This grant proposes to explore the hypothesis that Alzheimer's disease (AD) is a systemic disease caused by a chronic ATP deficiency resulting from diminished blood flow reactivity or defective glucose metabolism. Progressive damage to the nonregenerative central nervous system neurons is manifested early in the CNS because of the susceptibility of neurons to low blood flow and the limited ability of neurons to regenerate and to maintain mitochondrial enzymes. Specifically, we will investigate the role of systemic perfusion reactivity and systemic carbohydrate metabolism in AD. These hypotheses will be tested by experimental protocols including: (1) measurement of the deficit in acetylcholine neurons in AD by quantification of physostigmine stimulation of cerebral blood flow using high resolution PET with 122I-HIPDM; (2) measurement of endothelium-dependent vasodilatation of peripheral limb resistance vessels in AD patients in response to tourniquet-induced (blood pressure cuff) ischemia using a Doppler analysis method developed in previous; (3) evaluation of kinetics of 18F-fluorodeoxyglucose in exercising skeletal muscle of AD using positron emission tomography; (4) in vivo 4T magnetic resonance studies of oxidative phosphorylation potential in AD patients' (5) in vitro glucose metabolism studies using 14C glucose in leukocytes; and (6) mitochondrial function assays of leukocytes in AD and controls. This proposal involves 284 different patients and subjects in 405 in vivo and in vitro non-invasive studies. The procedures are currently validated technologies using unique resources at Lawrence Berkeley National Laboratory. New critical experiments in this proposal are the method of performing in vivo studies of peripheral vessel relaxivity, the in vivo skeletal muscle metabolism studies using FDG-PET, and the in vivo skeletal muscle oxidative phosphorylation potential studies utilizing 4T magnetic resonance spectroscopy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG005890-14
Application #
6168018
Study Section
Diagnostic Radiology Study Section (RNM)
Program Officer
Snyder, D Stephen
Project Start
1985-05-01
Project End
2004-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
14
Fiscal Year
2000
Total Cost
$265,225
Indirect Cost
Name
Lawrence Berkeley National Laboratory
Department
Type
Organized Research Units
DUNS #
078576738
City
Berkeley
State
CA
Country
United States
Zip Code
94720
Maltz, Jonathan S; Budinger, Thomas F (2005) Evaluation of arterial endothelial function using transit times of artificially induced pulses. Physiol Meas 26:293-307
Maltz, Jonathan S; Eberling, Jamie L; Jagust, William J et al. (2004) Enhanced cutaneous vascular response in AD subjects under donepezil therapy. Neurobiol Aging 25:475-81