White matters - The influence of cerebral small-vessel disease on depression, cognition and functioning

Depression and cognitive impairment are highly prevalent in later life, and frequently co-occur. One of the possible mechanisms that may underlie both conditions is the presence of cerebral small-vessel disease. The presence of cerebral small-vessel disease is strongly associated with common vascular risk factors, and is characterized by white matter lesions and lacunar infarcts on brain MRI. The 'vascular depression' hypothesis proposes that disruption of emotion-regulating frontal-subcortical pathways is an underlying mechanism by which cerebral small-vessel disease may precipitate or predispose to late-life depression. In this thesis, we investigated the influence of cerebral small-vessel disease on MRI on depressive symptoms, cognitive performance and self-rated functioning in patients with atherosclerotic disease. Our major findings were that: 1) Poorer self-rated functioning is an independent risk factor for mortality in patients with atherosclerotic disease, and patients with lacunar infarcts are particularly vulnerable for the adverse effect of poorer self-rated mental functioning on mortality; 2) The influence of white matter lesions, infarcts and atrophy on depressive symptoms and cognitive performance depends on lesion location rather than on lesion severity. We found that subcortical infarcts in deep white matter tracts were associated with depressive symptoms, poorer executive functioning and memory. Periventricular white matter lesions, cortical infarcts and atrophy were associated with poorer executive functioning and slowed processing speed, but not with depressive symptoms; 3) The depressive symptoms associated with cerebral small-vessel disease in frontal and deep white matter tracts are primarily characterized by motivational problems and not by mood problems; 4) The motivational problems associated with cerebral small-vessel disease are also present in patients without major depression, suggesting that these may be expressions of 'vascular apathy' rather than 'vascular depression'; 5) In persons without dementia, apathy is related to both cerebral small-vessel disease and neurodegeneration, and may therefore also be an early manifestation of cognitive decline