The aging brain in patients with manifest arterial disease

Cardiovascular disease is a major health problem worldwide. Accumulating evidence suggests that cardiovascular disease and a high cardiovascular risk play an important role in the etiology of cognitive decline and dementia. As intermediates in this relation between cardiovascular disease and functional decline in the aging population, structural brain changes have been proposed. The first objective of this thesis was to estimate longitudinal changes in brain volumes, cerebral small-vessel disease, and cerebral blood flow on MRI and to investigate their interrelations in patients with manifest arterial disease. We observed that global brain atrophy tended to accelerate with older age and that that was more pronounced in men than in women. We showed regression of white matter lesions in younger patients, but progression of white matter lesions with increasing age, similar for men and women. The incidence of new brain infarcts also increased with age and was stronger in men than in women. Across the different cardiovascular disease categories we showed that brain atrophy and progression of cerebrovascular lesions differed. To further study the longitudinal relations between brain atrophy and cerebral small-vessel disease, we studied how cerebral blood flow, as an indicator of cerebral perfusion, was associated with these features of the aging brain. We found that cerebral perfusion was part of a circular pathway in the etiology of structural brain changes; cerebral hypoperfusion leads to brain atrophy – brain atrophy is associated with more cerebral small-vessel disease – cerebral small-vessel disease leads to decline of cerebral blood flow and so on. However, it is not completely clear where this pathway starts and whether cerebral hypoperfusion is the cause or the consequence of brain atrophy and progression of cerebral small-vessel disease. Our second objective was to investigate two possible modifiable risk factors for brain aging and to study the long-term effect of brain aging on cardiovascular morbidity and mortality in patients with manifest arterial disease. We found that the combined presence of signs of hypertensive target organ damage, as measures of chronic hypertension, was associated with progression of global brain atrophy and more decline in memory performance, but not with progression of cerebral small-vessel disease or decline in executive functioning. We also studied hemoglobin and hematocrit as two hemorheological variables, which are of influence on the regulation of cerebral blood flow. We showed that higher hemoglobin and hematocrit resulted in lower levels of baseline cerebral blood flow and a decline in cerebral blood flow over time. Finally, we showed that smaller total brain volume increased the risk of death by any cause and the risk of an ischemic stroke.