Geriatrics Commons^™

Microglial P38Α Mapk Is Critical For Lps-Induced Neuron Degeneration, Through A Mechanism Involving Tnfα, Bin Xing, Adam D. Bachstetter, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: The p38α MAPK isoform is a well-established therapeutic target in peripheral inflammatory diseases, but the importance of this kinase in pathological microglial activation and detrimental inflammation in CNS disorders is less well understood. To test the role of the p38α MAPK isoform in microglia-dependent neuron damage, we used primary microglia from wild-type (WT) or p38α MAPK conditional knockout (KO) mice in co-culture with WT cortical neurons, and measured neuron damage after LPS insult.

RESULTS: We found that neurons in co-culture with p38α-deficient microglia were protected against LPS-induced synaptic loss, neurite degeneration, and neuronal death. The involvement of the proinflammatory …

Leaving Home Care: Decision Making, Risk Scenarios & Services Gaps In The Home Care System, Jacey J. Vaughan, Nina M. Silverstein

Gerontology Institute Publications

Home and community-based services (HCBS) enable older and disabled adults to age-in-place in their homes and communities by helping them function independently for as long as possible (Grabowski et al., 2010; Wong & Silverstein, 2011). Previous studies well document that older adults prefer receiving HCBS rather than institutional care at a nursing home (e.g., Walker, 2010; Fox-Grage, Coleman, & Freiman, 2006). Medicaid is a major source of funding for long-term care. Currently, a large proportion of Medicaid funds in most states has been spent on institutional care (National Conference of State Legislatures & AARP, 2009), and older adults and their …

Elevated Stearoyl-Coa Desaturase In Brains Of Patients With Alzheimer's Disease, Giuseppe Astarita, Kwang-Mook Jung, Vitaly Vasilevko, Nicholas V. Dipatrizio, Sarah K. Martin, David H. Cribbs, Elizabeth Head, Carl W. Cotman, Daniele Piomelli

Sanders-Brown Center on Aging Faculty Publications

The molecular bases of Alzheimer's disease (AD) remain unclear. We used a lipidomic approach to identify lipid abnormalities in the brains of subjects with AD (N = 37) compared to age-matched controls (N = 17). The analyses revealed statistically detectable elevations in levels of non-esterified monounsaturated fatty acids (MUFAs) and mead acid (20:3n-9) in mid-frontal cortex, temporal cortex and hippocampus of AD patients. Further studies showed that brain mRNAs encoding for isoforms of the rate-limiting enzyme in MUFAs biosynthesis, stearoyl-CoA desaturase (SCD-1, SCD-5a and SCD-5b), were elevated in subjects with AD. The monounsaturated/saturated fatty acid ratio ('desaturation index')--displayed a strong …

Activation Of Matrix Metalloproteinases Following Anti-Aβ Immunotherapy; Implications For Microhemorrhage Occurrence, Donna M. Wilcock, Dave Morgan, Marcia N. Gordon, Tiffany L. Taylor, Lisa A. Ridnour, David A. Wink, Carol A. Colton

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Anti-Aβ immunotherapy is a promising approach to the prevention and treatment of Alzheimer's disease (AD) currently in clinical trials. There is extensive evidence, both in mice and humans that a significant adverse event is the occurrence of microhemorrhages. Also, vasogenic edema was reported in phase 2 of a passive immunization clinical trial. In order to overcome these vascular adverse effects it is critical that we understand the mechanism(s) by which they occur.

METHODS: We have examined the matrix metalloproteinase (MMP) protein degradation system in two previously published anti-Aβ immunotherapy studies. The first was a passive immunization study in which …

Senior Transportation Abstracts: A Focus On Options, Helen Kerschner, Nina M. Silverstein

Gerontology Institute Publications

This collection of abstracts represents a publication of importance for understanding the needs, challenges, solutions, and/or every day issues related to senior transportation services. While several of the abstracts include information about senior driver safety, the collection’s primary purpose is to present a holistic approach to transportation options for older adults. Such a collection is timely because, although the practice of providing transportation to older adults is not new, research and preparation of practical informational and technical materials related to older adult transportation service needs and service delivery are quite recent.

Massachusetts Senior Legal Assistance Project Needs Evaluation: Current Demand For Legal Services, Alison Gottlieb, Lauren A. Martin, Ellen A. Bruce

Gerontology Institute Publications

The Gerontology Institute at the University of Massachusetts Boston was contracted to conduct a statewide needs assessment for the MSLAP. As agreed upon by the MSLAP Advisory Board, the focus of this assessment was to analyze the demand for services Massachusetts legal service providers have experienced recently as a means to understanding the legal needs of Massachusetts elders (age 60 and older). A second needs assessment was conducted by the Massachusetts Executive Office of Elder Affairs. That needs assessment surveyed home care workers and other elder agency personnel to gauge their assessment of elders’ legal needs in Massachusetts. Read together, …

Evaluation Of The Global Association Between Cholesterol-Associated Polymorphisms And Alzheimer's Disease Suggests A Role For Rs3846662 And Hmgcr Splicing In Disease Risk, Christopher R. Simmons, Fanggeng Zou, Steven G Younkin, Steven Estus

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNP)s that are essentially unequivocally associated with peripheral cholesterol. Since the alleles of the APOE gene, which modulate peripheral cholesterol metabolism, and midlife plasma cholesterol are both associated with Alzheimer's disease (AD) risk, we have evaluated the hypothesis that SNPs associated with plasma cholesterol are also associated with AD.

RESULTS: Seventeen non-APOE SNPs reproducibly associated with cholesterol per GWAS were tested for association with AD in ~2,000 AD and ~4,000 non-AD subjects. As a group, these SNPs are associated with AD. Two SNPs in particular, rs3846662 and rs1532085, are …

Epigenetic Silencing Of Nucleolar Rrna Genes In Alzheimer's Disease, Maciej Pietrzak, Grzegorz Rempala, Peter T. Nelson, Jing-Juan Zheng, Michal Hetman

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Ribosomal deficits are documented in mild cognitive impairment (MCI), which often represents an early stage Alzheimer's disease (AD), as well as in advanced AD. The nucleolar rRNA genes (rDNA), transcription of which is critical for ribosomal biogenesis, are regulated by epigenetic silencing including promoter CpG methylation.

METHODOLOGY/PRINCIPAL FINDINGS: To assess whether CpG methylation of the rDNA promoter was dysregulated across the AD spectrum, we analyzed brain samples from 10 MCI-, 23 AD-, and, 24 age-matched control individuals using bisulfite mapping. The rDNA promoter became hypermethylated in cerebro-cortical samples from MCI and AD groups. In parietal cortex, the rDNA promoter …

Microglial P38Α Mapk Is A Key Regulator Of Proinflammatory Cytokine Up-Regulation Induced By Toll-Like Receptor (Tlr) Ligands Or Beta-Amyloid (Aβ), Adam D. Bachstetter, Bin Xing, Lucia De Almeida, Edgardo R. Dimayuga, D. Martin Watterson, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Overproduction of proinflammatory cytokines from activated microglia has been implicated as an important contributor to pathophysiology progression in both acute and chronic neurodegenerative diseases. Therefore, it is critical to elucidate intracellular signaling pathways that are significant contributors to cytokine overproduction in microglia exposed to specific stressors, especially pathways amenable to drug interventions. The serine/threonine protein kinase p38α MAPK is a key enzyme in the parallel and convergent intracellular signaling pathways involved in stressor-induced production of IL-1β and TNFα in peripheral tissues, and is a drug development target for peripheral inflammatory diseases. However, much less is known about the quantitative …

Analyzing The Impact Of 23 Mg/Day Donepezil On Language Dysfunction In Moderate To Severe Alzheimer's Disease, Steven H. Ferris, Frederick A. Schmitt, Judith Saxton, Sharon Richardson, Joan Mackell, Yijun Sun, Yikang Xu

Sanders-Brown Center on Aging Faculty Publications

INTRODUCTION: Progressive language impairment is among the primary components of cognitive decline in Alzheimer's disease (AD). Because expressive and receptive language help to maintain emotional connections to caregivers and support the management of AD patients' functional needs, language plays a critical role in patients' emotional and physical health. Using data from a large prospective clinical trial comparing two doses of donepezil in patients with moderate to severe AD, we performed a post hoc analysis to determine whether a higher dose of donepezil was associated with greater benefits in language function.

METHODS: In the original randomized, double-blind clinical trial, 1,467 patients …

Chronic Disease Self-Management Programs: Relevance For Persons With Dementia, Nina M. Silverstein, Alison S. Gottlieb

Gerontology Institute Publications

The context for this study is the work of the Healthy Brain Initiative. The CDC has established a cooperative agreement with the Alzheimer’s Association to develop and implement a multifaceted approach to look at cognitive health as a public health issue. Late in 2010, the Association commissioned a review of the major chronic disease prevention programs from a systems approach to begin to understand the source of findings that Medicare beneficiaries with Alzheimer’s and related disorders are much higher cost than those simply with a single chronic disease and no AD. This led to the conclusion that Chronic Disease Self‐Management …

Rheumatoid Arthritis-Associated Polymorphisms Are Not Protective Against Alzheimer's Disease, Christopher R. Simmons, Fanggeng Zou, Steven G Younkin, Steven Estus

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Rheumatoid arthritis (RA) and Alzheimer's disease (AD) are inversely associated. To test the hypothesis that genetic elements associated with increased RA risk are associated with decreased AD risk, we evaluated RA genetic risk factors recently identified in genome-wide association studies (GWAS) for their association with AD in a two-stage, case-control analysis.

RESULTS: In our Stage 1 analysis of ~800 AD and ~1,200 non-AD individuals, three of seventeen RA-associated SNPs were nominally associated with AD (p < 0.05) with one SNP, rs2837960, retaining significance after correction for multiple testing (p = 0.03). The rs2837960_G (minor) allele, which is associated with increased RA risk, was associated with increased AD risk. Analysis of these three SNPs in a Stage 2 population, consisting of ~1,100 AD and ~2,600 non-AD individuals, did not confirm their association with AD. Analysis of Stage 1 and 2 combined suggested that rs2837960 shows a trend for association with AD. When the Stage 2 population was age-matched for the Stage 1 population, rs2837960 exhibited a non-significant trend with AD. Combined analysis of Stage 1 and the age-matched Stage 2 subset showed a significant association of rs2837960 with AD (p = 0.002, OR 1.24) that retained significance following correction for age, sex and APOE (p = 0.02, OR = 1.20). Rs2837960 is near BACE2, which encodes an aspartic protease capable of processing the AD-associated amyloid precursor protein. Testing for an association between rs2837960 and the expression of BACE2 isoforms in human brain, we observed a trend between rs2837960 and the total expression of BACE2 and the expression of a BACE2 transcript lacking exon 7 (p = 0.07 and 0.10, respectively).

CONCLUSIONS: RA-associated SNPs are generally not associated with AD. Moreover, rs2837960_G is associated with increased risk of both RA and, in individuals less than …

Massachusetts’ Home Care Programs And Reasons For Discharge Into Nursing Homes, Cathy M. Wong, Nina M. Silverstein

Gerontology Institute Publications

Home and community-based services (HCBS) are a range of long-term care services intended to enable older adults and persons with disabilities to “age in place” in their own homes and communities. Previous studies well document that older adults prefer receiving HCBS rather than institutional care at a nursing home. One study concluded that 84 percent of older Americans, aged 50 years and older, want to remain in their homes for as long as possible. Medicaid is a major source of funding for long term care. Currently, a large proportion of Medicaid funds in most states has been spent on institutional, …

Cx3cl1 Reduces Neurotoxicity And Microglial Activation In A Rat Model Of Parkinson's Disease, Mibel M. Pabon, Adam D. Bachstetter, Charles E. Hudson, Carmelina Gemma, Paula C. Bickford

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Parkinson's disease is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. The cause of the neurodegeneration is unknown. Neuroinflammation has been clearly shown in Parkinson's disease and may be involved in the progressive nature of the disease. Microglia are capable of producing neuronal damage through the production of bioactive molecules such as cytokines, as well as reactive oxygen species (ROS), and nitric oxide (NO). The inflammatory response in the brain is tightly regulated at multiple levels. One form of immune regulation occurs via neurons. Fractalkine (CX3CL1), produced by neurons, suppresses the activation of microglia. CX3CL1 …

Risk Factors For Driving Cessation Vary By Race And Ethnicity, Elizabeth Dugan, Frank Porell, Chae Man Lee

Gerontology Institute Publications

Driving is related to our identity and independence as well as allowing us to get needed goods, services, and social opportunities that enrich daily life. Yet with increasing age, the risk for developing threats to medical fitness to drive increases. Driving cessation is related to a long list of negative outcomes, such as: depression, social isolation, diminished access to health care, and diminished quality of life. We investigated risks for driving cessation, paying close attention to racial differences. This study used data from the Health and Retirement Study (HRS), 1998-2008. The study included N=46, 528 older people (age 65 and …

Attention-Deficit/Hyperactivity Disorder In Childhood Is Associated With Cognitive Test Profiles In The Geriatric Population But Not With Mild Cognitive Impairment Or Alzheimer's Disease, N. Ivanchak, Erin L. Abner, S. A. Carr, S. J. Freeman, A. Seybert, John Ranseen, Gregory A. Jicha

Sanders-Brown Center on Aging Faculty Publications

The frequency of ADHD in the aging population and its relationship to late-life cognitive decline has not been studied previously. To address this gap in our understanding, the Wender-Utah ADHD Rating scale (WURS) was administered to 310 geriatric subjects with cognitive status ranging from normal cognition to mild cognitive impairment to overt dementia. The frequency of WURS-positive ADHD in this sample was 4.4%. WURS scores were not related to cognitive diagnoses, but did show nonlinear associations with tasks requiring sustained attention. The frequency of ADHD appears stable across generations and does not appear to be associated with MCI or dementia …

Physical Activity And Cognitive-Health Content In Top-Circulating Magazines, 2006–2008, Anna E. Greer, Sara J. Corwin, Daniela B. Friedman

All PTHMS Faculty Publications

Physical activity may promote cognitive health in older adults. Popular media play an important role in preventive health communication. This study examined articles discussing associations between physical activity and cognitive health in top-circulating magazines targeting older adults. 42,753 pages of magazines published from 2006 to 2008 were reviewed; 26 articles met inclusion criteria. Explanations regarding the link between physical activity and cognitive health were provided in 57.7% of articles. These explanations were generally consistent with empirical evidence; however, few articles included empirical evidence. Physical activity recommendations were presented in 80.8% of articles; a wide range was recommended (90–300 min of …