Alzheimer's disease (AD) is the most frequent form of dementia in the elderly, and its prevalence rises substantially between ages 65 and 85, doubling every 5 years such that one has a close to a 50% chance of expressing the disease by age 85. AD inexorably progresses to severe cognitive and functional states with subsequent increase risk of institutionalization and death. This proposal focuses on the understanding of the pathophysiological mechanisms that influence the rate of progression in the very early stages of the disease;the first year after the conversion from mild cognitive impairment (MCI) to AD. This is a cross-sectional and longitudinal study that will examine the relationship between sub-clinical vascular disease, structural and perfusion MRI, and in vivo amyloid cerebral deposition measures in subjects with early probable AD. Natural history studies as well clinical trials have shown a tremendous variability in the rates of progression of AD patients. However, we do not know why some patients with AD progress slowly or more rapidly. Whether this is related to a pathological heterogeneity of the disease, to the presence of comorbid factors, or both, still has to be determined. This study will test the hypothesis that vascular disease decreases grey matter volume and rCBF in limbic and paralimbic areas. This renders these individuals in their early stages of AD more vulnerable to a rapid clinical progression of the disease. These changes in brain structure and function will be due to tissue injury secondary to long-term effects of vascular disease, and they will be associated with altered kidney function and cardiovascular disease, which are also a general manifestation of vascular disease. In addition, this vulnerability state caused by cerebrovascular damage precludes the brain to mount compensatory mechanisms, especially in the early stages of the disease, and consequently, it needs less amyloid deposition for the expression and progression of the clinical symptoms. To accomplish the study objectives, we will obtain PET/PIB, structural MRI, arterial spin-labeled (ASL) MRI, and cardiovascular and kidney mesures (cystatin-C) in a group of subjects at the moment of the conversion from MCI to AD (n=20) and a group of normal controls (n=10). These subjects are part of a group of MCI patients and normal controls with PET/PIB and structural MRI completed through an on-going study conducted by Dr. W. Klunk (a co-investigator in this proposal), and who are being followed at the Alzheimer's Disease Research Center (ADRC).

Public Health Relevance

The study of how amyloid deposition, cerebral blood flow, and systemic and cerebral vascular factors influence the initial progression of AD has two important implications: 1) proper treatment of vascular disease in early stages of the disease may slow down progression of AD, and 2) the understanding of this initial process will improve the outcome and design of clinical trials;future disease modifying treatments will target subjects at their very early stages of the disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Specialized Center (P50)
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Special Emphasis Panel (ZAG1-ZIJ-4)
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University of Pittsburgh
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