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Ikonomovic M.D.,University of Pittsburgh | Ikonomovic M.D.,Geriatric Research Educational and Clinical Center | Klunk W.E.,University of Pittsburgh | Abrahamson E.E.,University of Pittsburgh | And 5 more authors.

Objective: This study examined the relationship between postmortem precuneus cholinergic enzyme activity, Pittsburgh compound B (PiB) binding, and soluble amyloid-β concentration in mild cognitive impairment (MCI) and Alzheimer disease (AD). Methods: Choline acetyltransferase (ChAT) activity, [3H]PiB binding, and soluble amyloid-β1-42 (Aβ42) concentration were quantified in precuneus tissue samples harvested postmortem from subjects with no cognitive impairment (NCI), MCI, and mild AD and correlated with their last antemortem Mini-Mental State Examination (MMSE) score and postmortem pathologic evaluation according to the National Institute on Aging-Reagan criteria, recommendations of the Consortium to Establish a Registry for Alzheimer's Disease, and Braak stage. Results: Precuneus ChAT activity was lower in AD than in NCI and was comparable between MCI and NCI. Precuneus [3H]PiB binding and soluble Aβ42 levels were elevated in MCI and significantly higher in AD than in NCI. Across all case subjects, reduced ChAT activity was associated with increased [3H]PiB binding, increased soluble Aβ42, lower MMSE score, presence of the APOE®4 allele, and more advanced AD pathology. Conclusions: Despite accumulating amyloid burden, cholinergic enzyme activity is stable in the precuneus during prodromal AD. A decline in precuneus ChAT activity occurs only in clinical AD, when PiB binding and soluble Aβ42 levels are substantially elevated compared with those in MCI. Anti-amyloid interventions in MCI case subjects with a positive PiB PET scan may aid in reducing cholinergic deficits and cognitive decline later in the disease process. Copyright © 2011 by AAN Enterprises, Inc. Source

Cohen A.D.,University of Pittsburgh | Zigmond M.J.,University of Pittsburgh | Smith A.D.,Geriatric Research Educational and Clinical Center | Smith A.D.,University of Pittsburgh
Brain Research

Glial cell line-derived neurotrophic factor (GDNF) protects dopamine (DA) neurons from 6-hydroxydopamine (6-OHDA) toxicity. We have now explored this protection over 8 weeks following toxin administration. Infusion of Fluoro-Gold (FG) into the striatum was followed 1 week later by GDNF (9 μg) or its vehicle. Six hours later, animals received 6-OHDA (4 μg) into the same site. 6-OHDA caused a loss of cells in the substantia nigra that expressed both FG and tyrosine hydroxylase (TH) and striatal terminals expressing TH, the high affinity dopamine transporter (DAT), and the vesicular monoamine transporter 2 (VMAT2) as assessed 2-8 weeks later. Loss of FG + cells, and striatal DA was completely blocked by GDNF by 2 weeks. In contrast, GDNF only slightly attenuated the loss of TH, DAT, or VMAT2 in the striatum at 2 weeks, but had restored these markers by 4-8 weeks. Thus, GDNF prevents DA cell death and loss of striatal DA content, but several weeks are required to fully restore the dopaminergic phenotype. These results provide insight into the mechanism of GDNF protection of DA neurons, and may help avoid incorrect interpretations of temporary phenotypic changes. © 2010 Elsevier B.V. Source

Scheff S.W.,University of Kentucky | Price D.A.,University of Kentucky | Schmitt F.A.,University of Kentucky | Roberts K.N.,University of Kentucky | And 3 more authors.
Journal of Alzheimer's Disease

Amnestic mild cognitive impairment (aMCI) is considered to be one of the early stages in the progression from no cognitive impairment (NCI) to Alzheimer's disease (AD). Individuals with aMCI have increased levels of AD-type neuropathology in multiple regions of the neocortex and hippocampus and demonstrate a loss of synaptic connectivity. Recent neuroimaging studies have reported increased levels of 11C-PiB (Pittsburgh, compound B) in regions of the neocortex including the precuneus region of the medial parietal lobe. This cortical region has been implicated in episodic memory, which is disrupted early in the progression of AD. In this study, unbiased stereology coupled with electron microscopy was used to quantify total synaptic numbers in lamina 3 of the precuneus from short postmortem autopsy tissue harvested from subjects who died at different cognitive stages during the progression of AD. Individuals with aMCI did not reveal a statistically significant decline in total synapses compared to the NCI cohort while the AD group did show a modest but significant decline. Synaptic numbers failed to correlate with several different cognitive tasks including the Mini-Mental State Examination scores and episodic memory scores. Although levels of [3H]PiB binding were elevated in both the aMCI and AD groups, it did not strongly correlate with synaptic counts. These results support the idea that despite increased amyloid load, the precuneus region does not show early changes in synaptic decline during the progression of AD. © 2013 - IOS Press and the authors. All rights reserved. Source

Scheff S.W.,University of Kentucky | Price D.A.,University of Kentucky | Ansari M.A.,University of Kentucky | Roberts K.N.,University of Kentucky | And 4 more authors.
Journal of Alzheimer's Disease

Mild cognitive impairment (MCI) is considered to be an early stage in the progression of Alzheimer's disease (AD) providing an opportunity to investigate brain pathogenesis prior to the onset of dementia. Neuroimaging studies have identified the posterior cingulate gyrus (PostC) as a cortical region affected early in the onset of AD. This association cortex is involved in a variety of different cognitive tasks and is intimately connected with the hippocampal/entorhinal cortex region, a component of the medial temporal memory circuit that displays early AD pathology. We quantified the total number of synapses in lamina 3 of the PostC using unbiased stereology coupled with electron microscopy from short postmortem autopsy tissue harvested from cases at different stage of AD progression. Individuals in the early stages of AD showed a significant decline in synaptic numbers compared to individuals with no cognitive impairment (NCI). Subjects with MCI exhibited synaptic numbers that were between the AD and NCI cohorts. Adjacent tissue was evaluated for changes in both pre and postsynaptic proteins levels. Individuals with MCI demonstrated a significant loss in presynaptic markers synapsin-1 and synaptophysin and postsynaptic markers PSD-95 and SAP-97. Levels of [3H]PiB binding was significantly increased in MCI and AD and correlated strongly with levels of synaptic proteins. All synaptic markers showed a significant association with Mini-Mental Status Examination scores. These results support the idea that the PostC synaptic function is affected during the prodromal stage of the disease and may underlie some of the early clinical sequelae associated with AD. © 2015-IOS Press and the authors. Source

Zirkin B.R.,Johns Hopkins University | Tenover J.L.,Johns Hopkins University | Tenover J.L.,Geriatric Research Educational and Clinical Center
Journal of Andrology

As men age, serum testosterone (T) levels decline, whereas serum luteinizing hormone (LH) levels increase somewhat or remain unchanged. Age-related reductions in T levels may be associated with alterations in body composition; energy level; muscle strength; physical, sexual, and cognitive functions; and mood. The predominant contributor to the decline in serum T levels is the decreased ability of the aging testes to make T. As in humans, the Brown Norway rat demonstrates age-related reductions in serum T levels in the setting of unchanged or modestly increased serum LH levels. In this rat model, the ability of aged Leydig cells, the terminally differentiated T-producing cells of the testis, to produce T in response to LH stimulation is significantly diminished. This review begins with a discussion of what is known of the molecular mechanisms by which T synthesis declines with Leydig cell aging. It concludes with a brief history of T replacement therapy, current guidelines, controversies related to T replacement therapy in older men, and proposed future clinical directions. © American Society of Andrology. Source

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