Positron emission tomographic studies of aging and Alzheimer disease.
ABSTRACT In this study the positron emission tomographic (PET)-18F-2-deoxy-2-fluoro-D-glucose (FDG) technique was used to study both normal aging and senile dementia. The results derived from 15 young normal subjects (mean age, 26 +/- 5 years) and 22 elderly normal subjects (mean age, 66 +/- 7 years) failed to indicate significant metabolic changes associated with age. A group of 24 patients with senile dementia (mean age, 73 +/- 7 years) showed consistent diminutions in regional glucose use relative to the elderly normals. Across all brain regions the diminutions were 17%-24%. There were also significant correlations between the measures of glucose use and the measures of cognitive functioning. Discriminant function classification analysis results indicate that better than 80% classification accuracy can be achieved for individual PET measures. These data suggest a possible future diagnostic use of PET in senile dementia.
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ABSTRACT: beta-site APP cleaving enzyme-1 (BACE1), the rate-limiting enzyme for beta-amyloid (Abeta) production, is elevated in Alzheimer's disease (AD). Here, we show that energy deprivation induces phosphorylation of the translation initiation factor eIF2alpha (eIF2alpha-P), which increases the translation of BACE1. Salubrinal, an inhibitor of eIF2alpha-P phosphatase PP1c, directly increases BACE1 and elevates Abeta production in primary neurons. Preventing eIF2alpha phosphorylation by transfection with constitutively active PP1c regulatory subunit, dominant-negative eIF2alpha kinase PERK, or PERK inhibitor P58(IPK) blocks the energy-deprivation-induced BACE1 increase. Furthermore, chronic treatment of aged Tg2576 mice with energy inhibitors increases levels of eIF2alpha-P, BACE1, Abeta, and amyloid plaques. Importantly, eIF2alpha-P and BACE1 are elevated in aggressive plaque-forming 5XFAD transgenic mice, and BACE1, eIF2alpha-P, and amyloid load are correlated in humans with AD. These results strongly suggest that eIF2alpha phosphorylation increases BACE1 levels and causes Abeta overproduction, which could be an early, initiating molecular mechanism in sporadic AD.Neuron 01/2009; 60(6):988-1009. DOI:10.1016/j.neuron.2008.10.047 · 15.98 Impact Factor
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ABSTRACT: Elderly controls and probable Alzheimer's disease patients underwent serial positron emission tomography (PET) studies during a baseline condition and while performing a verbal memory task. For the temporal lobes, all 7 Alzheimer patients demonstrated a relative shift in glucose metabolic rates to the right hemisphere during the memory condition relative to baseline, and 5 of 7 controls showed a shift to the left hemisphere. Baseline absolute regional metabolic rates replicate previous findings and were somewhat less useful than the memory challenge in differentiating patients from controls. These results indicate that a temporal lobe abnormality in Alzheimer's disease is related to memory performance.Journal of Cerebral Blood Flow & Metabolism 05/1987; 7(2):248-51. DOI:10.1038/jcbfm.1987.50 · 5.34 Impact Factor
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ABSTRACT: There are two paradigms regarding the relation of the brain's energy consumption and intelligence. According to the first paradigm the more intelligent a person is, the more energy the person's brain consumes. According to the second paradigm the more intelligent the person is the less energy the person's brain consumes. It is suggested that this apparent contradiction can be explained by relating the first paradigm to the maintenance energy of the brain, while the second paradigm is related to the operational energy of the brain. According to the experimental findings intelligence is related more to the operational energy of the brain than to the maintenance energy. Several paradigms of intelligence are compared, and the biological origin of intelligence is discussed. It is suggested that Hendrickson's paradigm explains all these paradigms of intelligence.Personality and Individual Differences 01/1993; 14(1):283-286. DOI:10.1016/0191-8869(93)90206-I · 1.86 Impact Factor