Brain amyloidosis is a constant feature of Alzheimer's disease (AD);almost all patients with AD have high uptake of PET amyloid-binding radioligands such as PiB when scanned during life and extensive amyloid deposits at death. Cognitively normal individuals who have amyloid positive PET scans however present an unresolved conundrum: are they on the road to AD and will develop dementia given enough time, or do their brains have specific features that render them less vulnerable to the neurotoxic effects of A. This project will directly address this question by defining the neuropathological phenotype of individuals who are amyloid imaging positive and cognitively normal and document differences with those who are amyloid imaging positive and cognitively impaired. Further, by conducting detailed analyses of the pathological changes that occur during the earliest point in disease, we will be able to identify the evolution of changes that lead to dementia symptoms and identify useful surrogate markers to guide early diagnosis such as novel in vivo neuroimaging techniques. We will test these major hypotheses: 1) neuronal loss in the entorhinal cortex builds gradually during the preclinical phase of AD before an individual becomes symptomatic;2) soluble oligomeric A levels will be greater in the impaired cases: 3) non-amyloid changes, such as tau lesions, will correlate closely with neuronal loss in amyloid imaging positive cases and 4) synaptic loss and glia activation will correlate with clinical symptoms and mark the transition to symptomatic stages;these changes will be less prominent in the resilient cases. In order to accomplish these goals, we have established working collaborations with four other ADCs (Mayo, University of Pittsburgh, Washington University and Columbia) to share clinical and neuroimaging data as well as brain tissue from three groups of subjects: Amyloid imaging positive and cognitively normal, amyloid imaging positive and cognitively impaired, and amyloid imaging negative and cognitively normal. By identifying neurobiologic factors that occur during the years after amyloid begins to accumulate but before symptoms manifest, we will set the stage for guiding the next generation of neuroimaging and other diagnostic tests as well as define rational targets for future effective therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
2P50AG005134-31
Application #
8676357
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4 (J1))
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
31
Fiscal Year
2014
Total Cost
$217,500
Indirect Cost
$92,500
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Ward, Andrew M; Mormino, Elizabeth C; Huijbers, Willem et al. (2015) Relationships between default-mode network connectivity, medial temporal lobe structure, and age-related memory deficits. Neurobiol Aging 36:265-72
Aganj, Iman; Reuter, Martin; Sabuncu, Mert R et al. (2015) Avoiding symmetry-breaking spatial non-uniformity in deformable image registration via a quasi-volume-preserving constraint. Neuroimage 106:238-51
Bickart, Kevin C; Brickhouse, Michael; Negreira, Alyson et al. (2014) Atrophy in distinct corticolimbic networks in frontotemporal dementia relates to social impairments measured using the Social Impairment Rating Scale. J Neurol Neurosurg Psychiatry 85:438-48
Riascos, David; Nicholas, Alexander; Samaeekia, Ravand et al. (2014) Alterations of Ca²?-responsive proteins within cholinergic neurons in aging and Alzheimer's disease. Neurobiol Aging 35:1325-33
Papp, Kathryn V; Amariglio, Rebecca E; Dekhtyar, Maria et al. (2014) Development of a psychometrically equivalent short form of the Face-Name Associative Memory Exam for use along the early Alzheimer's disease trajectory. Clin Neuropsychol 28:771-85
Jackson, John W; Schneeweiss, Sebastian; VanderWeele, Tyler J et al. (2014) Quantifying the role of adverse events in the mortality difference between first and second-generation antipsychotics in older adults: systematic review and meta-synthesis. PLoS One 9:e105376
Schultz, Aaron P; Chhatwal, Jasmeer P; Huijbers, Willem et al. (2014) Template based rotation: a method for functional connectivity analysis with a priori templates. Neuroimage 102 Pt 2:620-36
Spires-Jones, Tara L; Friedman, Taylor; Pitstick, Rose et al. (2014) Methylene blue does not reverse existing neurofibrillary tangle pathology in the rTg4510 mouse model of tauopathy. Neurosci Lett 562:63-8
Mormino, Elizabeth C; Betensky, Rebecca A; Hedden, Trey et al. (2014) Amyloid and APOE ?4 interact to influence short-term decline in preclinical Alzheimer disease. Neurology 82:1760-7
Stoub, Travis R; Detoledo-Morrell, Leyla; Dickerson, Bradford C (2014) Parahippocampal white matter volume predicts Alzheimer's disease risk in cognitively normal old adults. Neurobiol Aging 35:1855-61

Showing the most recent 10 out of 440 publications