Fatigue in Cerebral Small Vessel Disease and its Relationship to Cognitive Behavioural Symptoms
Introduction Cerebral Small Vessel Disease (SVD) is a disease affecting the small blood vessels in the brain. SVD is a leading cause of both stroke and vascular dementia, whilst cognitive behavioural symptoms such as fatigue are also frequent. Fatigue has a major impact on quality of life, yet little is known about its pathogenesis. This thesis aimed to assess the prevalence of, and possible mechanisms driving, fatigue whilst also assessing the role of other cognitive behavioural symptoms. Methods Both monogenic SVD (*n*=251) and sporadic (*n*=36) SVD cohorts were utilised. Neuroimaging features and inflammation (both central nervous system (CNS) as assessed by 11C-PK11195 PET and peripheral as assessed by circulating blood biomarkers) were investigated as possible mechanisms associated with fatigue, before moving on to assess the role of cognitive behavioural symptoms in the prevalence and severity of fatigue. Results Fatigue was present in around half of both the sporadic SVD and CADASIL groups. There were no clear associations between neuroimaging features and fatigue, although meta-analysis highlighted some preliminary associations with network disconnection. There was no association between fatigue and CNS inflammation as measured using 11C-PK11195 PET. There was an association of elevated C-reactive protein, a marker of systemic inflammation, with some fatigue measures in the sporadic SVD cohort, however, there was no association with a wide variety of blood biomarkers on the Olink panel after adjustment for multiple comparisons. The strongest finding throughout was the association of fatigue prevalence with both depression and cognitive impairment, in both sporadic SVD and CADASIL cohorts. Cognitive behavioural symptoms did manifest alone but were frequently comorbid. Pathanalysis confirmed that these symptoms seemed to exacerbate both presence and severity of one another. This was most prominently seen for fatigue and depression. Conclusion Fatigue was prominent in both sporadic SVD and CADASIL cohorts. This thesis helps to further the research surrounding fatigue, a symptom which is poorly understood, and inform where future research may be best placed. Although there were no clear associations with neuroimaging or CNS inflammation seen in the projects, two areas that may show promise include network analysis and systemic inflammation. Further, the role of cognitive behavioural symptoms in the prevalence of fatigue cannot be understated and requires more research to disentangle their comorbid nature.
CADASIL, Cerebral Small Vessel Disease, Depression, Fatigue, Stroke, Vascular Cognitive Impairment
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