Geriatric Research Education Clinical Center

New York City, United States

Geriatric Research Education Clinical Center

New York City, United States
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Ashe K.H.,University of Minnesota | Ashe K.H.,Geriatric Research Education Clinical Center | Zahs K.R.,University of Minnesota
Neuron | Year: 2010

Alzheimer's disease (AD), the most common cause of dementia among the elderly, may either represent the far end of a continuum that begins with age-related memory decline or a distinct pathobiological process. Although mice that faithfully model all aspects of AD do not yet exist, current mouse models have provided valuable insights into specific aspects of AD pathogenesis. We will argue that transgenic mice expressing amyloid precursor protein should be considered models of accelerated brain aging or asymptomatic AD, and the results of interventional studies in these mice should be considered in the context of primary prevention. Studies in mice have pointed to the roles of soluble beta-amyloid (Aβ) oligomers and soluble tau in disease pathogenesis and support a model in which soluble Aβ oligomers trigger synaptic dysfunction, but formation of abnormal tau species leads to neuron death and cognitive decline severe enough to warrant a dementia diagnosis. © 2010 Elsevier Inc.


Zahs K.R.,University of Minnesota | Ashe K.H.,University of Minnesota | Ashe K.H.,Geriatric Research Education Clinical Center
Trends in Neurosciences | Year: 2010

Scores of compounds ameliorate cognitive deficits or neuropathology in transgenic mouse models of Alzheimer's disease (AD), yet these triumphs in mice have not translated into successful therapies for people. Why have studies in mice failed to predict results of human trials? We argue that most transgenic mouse 'models of AD' actually simulate the asymptomatic phase of the disease, and the results of interventional studies in these mice should be considered in the context of disease prevention. In addition, recent advances in imaging technology and biomarker discovery should aid in comparisons of mouse and human neurological status and, importantly, might allow us to predict better the response of people to drugs tested in mice. © 2010.


Hullinger R.,University of Wisconsin - Madison | Puglielli L.,University of Wisconsin - Madison | Puglielli L.,Geriatric Research Education Clinical Center
Behavioural Brain Research | Year: 2017

As the population of people aged 60 or older continues to rise, it has become increasingly important to understand the molecular basis underlying age-related cognitive decline. In fact, a better understanding of aging biology will help us identify ways to maintain high levels of cognitive functioning throughout the aging process. Many cellular and molecular aspects of brain aging are shared with other organ systems; however, certain age-related changes are unique to the nervous system due to its structural, cellular and molecular complexity. Importantly, the brain appears to show differential changes throughout the aging process, with certain regions (e.g. frontal and temporal regions) being more vulnerable than others (e.g. brain stem). Within the medial temporal lobe, the hippocampus is especially susceptible to age-related changes. The important role of the hippocampus in age-related cognitive decline and in vulnerability to disease processes such as Alzheimer's disease has prompted this review, which will focus on the complexity of changes that characterize aging, and on the molecular connections that exist between normal aging and Alzheimer's disease. Finally, it will discuss behavioral interventions and emerging insights for promoting healthy cognitive aging. © 2016 Elsevier B.V.


Hwang U.,Mount Sinai School of Medicine | Hwang U.,Geriatric Research Education Clinical Center | Shah M.N.,University of Rochester | Han J.H.,Vanderbilt University | And 4 more authors.
Health Affairs | Year: 2013

Already crowded and stressful, US emergency departments (EDs) are facing the challenge of serving an aging population that requires complex and lengthy evaluations. Creative solutions are necessary to improve the value and ensure the quality of emergency care delivered to older adults while more fully addressing their complex underlying physical, social, cognitive, and situational needs. Developing models of geriatric emergency care, including some that are already in use at dedicated geriatric EDs, incorporate a variety of physical, procedural, and staffing changes. Among the options for "geriatricizing" emergency care are approaches that may eliminate the need for an ED visit, such as telemedicine; for initial hospitalization, such as patient observation units; and for rehospitalization, such as comprehensive discharge planning. By transforming their current safety-net role to becoming a partner in care coordination, EDs have the opportunity to become better integrated into the broader health care system, improve patient health outcomes, contribute to optimizing the health care system, and reduce overall costs of care-keys to improving emergency care for patients of all ages. © 2013 Project HOPE-The People-to-People Health Foundation, Inc.


Zahs K.R.,University of Minnesota | Ashe K.H.,University of Minnesota | Ashe K.H.,Geriatric Research Education Clinical Center
Neuron | Year: 2015

Mutations in presenilins are linked to familial autosomal dominant Alzheimer's disease. In this issue of Neuron, Xia etal. (2015) show that a disease-linked mutation leads to loss of γ-secretase function, cognitive decline, and neurodegeneration when knocked into the mouse genome. Mutations in presenilins are linked to familial autosomal dominant Alzheimer's disease. In this issue of Neuron, Xia etal. (2015) show that a disease-linked mutation leads to loss of γ-secretase function, cognitive decline, and neurodegeneration when knocked into the mouse genome. © 2015 Elsevier Inc.


Zahs K.R.,University of Minnesota | Ashe K.H.,University of Minnesota | Ashe K.H.,Geriatric Research Education Clinical Center
Frontiers in Aging Neuroscience | Year: 2013

Alzheimer's disease (AD) is a fatal neurodegenerative disorder, and the most common cause of dementia in the elderly. The cause of AD is not known, but genetic evidence strongly supports the hypothesis that pathological aggregation of the β-amyloid protein (Aβ) triggers the disease process. AD has a long preclinical phase, lasting a decade or more. It is during this preclinical phase, before the irreversible neuron loss that characterizes the dementia phase of the disease, that therapies are most likely to be effective. If we are to block AD during the preclinical phase, we must identify the A.. species that are present before there are overt symptoms and that are associated with downstream markers of pathology. A specific soluble Aβ assembly, the putative dodecamer "Aβ*56," is present in the brains and cerebrospinal fluid of cognitively intact individuals and correlates with markers of synaptic dysfunction and neuronal injury. This assembly also correlates with memory dysfunction in multiple lines of transgenic mice that model the preclinical phase of AD. We suggest that Aβ*56 has a critical role during the earliest phase of AD and might serve as a molecular trigger of the disease. © 2013 Zahs and Ashe.


Pehar M.,University of Wisconsin - Madison | Pehar M.,Medical University of South Carolina | Puglielli L.,University of Wisconsin - Madison | Puglielli L.,Geriatric Research Education Clinical Center
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2013

The Nε-amino group of lysine residues can be transiently modified by the addition of an acetyl group. Recognized functions of Nε-lysine acetylation include regulation of activity, molecular stabilization and conformational assembly of a protein. For more than forty years lysine acetylation was thought to occur only in the cytosol and nucleus. Targets included cytoskeletal-associated proteins as well as transcription factors, histone proteins and proteins involved in DNA recombination and repair. However, in 2007 we reported that a type I membrane protein involved in the pathogenesis of Alzheimer's disease was transiently acetylated on the ε amino group of seven lysine residues while transiting along the secretory pathway. Surprisingly, the acetylation occurred in the lumen of the endoplasmic reticulum (ER) forcing us to reconsider old paradigms. Indeed, if lysine acetylation can occur in the lumen of the ER, then all the essential biochemical elements of the reaction must be available in the lumen of the organelle. Follow-up studies revealed the existence of ER-based acetyl-CoA:lysine acetyltransferases as well as a membrane transporter that translocates acetyl-CoA from the cytosol into the ER lumen. Large-scale proteomics showed that the list of substrates of the ER-based acetylation machinery includes both transiting and resident proteins. Finally, genetic studies revealed that this machinery is tightly linked to human diseases. Here, we describe these exciting findings as well as recent biochemical and cellular advances, and discuss possible impact on both human physiology and pathology. © 2012 Elsevier B.V.


Kramer B.J.,Geriatric Research Education Clinical Center
Journal of general internal medicine | Year: 2011

To determine if the combined effects of patient-level (demographic and clinical characteristics) and organizational-level (structure and strategies to improve access) factors are uniformly associated with utilization of Indian Health Service (IHS) and/or Veterans Health Administration (VHA) by American Indian and Alaska Native (AIAN) Veterans to inform policy which promotes dual use. We estimated correlates and compared two separate multilevel logistic regression models of VHA-IHS dual versus IHS-only and VHA-IHS dual versus VHA-only in a sample of 18,892 AIAN Veterans receiving care at 201 VHA and IHS facilities during FY02 and FY03. Demographic, diagnostic, eligibility, and utilization data were drawn from administrative records. A survey of VHA and IHS facilities defined availability of services and strategies to enhance access to healthcare for AIAN Veterans. Facility level strategies that are generally associated with enhancing access to healthcare (e.g., population-based services and programs, transportation or co-location) were not significant factors associated with dual use. In both models the common variable of dual use was related to medical need, defined as the number of diagnoses per patient. Other significant demographic, medical need and organizational factors operated in opposing manners. For instance, age increased the likelihood of dual use versus IHS-only but decreased the likelihood of dual use versus VHA-only. Efforts to enhance access through population-based and consumer-driven strategies may add value but be less important to utilization than availability of healthcare resources needed by this population. Sharing health records and co-management strategies would improve quality of care while policies allow and promote dual use.


Jonas M.C.,University of Wisconsin - Madison | Pehar M.,University of Wisconsin - Madison | Puglielli L.,University of Wisconsin - Madison | Puglielli L.,Geriatric Research Education Clinical Center
Journal of Cell Science | Year: 2010

The transient or permanent modification of nascent proteins in the early secretory pathway is an essential cellular function that ensures correct folding and maturation of membrane and secreted proteins. We have recently described a new form of post-translational regulation of the membrane protein β-site APP cleaving enzyme 1 (BACE1) involving transient lysine acetylation in the lumen of the endoplasmic reticulum (ER). The essential components of this process are two ER-based acetyl-CoA:lysine acetyltransferases, ATase1 and ATase2, and a membrane transporter that translocates acetyl-CoA into the lumen of the ER. Here, we report the functional identification of acetyl-CoA transporter 1 (AT-1) as the ER membrane acetyl-CoA transporter. We show that AT-1 regulates the acetylation status of ER-transiting proteins, including the membrane proteins BACE1, low-density lipoprotein receptor and amyloid precursor protein (APP). Finally, we show that AT-1 is essential for cell viability as its downregulation results in widespread cell death and induction of features characteristic of autophagy.


DeGutis J.M.,Geriatric Research Education Clinical Center | van Vleet T.M.,Northern California VA Healthcare System
Frontiers in Human Neuroscience | Year: 2010

Hemispatial neglect is a debilitating disorder marked by a constellation of spatial and non-spatial attention deficits. Patients' alertness deficits have shown to interact with lateralized attention processes and correspondingly, improving tonic/general alertness as well as phasic/moment-to-moment alertness has shown to ameliorate spatial bias. However, improvements are often short-lived and inconsistent across tasks and patients. In an attempt to more effectively activate alertness mechanisms by exercising both tonic and phasic alertness, we employed a novel version of a continuous performance task (tonic and phasic alertness training, TAPAT). Using a between-subjects longitudinal design and employing sensitive outcome measures of spatial and non-spatial attention, we compared the effects of 9 days of TAPAT (36 min/day) in a group of patients with chronic neglect (N = 12) with a control group of chronic neglect patients (N = 12) who simply waited during the same training period. Compared to the control group, the group trained on TAPAT significantly improved on both spatial and non-spatial measures of attention with many patients failing to exhibit a lateralized attention bias at the end of training. TAPAT was effective for patients with a range of behavioral profiles and lesions, suggesting that its effectiveness may rely on distributed or lower-level attention mechanisms that are largely intact in patients with neglect. In a follow-up experiment, to determine if TAPAT is more effective in improving spatial attention than an active treatment that directly trains spatial attention, we trained three chronic neglect patients on both TAPAT and search training. In all three patients, TAPAT training was more effective in improving spatial attention than search training suggesting that, in chronic neglect, training alertness is a more effective treatment approach than directly training spatial attention. © 2010 DeGutis and Van Vleet.

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