Sanders Brown Center on Aging

South Shore, KY, United States

Sanders Brown Center on Aging

South Shore, KY, United States
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Scheff S.W.,Sanders Brown Center on Aging | Scheff S.W.,University of Kentucky | Smith B.N.,University of Kentucky
Journal of Neuroscience | Year: 2011

Functional plasticity of synaptic networks in the dentate gyrus has been implicated in the development of posttraumatic epilepsy and in cognitive dysfunction after traumatic brain injury, but little is known about potentially pathogenic changes in inhibitory circuits. We examined synaptic inhibition of dentate granulecells and excitability of surviving GABA ergic hilar interneurons 8-13 weeks after cortical contusion brain injury in transgenic mice that express enhanced green fluorescent protein in a subpopulation of inhibitory neurons. Whole-cell voltage-clamp recordings in granule cells revealed a reduction in spontaneous and miniature IPSC frequency after head injury; no concurrent change in paired-pulse ratio was found in granule cells after paired electrical stimulation of the hilus. Despite reduced inhibitory input to granule cells, action potential and EPSC frequencies were increased in hilar GABA neurons from slices ipsilateral to the injury versus those from control or contralateral slices. Furthermore, increased excitatory synaptic activity was detected in hilar GABA neurons ipsilateral to the injury after glutamate photostimulation of either the granule cell or CA3 pyramidal cell layers. Together, these findings suggest that excitatory drive to surviving hilar GABA neurons is enhanced by convergent input from both pyramidal and granule cells, but synaptic inhibition of granule cells is not fully restored after injury. This rewiring of circuitry regulating hilar inhibitory neurons may reflect an important compensatory mechanism, but it may also contribute to network destabilization by increasing the relative impact of surviving individual interneurons in controlling granule cell excitability in the posttraumatic dentate gyrus ©2011 the authors.

Meier S.,Sanders Brown Center on Aging | Bell M.,Sanders Brown Center on Aging | Lyons D.N.,Sanders Brown Center on Aging | Rodriguez-Rivera J.,Sanders Brown Center on Aging | And 7 more authors.
Journal of Neuroscience | Year: 2016

One of the most common symptoms of Alzheimer’s disease (AD) and related tauopathies is memory loss. The exact mechanisms leading to memory loss in tauopathies are not yet known; however, decreased translation due to ribosomal dysfunction has been implicated as a part of this process. Here we use a proteomics approach that incorporates subcellular fractionation and coimmunoprecipitation of tau from human AD and non-demented control brains to identify novel interactions between tau and the endoplasmic reticulum (ER). We show that ribosomes associate more closely with tau in AD than with tau in control brains, and that this abnormal association leads to a decrease in RNA translation. The aberrant tau-ribosome association also impaired synthesis of the synaptic protein PSD-95, suggesting that this phenomenon contributes to synaptic dysfunction. These findings provide novel information about tau-protein interactions in human brains, and they describe, for the first time, a dysfunctional consequence of tau-ribosome associations that directly alters protein synthesis. © 2016 the authors.

Alva G.,ATP Clinical Research | Schmitt F.A.,Sanders Brown Center on Aging | Meng X.,Novartis | Olin J.T.,Novartis
International Journal of Geriatric Psychiatry | Year: 2011

Objective: In Alzheimer's disease (AD), rivastigmine has demonstrated statistically significant efficacy versus placebo on cognition and activities of daily living (ADL). The aim of this retrospective analysis was to further evaluate the treatment effects of rivastigmine on individual ADL items. Methods: This exploratory analysis focused on the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) outcome from a large, international, 24-week, controlled trial of rivastigmine once-daily transdermal patch and twice-daily capsules in AD (CENA713D2320, NCT00099242). Percentages of patients "improving" or "not worsening" on individual ADL items were calculated and changes from baseline with rivastigmine versus placebo were evaluated. Results: Patients received rivastigmine patch (9.5 mg/24 h; n=247), capsule (12 mg/day; n=254), and placebo (n=281). Statistically significant changes from baseline in composite ADCS-ADL scores in both rivastigmine treatment groups versus placebo (p<0.05) had previously been reported. In this responder analysis of the subset of patients who showed baseline functional impairments on each item, statistically significant differences favoring rivastigmine were seen on the following functions: bathing, clearing dishes, obtaining a beverage, garbage disposal, traveling, shopping, writing, using household appliances, and talking about current events. A responder analysis of emergence of ADL impairment was not as sensitive to treatment effects. Conclusions: These findings suggest that rivastigmine may benefit specific ADL, particularly in patients who are already exhibiting functional impairment. Further research is required to improve understanding of how drugs such as rivastigmine exert their clinical effects. Copyright © 2010 John Wiley & Sons, Ltd.

Schmitt F.A.,Sanders Brown Center on Aging | Xiangyi Meng,Novartis | Tekin S.,Novartis | Olin J.,Novartis
American Journal of Alzheimer's Disease and other Dementias | Year: 2010

Alzheimer's disease (AD) patients treated with rivastigmine transdermal patch have shown statistically significant differences versus placebo on the AD Assessment scale-cognitive subscale (ADAS-cog). In this retrospective analysis of a double-blind, placebo- and active-controlled, 24-week clinical trial, the specific effects of rivastigmine patch on individual ADAS-cog items and cognitive domains (memory, language, and praxis) were explored. The mean baseline to week 24 changes were calculated for each ADAS-cog item and domain in this exploratory, hypothesis-generating analysis. Patients on 9.5 mg/24 h rivastigmine patch, 17.4 mg/24 h rivastigmine patch, and 3 to 12 mg/d rivastigmine capsules showed improvements over placebo on the memory and praxis ADAS-cog subscales. The rivastigmine patch groups also showed improvements on the language subscale. Significant differences versus placebo were seen on several individual item scores in the rivastigmine-treated groups. Rivastigmine patch was associated with improvements on the memory, praxis, and language domains of cognition in patients with mild-to-moderate AD. © The Author(s) 2010.

Gleichmann M.,U.S. National Institute on Aging | Zhang Y.,U.S. National Institute on Aging | Wood W.H.,U.S. National Institute on Aging | Becker K.G.,U.S. National Institute on Aging | And 8 more authors.
Neurobiology of Aging | Year: 2012

Activity-dependent modulation of neuronal gene expression promotes neuronal survival and plasticity, and neuronal network activity is perturbed in aging and Alzheimer's disease (AD). Here we show that cerebral cortical neurons respond to chronic suppression of excitability by downregulating the expression of genes and their encoded proteins involved in inhibitory transmission (GABAergic and somatostatin) and Ca 2+ signaling; alterations in pathways involved in lipid metabolism and energy management are also features of silenced neuronal networks. A molecular fingerprint strikingly similar to that of diminished network activity occurs in the human brain during aging and in AD, and opposite changes occur in response to activation of N-methyl-D-aspartate (NMDA) and brain-derived neurotrophic factor (BDNF) receptors in cultured cortical neurons and in mice in response to an enriched environment or electroconvulsive shock. Our findings suggest that reduced inhibitory neurotransmission during aging and in AD may be the result of compensatory responses that, paradoxically, render the neurons vulnerable to Ca 2+-mediated degeneration. © 2012.

Cykowski M.D.,Houston Methodist Hospital | Takei H.,Houston Methodist Hospital | Van Eldik L.J.,Sanders Brown Center on Aging | Schmitt F.A.,Sanders Brown Center on Aging | And 4 more authors.
Journal of Neuropathology and Experimental Neurology | Year: 2016

Transactivating responsive sequence (TAR) DNA-binding protein 43-kDa (TDP-43) pathology has been described in various brain diseases, but the full anatomical distribution and clinical and biological implications of that pathology are incompletely characterized. Here, we describe TDP-43 neuropathology in the basal forebrain, hypothalamus, and adjacent nuclei in 98 individuals (mean age, 86 years; median final mini-mental state examination score, 27). On examination blinded to clinical and pathologic diagnoses, we identified TDP-43 pathology that most frequently involved the ventromedial basal forebrain in 19 individuals (19.4%). As expected, many of these brains had comorbid pathologies including those of Alzheimer disease (AD), Lewy body disease (LBD), and/or hippocampal sclerosis of aging (HS-Aging). The basal forebrain TDP-43 pathology was strongly associated with comorbid HS-Aging (odds ratio = 6.8, p = 0.001), whereas there was no significant association between basal forebrain TDP-43 pathology and either AD or LBD neuropathology. In this sample, there were some cases with apparent preclinical TDP-43 pathology in the basal forebrain that may indicate that this is an early affected area in HS-Aging. We conclude that TDP-43 pathology in the basal forebrain is strongly associated with HS-Aging. These results raise questions about a specific pathogenetic relationship between basal forebrain TDP-43 and non-HSAging comorbid diseases (AD and LBD). © 2016 American Association of Neuropathologists, Inc. All rights reserved.

Ivanchak N.,University of Kentucky | Fletcher K.,University of Kentucky | Jicha G.A.,University of Kentucky | Jicha G.A.,Sanders Brown Center on Aging
Current Psychiatry Reports | Year: 2012

Attentional deficits are frequently seen in isolation as the presenting sign and symptom of neurodegenerative disease, manifest as mild cognitive impairment (MCI). Persistent ADHD in the geriatric population could well be misconstrued as MCI, leading to the incorrect assumption that such persons are succumbing to a neurodegenerative disease process. Alternatively, the molecular, neuroanatomic, or neurochemical abnormalities seen in ADHD may contribute to the development of de novo late life neurodegenerative disease. The present review examines the issue of causality vs confound regarding the association of ADHD with MCI, suggesting that both are tenable hypotheses. © Springer Science+Business Media, LLC 2012.

Bieging K.T.,Northwestern University | Fish K.,Northwestern University | Bondada S.,Sanders Brown Center on Aging | Bondada S.,University of Kentucky | Longnecker R.,Northwestern University
Blood | Year: 2011

The link between EBV infection and Burkitt lymphoma (BL) is strong, but the mechanism underlying that link has been elusive. We have developed a mouse model for EBV-associated BL in which LMP2A, an EBV latency protein, and MYC are expressed in B cells. Our model has demonstrated the ability of LMP2A to accelerate tumor onset, increase spleen size, and bypass p53 inactivation. Here we describe the results of total gene expression analysis of tumor and pretumor B cells from our transgenic mouse model. Although we see many phenotypic differences and changes in gene expression in pretumor B cells, the transcriptional profiles of tumor cells from LMP2A/λ-MYC and λ-MYC mice are strikingly similar, with fewer than 20 genes differentially expressed.We evaluated the functional significance of one of the most interesting differentially expressed genes, Egr1, and found that it was not required for acceleration of tumor onset by LMP2A. Our studies demonstrate the remarkable ability of LMP2A to affect the pretumor B-cell phenotype and tumorigenesis without substantially altering gene expression in tumor cells. © 2011 by The American Society of Hematology.

Neltner J.H.,University of Kentucky | Abner E.L.,Sanders Brown Center on Aging | Schmitt F.A.,Sanders Brown Center on Aging | Denison S.K.,Sanders Brown Center on Aging | And 3 more authors.
Journal of Neuropathology and Experimental Neurology | Year: 2012

Quantitative neuropathologic methods provide information that is important for both research and clinical applications. The technologic advancement of digital pathology and image analysis offers new solutions to enable valid quantification of pathologic severity that is reproducible between raters regardless of experience. Using an Aperio ScanScope XT and its accompanying image analysis software, we designed algorithms for quantitation of amyloid and tau pathologies on 65 amyloid (6F/3D antibody) and 48 phospho-tau (PHF-1)-immunostained sections of human temporal neocortex. Quantitative digital pathologic data were compared with manual pathology counts. There were excellent correlations between manually counted and digitally analyzed neuropathologic parameters (R = 0.56-0.72). Data were highly reproducible among 3 participants with varying degrees of expertise in neuropathology (intraclass correlation coefficient values, >0.910). Digital quantification also provided additional parameters, including average plaque area, which shows statistically significant differences when samples are stratified according to apolipoprotein E allele status (average plaque area, 380.9 Î1/2m in apolipoprotein E [Latin Small Letter Open E]4 carriers vs 274.4 m for noncarriers; p < 0.001). Thus, digital pathology offers a rigorous and reproducible method for quantifying Alzheimer disease neuropathologic changes and may provide additional insights into morphologic characteristics that were previously more challenging to assess because of technical limitations. © 2012 by the American Association of Neuropathologists, Inc.

Lim Y.-b.,Yonsei University | Mays C.E.,Sanders Brown Center on Aging | Mays C.E.,University of Kentucky | Kim Y.,Sanders Brown Center on Aging | And 5 more authors.
Biomaterials | Year: 2010

Branched polyamines are effective in inhibiting prions in a cationic surface charge density dependent manner. However, toxicity associated with branched polyamines, in general, often hampers the successful application of the compounds to treat prion diseases. Here, we report that constitutively maintained cationic properties in branched polyamines reduced the intrinsic toxicity of the compounds while retaining the anti-prion activities. In prion-infected neuroblastoma cells, quaternization of amines in polyethyleneimine (PEI) and polyamidoamine (PAMAM) dendrimers markedly increased the nontoxic concentration ranges of the compounds and still supported, albeit reduced, an appreciable level of anti-prion activity in clearing prions from the infected cells. Furthermore, quaternized PEI was able to degrade prions at acidic pH conditions and inhibit the in vitro prion propagation facilitated by conversion of the normal prion protein isoform to its misfolded counterpart, although such activities were decreased by quaternization. Quaternized PAMAM was least effective in degrading prions but efficiently inhibited prion conversion with the same efficacy as unmodified PAMAM. Our results suggest that quaternization represents an effective strategy for developing nontoxic branched polyamines with potent anti-prion activity. This study highlights the importance of polyamine structural control for developing polyamine-based anti-prion agents and understanding of an action mechanism of quaternized branched polyamines. © 2009 Elsevier Ltd. All rights reserved.

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