The proposed longitudinal FDG-PET investigation is designed to identify the earliest predictors of memory and brain deterioration in preclinical Alzheimer's disease (AD) and to examine a potential mechanism for this early damage. Four important new observations converge to support our aims: 1. longitudinal FDG-PET and MRI studies show reductions at baseline in the entorhinal cortex (EC) rate of glucose metabolism (MRglu) and size in normal subjects (NL) who decline to mild cognitive impairment (MCI), a known risk factor for AD; 2. reduced EC MRgIu and size changes predict over 3 years the appearance of hippocampal deficits in subjects that declined to MCI; the MRglu of the EC and hippocampus obtained using MRI-registered and atrophy- corrected procedures are superior to MRI volumes in the classification of NL, MCI and AD; 4. in vivo, AD patients show a reduction in the ratio of glucose to 02 consumed and a reduction of the hippocampal MRgIu response to cortisol, glucose, or cognitive challenge. Together these observations show that the earliest known brain lesions of AD are in the hippocampal formation (HipForm) and suggest a physiological defect in the regulation of glucose metabolism. We will conduct over 5 years a 3-year follow-up study of NL subjects.
Aim 1 : to evaluate the EC MRglu as a predictor of MCI. We will test two hypotheses: 1) EC MRgIu reductions predict progressive declarative memory decline and progressive hippocampal and neocortical metabolism and volume reductions, and 2) EC MRglu reductions are anatomically specific predictors of progressive memory impairment. Three groups (each n=35) will be studied. Group 1: healthy NL 50-70 yr old subjects with longitudinally observed memory decline; Group 2 a demographically matched NL group without a history of memory decline; and Group 3,20-40 year old NL subjects studied once for use as a reference. Over 36 months, Groups 1 and 2 will receive 3 clinical evaluations with MRI. FDG-PET will be obtained twice, at baseline and endpoint.
Aim 2 : to evaluate the effects of acute steady state hyperglycemia vs. saline on memory performance and on HipFom, MRglu and kinetics (dynamic PET scan). Fifteen subjects from each of groups 1 and 2 will be selected. We will test two hypotheses: 1) under acute hyperglycemia, Group 1 will show deficits in HipForm MRglu and kinetics and will not enhance memory function, and 2) diminished HipForm glucose transport predicts longitudinal brain and memory changes. We have strong preliminary evidence in support of our hypotheses and all the facilities are in place.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG013616-13A1
Application #
6331140
Study Section
Special Emphasis Panel (ZRG1-BDCN-6 (01))
Program Officer
Buckholtz, Neil
Project Start
1991-09-01
Project End
2007-04-30
Budget Start
2002-06-01
Budget End
2003-04-30
Support Year
13
Fiscal Year
2002
Total Cost
$415,871
Indirect Cost
Name
New York University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10016
Snyder, Heather M; Carare, Roxana O; DeKosky, Steven T et al. (2018) Military-related risk factors for dementia. Alzheimers Dement 14:1651-1662
Mosconi, Lisa; Walters, Michelle; Sterling, Joanna et al. (2018) Lifestyle and vascular risk effects on MRI-based biomarkers of Alzheimer's disease: a cross-sectional study of middle-aged adults from the broader New York City area. BMJ Open 8:e019362
Ramos-Cejudo, Jaime; Wisniewski, Thomas; Marmar, Charles et al. (2018) Traumatic Brain Injury and Alzheimer's Disease: The Cerebrovascular Link. EBioMedicine 28:21-30
Chen, Jingyun; Li, Yi; Pirraglia, Elizabeth et al. (2018) Quantitative evaluation of tau PET tracers 18F-THK5351 and 18F-AV-1451 in Alzheimer's disease with standardized uptake value peak-alignment (SUVP) normalization. Eur J Nucl Med Mol Imaging 45:1596-1604
de Leon, Mony J; Li, Yi; Rusinek, Henry (2018) Reply: Cerebrospinal Fluid, Hyposmia, and Dementia in Alzheimer Disease: Insights from Dynamic PET and a Hypothesis. J Nucl Med 59:718-719
Sharma, Ram A; Varga, Andrew W; Bubu, Omonigho M et al. (2018) Obstructive Sleep Apnea Severity Affects Amyloid Burden in Cognitively Normal Elderly. A Longitudinal Study. Am J Respir Crit Care Med 197:933-943
Solesio, MarĂ­a E; Peixoto, Pablo M; Debure, Ludovic et al. (2018) Carbonic anhydrase inhibition selectively prevents amyloid ? neurovascular mitochondrial toxicity. Aging Cell :e12787
Sims, Rebecca (see original citation for additional authors) (2017) Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet 49:1373-1384
de Leon, Mony J; Li, Yi; Okamura, Nobuyuki et al. (2017) Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET. J Nucl Med 58:1471-1476
Kim, H-J; Oh, S-I; de Leon, M et al. (2017) Structural explanation of poor prognosis of amyotrophic lateral sclerosis in the non-demented state. Eur J Neurol 24:122-129

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