Nonfocal symptoms of cerebral small vessel disease

Cerebral small vessel disease (SVD) is highly prevalent in the general population, increases with advancing age, and is a common cause of stroke and dementia. SVD affects multiple clinical domains and manifests on neuroimaging primarily as white matter hyperintensities (WMH), subcortical infarcts, lacunes, perivascular spaces, and microbleeds. Apart from stroke and dementia, SVD was previously thought to be clinically 'silent' but it is becoming apparent from cross-sectional studies that SVD is accompanied by neuropsychiatric, cognitive, and gait symptoms that do not meet the current clinical lexicon for stroke or dementia. Identifying earlier clinical markers of brain damage is essential for identifying patients for SVD treatment trials. We aimed to track and characterise whether subtle nonfocal symptoms are longitudinally associated with SVD lesion progression on brain MRI. We conducted a literature review of all SVD clinical features and a systematic review and meta-analysis of SVD-associated neuropsychiatric and cognitive features. We recruited patients with recent non-disabling ischaemic stroke, performed diagnostic MRI, and questioned participants and informants about neuropsychiatric, cognitive and gait symptoms. We repeated MRI and subjective symptom assessments at 3-6 monthly intervals for 12 months, longitudinally assessing WMH volume change and incident infarcts. We also analysed combined functional and cognitive associations with SVD progression in a separate stroke population. Finally, we assessed neuropsychiatric symptom-lesion associations in cognitively impaired and older adult populations. In our systematic review and meta-analysis, we found small but important associations between SVD severity and apathy, fatigue, and delirium, but not with subjective memory complaints, while anxiety and other neuropsychiatric symptoms were inconclusive. In 203 patients followed up for one year after a stroke (55% lacunar/45% cortical), we found that incident infarcts occur in 20% of patients, are mostly subcortical, co-associate with depression and brain fog, and there were trends towards associations with fatigue, falls, unsteadiness, episodes of confusion, and informant-reported cognitive and functional decline. We identified that that worse baseline WMH are associated with falls, apathy and brain fog, worse six-month WMH with falls and unsteadiness, and worse 12-month WMH with a trend towards falls. We found that longitudinal WMH progression is associated with falls and brain fog, with trends towards associations with worsening informant-reported neuropsychiatric symptoms and subjective memory complaints. In 264 separate stroke patients, we identified that one-year, but not baseline, WMH volumes associate strongly with contemporaneous cognitive scores, and co-varying longitudinal worsening of cognition and function post-stroke is associated with increasing WMH volumes. We found that worsening neuropsychiatric symptoms are associated with WMH progression in a cognitively impaired population. We established that in an older population, apathy independently associates with longitudinal WMH progression, while depression, anxiety, and subjective memory complaints do not. Overall, these findings highlight the existence of a potential clinical syndrome for identifying future SVD progression in high-risk patients. SVD progression is dynamic and can progress rapidly. These results support a need to clarify the prevalence of the SVD syndrome in the general population and to develop clinical prediction models to guide whether treatments could be trialled in individuals who are at high risk for SVD progression.