Vascular brain injury from small (micro) vessel dysfunction (?VBI) and Alzheimer's disease (AD) are highly prevalent in older adults, are commonly co-morbid, are major contributors to the dementia syndrome in the elderly, and are present in over 85% of cognitively normal individuals 75 years of age or older where these diseases presumably contribute to age-related cognitive decline. Enigmatically, while tremendous effort has been invested in understanding mechanisms of gray matter damage and neuron death in neurodegenerative diseases, carefully executed studies in humans and non-human primates have shown that neuron loss is not a feature of advancing age. In contrast, numerous studies, mostly neuroimaging-based, have associated white matter (WM) changes with advancing age;however, the molecular and cellular bases of this WM injury (WMI) with advancing age remain unclear. In this renewal, we hypothesize that ?VBI and AD cause WMI through direct and indirect mechanisms that converge on deleterious responses that impede myelin repair. Indeed, our observations from the current cycle indicate that ?VBI and AD conspire in the adult human brain to produce WMI and perturb response and repair of WMI through cellular and molecular mechanisms that are very similar to what we and others have demonstrated previously in pediatric WMI and adult demyelinating diseases. Our highly integrated multi-component R01 will continue to pursue the following Specific Aims: (1) Developing a unique and highly complementary resource of brain tissue from a human population-based study of brain aging and incident MCI. Tissue is prepared to maximize investigation of white matter. Using tissue from this unique resource, we will continue our work determining associations magnetic resonance imaging (MRI), histological, and immunohistochemical measures of white matter damage, (3) free radical damage to myelin or axons, (4) specific subpopulations of oliogodendrocyte precursor cells (OPCs), and (5) biochemical factors that suppress appropriate maturation and function of OPCs in aged brain. This project not only will continue to develop a unique resource for the community of scientists investigating white matter injury, but also employs this resource to answer key questions about the structural, cellular, and biochemical bases of WMI associated with cognitive decline in the elderly.

Public Health Relevance

Age-related cognitive decline and prodromal dementia are of paramount public health import given the projected demographics of the US population. While numerous studies have associated white matter changes with advancing age, the structural and cellular bases of this white matter damage remain enigmatic. Continuation of our research project not only will continue to develop a unique resource for the community of scientists investigating white matter injury, but also will employ this resource to answer key questions about the structural, cellular, and biochemical bases of white matter damage associated with cognitive decline in the elderly.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Petanceska, Suzana
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University of Washington
Schools of Medicine
United States
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Srivastava, Taasin; Diba, Parham; Dean, Justin M et al. (2018) A TLR/AKT/FoxO3 immune tolerance-like pathway disrupts the repair capacity of oligodendrocyte progenitors. J Clin Invest 128:2025-2041
Bagi, Zsolt; Brandner, Dieter D; Le, Phuong et al. (2018) Vasodilator dysfunction and oligodendrocyte dysmaturation in aging white matter. Ann Neurol 83:142-152
Back, Stephen A (2017) White matter injury in the preterm infant: pathology and mechanisms. Acta Neuropathol 134:331-349
McNeal, David W; Brandner, Dieter D; Gong, Xi et al. (2016) Unbiased Stereological Analysis of Reactive Astrogliosis to Estimate Age-Associated Cerebral White Matter Injury. J Neuropathol Exp Neurol 75:539-54
Beckelman, Brenna C; Day, Stephen; Zhou, Xueyan et al. (2016) Dysregulation of Elongation Factor 1A Expression is Correlated with Synaptic Plasticity Impairments in Alzheimer's Disease. J Alzheimers Dis 54:669-78
Flanagan, Margaret; Larson, Eric B; Latimer, Caitlin S et al. (2016) Clinical-pathologic correlations in vascular cognitive impairment and dementia. Biochim Biophys Acta 1862:945-51
White, Lon R; Edland, Steven D; Hemmy, Laura S et al. (2016) Neuropathologic comorbidity and cognitive impairment in the Nun and Honolulu-Asia Aging Studies. Neurology 86:1000-8
Wang, Jieqi; Wegener, Jan Eike; Huang, Teng-Wei et al. (2015) Wild-type microglia do not reverse pathology in mouse models of Rett syndrome. Nature 521:E1-4
Back, Stephen A (2015) Brain Injury in the Preterm Infant: New Horizons for Pathogenesis and Prevention. Pediatr Neurol 53:185-92
Li, Ge; Millard, Steven P; Peskind, Elaine R et al. (2014) Cross-sectional and longitudinal relationships between cerebrospinal fluid biomarkers and cognitive function in people without cognitive impairment from across the adult life span. JAMA Neurol 71:742-51

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