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Global cerebral hypoperfusion may be involved in the aetiology of brain atrophy; however, long-term longitudinal studies on this relationship are lacking. We examined whether reduced cerebral blood flow was associated with greater progression of brain atrophy. Data of 1165 patients (61 ± 10 years) from the SMART-MR study, a prospective cohort study of patients with arterial disease, were used of whom 689 participated after 4 years and 297 again after 12 years. Attrition was substantial. Total brain volume and total cerebral blood flow were obtained from magnetic resonance imaging scans and expressed as brain parenchymal fraction (BPF) and parenchymal cerebral blood flow (pCBF). Mean decrease in BPF per year was 0.22% total intracranial volume (95% CI: –0.23 to –0.21). Mean decrease in pCBF per year was 0.24 ml/min per 100 ml brain volume (95% CI: –0.29 to –0.20). Using linear mixed models, lower pCBF at baseline was associated with a greater decrease in BPF over time ( p = 0.01). Lower baseline BPF, however, was not associated with a greater decrease in pCBF ( p = 0.43). These findings indicate that reduced cerebral blood flow is associated with greater progression of brain atrophy and provide further support for a role of cerebral blood flow in the process of neurodegeneration.

Brain atrophy is a strong predictor for cognitive decline and dementia, and these are, in turn, associated with increased mortality in the general population. Patients with cardiovascular disease have more brain atrophy and a higher morbidity and mortality. We investigated if brain volumes on magnetic resonance imaging were associated with the risk of cardiovascular events and mortality in patients with manifest arterial disease (n = 1215; mean age 58 years). Automated brain segmentation was used to quantify intracranial volume, and volumes of total brain, sulcal cerebrospinal fluid, and ventricles. After a median follow-up of 8.3 years, 184 patients died, 49 patients had an ischemic stroke, and 100 patients had an ischemic cardiac complication. Smaller relative brain volumes increased the risk of all-cause death (hazard ratio [HR] per standard deviation decrease in total brain volume: 1.58, 95% confidence interval [95% CI]: 1.33-1.88), vascular death (HR 1.69, 95% CI: 1.35-2.13), and ischemic stroke (HR 1.96, 95% CI: 1.43-2.69), independent of cardiovascular risk factors. These results suggest that brain volumes are an important determinant of poor outcome in patients with high cardiovascular risk.

Objective: To estimate the association between hippocampal and total brain volume and the course of depressive symptoms over eight years of follow-up in patients with a history of vascular disease. Method: Within the SMART-Medea study, 636 participants (62 ± 10 years) had a 1.5-tesla brain MRI obtaining hippocampal and total brain volumes. Depressive symptoms were assessed with the Patient Health Questionnaire-9 biannually during eight-year follow-up. Generalized estimating equation models with robust standard errors were used to assess the associations of hippocampal and total brain volumes with depressive symptoms during follow-up adjusting for age, sex, education, and intracranial volume. An interaction term between volume and time (6-month intervals) was included to examine whether the course of depressive symptoms differed according to hippocampal and total brain volume. Results: The mean PHQ-9 score was 2.8 ± 3.5. Smaller hippocampal volumes were associated with an increasing course of depressive symptom levels, while larger volumes were associated with decreasing levels (P-value interaction = 0.07). Smaller total brain volume was associated with consistently higher levels of depressive symptoms, but not with change in course of depressive symptoms (P-value interaction = 0.45). Conclusion: Smaller hippocampal volume but not total brain volume is associated with poorer course of depressive symptoms over eight years of follow-up.

Cardiovascular disease is a major health problem worldwide. However, the mortality risk in patients with cardiovascular disease has decreased due to early detection of the disease and improved treatment possibilities. The downside of increased survival rates are higher rates of long-term functional disability. Cardiovascular disease and an increased cardiovascular risk are associated with loss of function such as cognitive dysfunction, motor dysfunction, and depression. Vascular damage on brain MRI, reflected in markers of small vessel disease, is increasingly recognized as potential underlying factor for age-related function loss that is frequently found in patients with cardiovascular disease. The present thesis aimed to gain more insight in the cross-sectional, but particularly in the longitudinal relationship between risk factors, MRI markers of small vessel disease, and functional disability. In the first part of the thesis we investigated the association between risk factors, MRI markers of small vessel disease, and cognitive decline. We found that potentially modifiable risk factors (e.g. diabetes mellitus and physical activity) may have small impact on slowing down cerebral vascular damage and cognitive dysfunction in middle-aged patients already burdened with vascular disease. Cognitive dysfunction is a slowly developing process that may follow a stepwise progression over time. MRI markers of small vessel disease may be more sensitive to detect the influence of modifiable risk factors and may precede differences in cognitive decline. In part II of the thesis we were interested in the relationship of subclinical features of small vessel disease on brain MRI with motor dysfunction. We performed an explorative study to examine the association of microstructural abnormalities in specific white matter tracts with motor dysfunction in patients with type 2 diabetes mellitus with and without cognitive impairment. We found that in a small group of older patients with type 2 diabetes mellitus with slightly impaired motor performance scores, microstructural abnormalities in the corpus callosum were associated with motor performance scores in the expected directions, although the results were not statistically significant. In part III of the thesis we investigated the course of depression in patients with cardiovascular disease. 30% of these patients had an intermittent or chronic course of depression. Furthermore, of the patients with a history of vascular disease, those with cerebrovascular disease most often showed a chronic course of depression. Cerebral small vessel disease, on top of existing cardiovascular disease contributes to depression. Depression is therefore an important clinical manifestation of both large (e.g. stroke) and small vessel disease in patients with high vascular burden. Patients with cardiovascular disease may require more careful clinical monitoring and management of depressive symptoms.