Prevalence of Fatigue and associations with Depression and Cognitive Impairment in patients with CADASIL

Background and Objective Fatigue is a common and disabling symptoms in cerebrovascular disease, and has been associated with white matter damage, but the underlying disease mechanisms are poorly understood. CADASIL is the most common genetic form of stroke and causes a cerebral small vessel disease (SVD) arteriopathy with white matter ischaemia. We determined the prevalence of fatigue in CADASIL, the factors associated with it, and its relationship to both depression and cognitive impairment. Methods Prospectively recruited genetically confirmed CADASIL patients were assessed on the Fatigue Severity Scale (FSS). The prevalence of fatigue in CADASIL was compared with that of healthy controls from the community. We determined associations between fatigue and: clinical features, cardiovascular risk factors, MRI parameters, cognition, and depression. Cognition was measured using the Brief Memory and Executive Test (BMET) and depression using the Geriatric Depression Scale (GDS). Mediation and path analysis was performed to determine relationships between fatigue, depression and cognitive impairment. Results 174 CADASIL patients (mean age (SD) of 51.3 (12.30), 59.66% female) and 50 healthy controls were included in the analysis (mean age (SD) of 51.42 (12.58), 38.0% female). Fatigue was present in 51.7% of CADASIL patients and was almost 5 times more common than in controls (OR: 4.99, 95% CI [2.28, 10.95], p<0.001). There was no association of fatigue with history of stroke or MRI parameters including white matter hyperintensity lesion volume. Logistic regression showed both total GDS score (OR: 1.11, [1.05, 1.17], p=0.0002) and total BMET score (OR: 0.86, [0.75, 0.98], p=0.02) to be predictors of fatigue. Fatigue, depression and cognition were frequently comorbid. Mediation analysis showed depression to have a greater effect on fatigue prevalence than cognitive impairment. Path analysis confirmed depression to be the largest predictor of fatigue and found this relationship to be bi-directional. Discussion Fatigue is present in over half of CADASIL patients. Depression and cognition were the main predictors of fatigue, and all three symptoms were frequently comorbid. The relationship between depression and fatigue was the strongest and was bi-directional. This suggests targeting depressive symptoms may have benefit in fatigue management.