The present proposal seeks to characterize neural processes that affect cognition in normal aging distinct from early-stages of pathological change. Multiple brain changes are present in clinically normal aging including white-matter disruption, depletion of neurotransmitter systems, and preclinical Alzheimer's disease (AD) pathology. While it is common for all of these brain changes to be present in the same individuals, dissociations raise the possibility that certain components may reflect normal aging independent of the progression to clinical dementia. For example, we recently observed that white-matter integrity in normal aging was linked to executive dysfunction in the absence of amyloid deposition. Advanced aging is also associated with increased (often bilateral) recruitment of cortical systems, similar to that observed in other situations where brain systems are stressed. Activity increases are prominent in older adults who, as a group, display the brain changes noted above raising the possibility that they reflect a compensatory response. Testing hypotheses associated with cognitive aging is challenging because it is extremely difficult to identify a pure cohort of normal older adults that is sparred the preclinical stages of AD pathology. As a novel approach to the study of cognitive aging, we will explore the link between brain aging and executive dysfunction in a group of older adults screened for the presence of amyloid deposition using PET molecular markers. Specifically, we aim to (1) explore whether disruption of large-scale brain networks (via DTI and fcMRI) accounts for cognitive variation in the absence of amyloid deposition, (2) explore whether there is MTL-linked memory variance in normal aging that is independent of preclinical AD, and (3) explore whether activity increases are present in normal aging and mitigate cognitive decline. We hypothesize that there exists a prominent cascade affecting executive function during normal aging that is independent of amyloid plaque pathology and that activity increases are a response to mitigate the effects of this cascade. The cascade is proposed to arise from white-matter disruption and impaired coordination of large-scale brain systems. By completing this project, in addition to testing our specific hypotheses, we will generate and openly share a normative data set on aging that includes structural, functional, and cognitive data that is stratified by high or low amyloid deposition.

Public Health Relevance

An increasing percentage of the population is living well beyond retirement age. Here we seek to understand the brain factors in normal aging that impair cognition as well as compensate to mitigate cognitive decline. By understanding these factors we hope to promote healthy, graceful aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG034556-05
Application #
8523721
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (M2))
Program Officer
Wagster, Molly V
Project Start
2009-09-15
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$491,609
Indirect Cost
$213,864
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
LaPoint, Molly R; Chhatwal, Jasmeer P; Sepulcre, Jorge et al. (2017) The association between tau PET and retrospective cortical thinning in clinically normal elderly. Neuroimage 157:612-622
Dekhtyar, Maria; Papp, Kathryn V; Buckley, Rachel et al. (2017) Neuroimaging markers associated with maintenance of optimal memory performance in late-life. Neuropsychologia 100:164-170
Schultz, Aaron P; Chhatwal, Jasmeer P; Hedden, Trey et al. (2017) Phases of Hyperconnectivity and Hypoconnectivity in the Default Mode and Salience Networks Track with Amyloid and Tau in Clinically Normal Individuals. J Neurosci 37:4323-4331
Marquié, Marta; Verwer, Eline E; Meltzer, Avery C et al. (2017) Lessons learned about [F-18]-AV-1451 off-target binding from an autopsy-confirmed Parkinson's case. Acta Neuropathol Commun 5:75
Rieckmann, Anna; Hedden, Trey; Younger, Alayna P et al. (2016) Dopamine transporter availability in clinically normal aging is associated with individual differences in white matter integrity. Hum Brain Mapp 37:621-31
Mormino, Elizabeth C; Papp, Kathryn V; Rentz, Dorene M et al. (2016) Heterogeneity in Suspected Non-Alzheimer Disease Pathophysiology Among Clinically Normal Older Individuals. JAMA Neurol 73:1185-1191
Maye, Jacqueline E; Betensky, Rebecca A; Gidicsin, Christopher M et al. (2016) Maternal dementia age at onset in relation to amyloid burden in non-demented elderly offspring. Neurobiol Aging 40:61-7
Hedden, Trey; Schultz, Aaron P; Rieckmann, Anna et al. (2016) Multiple Brain Markers are Linked to Age-Related Variation in Cognition. Cereb Cortex 26:1388-400
Hu, Chenhui; Sepulcre, Jorge; Johnson, Keith A et al. (2016) Matched signal detection on graphs: Theory and application to brain imaging data classification. Neuroimage 125:587-600
Papp, Kathryn V; Amariglio, Rebecca E; Mormino, Elizabeth C et al. (2015) Free and cued memory in relation to biomarker-defined abnormalities in clinically normal older adults and those at risk for Alzheimer's disease. Neuropsychologia 73:169-75

Showing the most recent 10 out of 35 publications