Deposition of amyloid-beta (A-beta) protein in the brain has been postulated to be a primary cause of Alzheimer's disease (AD). Identification of hallmarks of amyloid deposition that occur prior to onset of AD symptoms and the natural history of this deposition is essential. However, in the general population, despite identifiable risk factors that increase the likelihood of acquiring AD, such as increased age and the presence of an apolipoprotein-E4 allele (ApoE4), we have no way of identifying with certainty those individuals destined to develop AD. Conversely, the Down syndrome (DS) adult population provides a unique opportunity to study pre-clinical amyloid deposition. Approximately 10% of adults with DS are diagnosed with AD between 40 and 49 years of age. The rate increases to 36% for individuals 50-59 years of age and is ?50% for those 60 years of age and older. This early onset of AD in DS is thought to be caused by multiple mutations in the A-beta precursor protein (APP) gene on chromosome 21, all lying in or near the A-beta peptide region. A group of researchers at the University of Pittsburgh has performed pioneering human studies of an in vivo amyloid imaging positron emission tomography (PET) tracer known as PiB (Pittsburgh compound-B). PiB is selectively retained in brain areas known to have heavy post-mortem amyloid loads in AD and is not retained in regions, such as cerebellum, where fibrillar amyloid deposits are found only sporadically. In 2007, this group completed a pilot study of the use of PiB in a sample of 8 adults with DS. Subsequently, in 2009, ARRA funding was obtained to begin to recruit a new cohort of 84 healthy subjects with DS and recently was awarded a five-year continuation grant (with the University of Wisconsin, Madison). Sixty-seven subjects have been enrolled, with recruitment to be completed by August 2014. The continuation grant has allowed for the maintenance of recruitment efforts and the initiation of 30 and 60 month reassessments of enrolled subjects to examine the natural course of amyloid deposition and dementia in this population. Measures include an extensive neuropsychological assessment battery as well as assessment of adaptive functioning, AD symptoms and emotional/behavioral concerns. In addition, ApoE status is obtained along with an MRI and PET scan. The primary objective of the current proposal is to leverage this unique cohort of individuals by expanding the Parent Study protocol to include 4 promising and important biomarkers: [18F]fluoro-2-deoxy-D-glucose (FDG-PET), an MRI measure of cerebrovascular reactivity (CVR), diffusion tensor imaging (DTI) and assessment of plasma A?-40 and 42. Measures will be obtained when currently enrolled subjects return for a follow-up assessment and will allow us to examine the association between these biomarkers and amyloid deposition and functioning. This information will also be of considerable significance as we continue to follow this cohort of individuals and early signs of dementia are detected (providing the opportunity to further examine the relationship between these moderators and amyloid deposition, cognitive decline and dementia).

Public Health Relevance

Adults with Down syndrome are at high risk for developing Alzheimer's disease, with most individuals over age 40 showing the presence of amyloid deposits in the brain (which are thought to be associated with the appearance of symptoms of Alzheimer's disease). The goal of the currently funded parent grant is to document the presence of amyloid deposits in 84 healthy adults with Down syndrome and to follow these individuals over time to assess the effect of increased deposits on functioning. This revision application seeks to add a number of additional tests to the study that might help to better predict who will develop early signs of Alzheimer's disease (both among individuals with Down syndrome and in the general population).

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
3R01AG031110-05S1
Application #
8759540
Study Section
Adult Psychopathology and Disorders of Aging Study Section (APDA)
Program Officer
Hsiao, John
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Hartley, Sigan L; Handen, Benjamin L; Devenny, Darlynne A et al. (2014) Cognitive functioning in relation to brain amyloid-? in healthy adults with Down syndrome. Brain 137:2556-63