The main goal of this Project is to investigate mechanisms that define the transition from healthy aging to mild cognitive impairment and to mild Alzheimer's disease (AD) using structural imaging techniques. Such techniques allow the in vivo measurement of structural changes in the brain that are surrogate markers of the ongoing pathological changes associated with AD. In addition, such techniques make it possible to: a) relate alterations in given brain regions to cognitive decline, and b) examine the specific role of certain brain structures in human memory function because of the age- or disease-related occurrence of "lesions" in these structures. The Project uses a longitudinal design with yearly MRI scans and clinical evaluations. Because of the opportunities that a longitudinal design affords, an additional goal of the Project is to develop sensitive MRI risk factors of incident dementia. Since pathology in given brain regions probably occurs many years prior to the clinical manifestations of AD, such markers are important for differentiating individuals at risk from healthy elderly people so that possible interventional strategies can be targeted early. An important feature of the application is the use of diffusion tensor imaging (DTI) to define and quantify deterioration of white matter as a function of age and disease progression. This is a structural imaging technique that can detect alterations in the microstructure of normal appearing white matter. A novel feature of this application is the use of high resolution DTI to define and quantify pathology in the angular bundle that includes the perforant path, in order to distinguish those at risk of developing AD. In addition to volumetric measures of regions of interest, whole brain voxel based morphometry will be used to delineate patterns of change that define the transition from healthy aging to MCI and from MCI to mild AD. Summary of the Project 1 Discussion: The overall discussion of the Project emphasized the positive aspects of the well-characterized group of individuals and the yearly follow-up. Despite some concerns about the Regions of Interest (ROI) approach raised by some reviewers, a general consensus formed that the ROI approach remains an excellent research tool. It was noted that, while the ongoing work is limited by subject sample size, it is focused on novel biological hypotheses that will extend current knowledge about transition states from normal aging to AD and is therefore quite relevant. Concerns, however, remain regarding the focus on AD as the sole process by which individuals transition from normal aging to mild cognitive impairment and then on to dementia. There was general agreement that there may be different mechanisms by which individuals could transition from normal aging to mild cognitive impairment. For example, cerebrovascular disease is common amongst older individuals and would likely contribute to such changes. In fact, one reviewer pointed to the fact that the Project has the ability to examine this question directly (e.g. relevant clinical information and imaging) and should do so. Finally, it was noted that there remained some question of integration between Project 1 and Project 2. It was unclear the extent to which the projects shared subjects and, if so, how this was done. In conclusion, the reviewers felt that overall the Project was very good to excellent, but that some conceptual and methodological issues still remained.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
3P01AG009466-18S2
Application #
8456248
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9)
Project Start
1997-04-01
Project End
2013-09-30
Budget Start
2012-04-15
Budget End
2013-03-31
Support Year
18
Fiscal Year
2012
Total Cost
$37,868
Indirect Cost
$13,118
Name
Rush University Medical Center
Department
Type
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612
Mufson, Elliott J; Malek-Ahmadi, Michael; Perez, Sylvia E et al. (2016) Braak staging, plaque pathology, and APOE status in elderly persons without cognitive impairment. Neurobiol Aging 37:147-53
Cade, Brian E; Gottlieb, Daniel J; Lauderdale, Diane S et al. (2016) Common variants in DRD2 are associated with sleep duration: the CARe consortium. Hum Mol Genet 25:167-79
Lim, Andrew S P; Yu, Lei; Schneider, Julie A et al. (2016) Sleep Fragmentation, Cerebral Arteriolosclerosis, and Brain Infarct Pathology in Community-Dwelling Older People. Stroke 47:516-8
Lim, Andrew S P; Bennett, David A; Buchman, Aron S (2016) Response to Letter Regarding Article, "Sleep Fragmentation, Cerebral Arteriolosclerosis, and Brain Infarct Pathology in Community-Dwelling Older People". Stroke 47:e175
Perez, Sylvia E; He, Bin; Nadeem, Muhammad et al. (2015) Resilience of precuneus neurotrophic signaling pathways despite amyloid pathology in prodromal Alzheimer's disease. Biol Psychiatry 77:693-703
Ramanan, Vijay K; Risacher, Shannon L; Nho, Kwangsik et al. (2015) GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer's disease implicates microglial activation gene IL1RAP. Brain 138:3076-88
Alldred, Melissa J; Lee, Sang Han; Petkova, Eva et al. (2015) Expression profile analysis of hippocampal CA1 pyramidal neurons in aged Ts65Dn mice, a model of Down syndrome (DS) and Alzheimer's disease (AD). Brain Struct Funct 220:2983-96
Sohail, Shahmir; Yu, Lei; Bennett, David A et al. (2015) Irregular 24-hour activity rhythms and the metabolic syndrome in older adults. Chronobiol Int 32:802-13
Beckett, Laurel A; Donohue, Michael C; Wang, Cathy et al. (2015) The Alzheimer's Disease Neuroimaging Initiative phase 2: Increasing the length, breadth, and depth of our understanding. Alzheimers Dement 11:823-31
Counts, Scott E; Alldred, Melissa J; Che, Shaoli et al. (2014) Synaptic gene dysregulation within hippocampal CA1 pyramidal neurons in mild cognitive impairment. Neuropharmacology 79:172-9

Showing the most recent 10 out of 195 publications