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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.

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.

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