We propose to study the association between MRI markers of cerebral small vessel disease and cognitive decline in a population with mild impairment, both in individuals who meet research criteria for MCI and in individuals who fall short of these criteria but have some evidence of cognitive decline. Because evidence shows that pathological brain changes associated with Alzheimer's disease (including neurofibrillary tangles and senile plaques) modify the relationship between small vessel disease and cognition, there is a critical need to incorporate in vivo markers of Alzheimer's pathology into longitudinal studies of the effect of cerebral small vessel disease. The current proposal therefore represents an important advance by measuring a hallmark feature of Alzheimer's pathology, fibrillar beta-amyloid deposition by evidence of Pittsburgh Compound B (PIB) retention on PET, in addition to MRI markers of small vessel disease. The proposed study will complement current ongoing large neuroimaging studies by specifically addressing the relationship between advanced MRI markers of small vessel disease and perfusion, a PET marker of fibrillar beta-amyloid deposition, and cognitive decline. The following hypotheses will be tested: 1) white matter damage from small vessel disease is associated with cognitive decline, independent of the amount of cerebral beta-amyloid deposition, 2) white matter damage from small vessel disease causes cognitive impairment by damaging specific brain regions, and 3) progression of white matter damage from small-vessel disease is caused by ischemia in areas of relative hypoperfusion. Mildly impaired non-demented subjects will be recruited from the community and followed annually for cognitive decline. This is an population for study because it is an ideal target for therapies designed to reduce the burden of cognitive decline caused by vascular disease. Study procedures will include PET and MRI at baseline, with a second MRI during follow-up. This longitudinal study will 1) provide estimates of the rate of decline associated with MRI markers of small vessel disease that may be used in the design of future clinical trials in mildly impaired subjects, 2) identify a neuroanatomic phenotype of damage from small vessel disease that will more accurately predict cognitive decline than current global disease measures, and 3) identify cerebral perfusion as a potential target for therapies to prevent progression of white matter damage. Age-related small-vessel disease of the brain is common and causes silent stroke and damage to the white matter, visible on MRI, resulting in cognitive decline. It is not known how often these MRI abnormalities coexist with Alzheimer's disease, another common pathology of aging, and whether the relationship between these MRI abnormalities and cognitive decline is influenced by the presence or absence of Alzheimer-type pathology. We plan to study the relationship between MRI markers of small vessel disease, a PET marker of Alzheimer-type pathology, brain perfusion and cognition in subjects with mild impairments. Our results will aid the design of clinical trials to prevent dementia by defining imaging markers of small vessel disease and Alzheimer-type pathology and their effects on cognitive decline.
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