Reduced glutamate neurotransmission in patients with Alzheimer's disease -- an in vivo (13)C magnetic resonance spectroscopy study.
Cognitive impairment in Alzheimer's disease (AD) is not fully explained. PET indicates reduced cerebral metabolic rate for glucose. Since glutamate neurotransmission (GNT) consumes more than 80% of the ATP generated from metabolism, a pilot study was carried out to determine the neuronal tricarboxylic acid cycle (TCA) based on the hypothesis that reduced GNT could contribute to cognitive impairment in AD. Three AD patients with cognitive impairment (mini-mental state exam: 24 vs 30, P<0.05) and significant reduction in both N-acetyl aspartate (NAA)/Creatine (Cr) ( P<0.009) and NAA/myo-inositol (mI) ratio ( P<0.01), and three age-matched controls each received 0.014-0.016 g/kg/min 99%1-13C glucose IV. Quantitative (1)H and proton-decoupled (13)C MR brain spectra were acquired from combined posterior-parietal white matter and posterior-cingulate gray matter every 5 min for 140 min.(13)C magnetic resonance spectroscopy (MRS) measures of glucose oxidation and neuronal TCA rate, including prolonged time to (13)C enrichment of glutamate (Glu2) ( P<0.004) and bicarbonate (HCO(3)) ( P<0.03) as well as reduced relative enrichment of Glu(2)/Glu(4) between 60 and 100 min ( P<0.04), were significantly different in AD patients vs. controls. (13)C measures of GNT, glutamine (Gln)(2)/Glu(2) ( P<0.02) and rates of glutamate enrichment (Glu(2)/glucose: 0.34 vs 0.86, P=ns and Glu(4)/glucose 0.26 vs 0.83, P=ns), were also reduced.(13)C MRS measures of neuronal TCA cycle, glucose oxidation and GNT were significantly correlated with measures of neuronal integrity: NAA/Cr, [NAA] and mI/NAA as determined by (1)H MRS ( R(2)=0.73-0.95; P<0.05-0.01), suggesting that impairment of GNT may be a contributing factor in the cognitive impairment characteristic of AD.
Lin
Alexander P
AP
Clinical Spectroscopy Unit, Huntington Medical Research Institutes, 660 S Fair Oaks Avenue, Pasadena, CA 91105, USA. mrs@hmri.org
Shic
Frederick
F
Enriquez
Cathleen
C
Ross
Brian D
BD
D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D002247:Carbon Isotopes; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008875:Middle Aged; D018377:Neurotransmitter Agents / Q000737:chemistry / Q000378:metabolism*; D010865:Pilot Projects; D011522:Protons; D009435:Synaptic Transmission
D002247:Carbon Isotopes; D018377:Neurotransmitter Agents; D011522:Protons; D018698:Glutamic Acid; D005947:Glucose