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.
SourceAvailable from: Hilkka Soininen[Show abstract] [Hide abstract]
ABSTRACT: The potential similarity between the brain pathology of idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer disease (AD) is intriguing and thus further studies focusing on the underlying molecular mechanisms may offer valuable information for differential diagnostics and the development of treatments for iNPH. Here, we investigated β- and γ-secretase activities in relation to amyloid-β (Aβ) pathology in the brain tissue samples collected from iNPH and AD patients. β- and γ-secretase activities were measured from the frontal cortical biopsies of 26 patients with suspected iNPH as well as post-mortem tissue samples from the inferior temporal cortex of 74 AD patients and eight subjects without neurofibrillary pathology. In iNPH samples with detectable Aβ plaques, γ-secretase activity was significantly increased (∼1.6-fold) when compared to iNPH samples without Aβ plaques (p = 0.009). In the AD samples, statistically significant differences in the γ-secretase activity were not observed with respect to disease severity (mild, moderate and severe AD according to neurofibrillary pathology). Conversely, β-secretase activity was unaltered in iNPH samples with or without Aβ plaques, while it was significantly increased in relation to disease severity in the AD patients. These results show for the first time increased γ-secretase but not β-secretase activity in the biopsy samples from the frontal cortex of iNPH patients with AD-like Aβ pathology. Conversely, the opposite was observed in these secretase activities in AD patients with respect to neurofibrillary pathology. Despite the resemblances in the Aβ pathology, iNPH and AD patients appear to have marked differences in the cellular mechanisms responsible for the production of Aβ.PLoS ONE 07/2014; 9(4):e93717. DOI:10.1371/journal.pone.0093717 · 3.53 Impact Factor
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ABSTRACT: Amyloid-beta (Aβ) containing plaques are a major neuropathological feature of Alzheimer's disease (AD). The two major isoforms of Aβ peptide associated with AD are Aβ40 and Aβ42, of which the latter is highly prone to aggregation. Increased presence and aggregation of intracellular Aβ42 peptides is an early event in AD progression. Improved understanding of cellular processes affecting Aβ42 aggregation may have implications for development of therapeutic strategies. Aβ42 fused to green fluorescent protein (Aβ42GFP) was expressed in ∼4600 mutants of a Saccharomyces cerevisiae genome-wide deletion library to identify proteins and cellular processes affecting intracellular Aβ42 aggregation by assessing the fluorescence of Aβ42GFP. This screening identified 110 mutants exhibiting intense Aβ42GFP-associated fluorescence. Four major cellular processes were overrepresented in the data set, including phospholipid homeostasis. Disruption of phosphatidylcholine, phosphatidylserine and/or phosphatidylethanolamine metabolism had a major effect on intracellular Aβ42 aggregation and localisation. Confocal microscopy indicated that Aβ42GFP localisation in the phospholipid mutants was juxtaposed to the nucleus, most likely associated with the endoplasmic reticulum/ER membrane. These data provide a genome-wide indication of cellular processes that affect intracellular Aβ42GFP aggregation and may have important implications for understanding cellular mechanisms affecting intracellular Aβ42 aggregation and AD disease progression.Molecular Biology of the Cell 05/2014; DOI:10.1091/mbc.E13-04-0216 · 4.55 Impact Factor
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ABSTRACT: Objective: To examine the effect of 109 days of caprylic triglyceride (CT) in a 70-year-old male with mild Alzheimer’s disease (AD).Background: Cerebral metabolism is limited to glucose under most conditions, and diminished cerebral glucose metabolism is a characteristic feature of AD. Another substrate available for cerebral metabolism is ketone bodies. Ketone bodies (KB) are normally derived from fat stores under conditions of low glucose availability as an alternative energy substrate to glucose. KB can also be produced by oral administration of CT. Prior studies suggest that the alternative energy source of CT may improve cognitive function due to mild to moderate AD, by circumventing the diminished glucose metabolism.Method: The effect of CT was analyzed in a single-case of mild AD with cognitive alterations in an open label study. Study outcomes included the Montreal cognitive assessment (MoCA), mini mental state exam (MMSE), and 18-fluorodeoxyglucose (18F) positron emission tomography (FDG PET) scans.Results: After 109 days of CT, MoCA scores changed from a baseline value of 24–28, and MMSE scores changed from 23 to 28. No changes were observed on FDG PET scans.Conclusion: The results suggest that, in a case of mild AD, CT may have affected cognitive function, assessed by means of MMSE and MoCA, although glucose uptake and metabolism remained unchanged.Frontiers in Aging Neuroscience 07/2014; 6:133. DOI:10.3389/fnagi.2014.00133 · 2.84 Impact Factor