OR 1·63, 95% CI 1·20-2·22). WMHs were not consistently associated with subjective memory complaints (OR 1·34, 95% CI 0·61-2·94) and unadjusted SMD for WMH severity between these groups was 0·08 (95% CI -0·31 to 0·47). Anxiety, dementia-related behaviours, emotional lability, and psychosis were too varied or sparse for meta-analysis; these factors were reviewed narratively. Overall heterogeneity varied from 0% to 79%. Only five studies had a low risk of bias across all domains.

Apathy, fatigue, and delirium associated independently with worse WMH, whereas subjective cognitive complaints did not. The association of anxiety, dementia-related behaviours, emotional lability, and psychosis with cerebral small vessel disease require further investigation. These symptoms should be assessed longitudinally to improve early clinical detection of small vessel disease and enable prevention trials to happen early in the disease course, long before cognition declines.

Chief Scientist Office of the Scottish Government, UK Dementia Research Institute, Fondation Leducq, Stroke Association Garfield-Weston Foundation, Alzheimer's Society, and National Health Service Research Scotland.