2010 — 2021 |
Woltjer, Randall L |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Neuropathology Core @ Oregon Health & Science University
Project Summary: Neuropathology Core! The Neuropathology Core is aligned to support the overall specific aims of the OADC's 5 overarching aims: 1) catalyze and sustain innovative research and discovery in AD and related disorders through an organizational infrastructure supporting a rich collaborative environment; 2) focus resources toward specific areas of emphasis: preclinical dementia and activity of disease emphasizing the oldest old; markers of meaningful change captured through studies of peripheral biomarkers, neuroimaging and continuous in-home behavioral monitoring; neuropathology of brain aging and late life dementia; novel testing of novel treatments; and improving education and knowledge about dementia; 3) provide materials to support the science through well- characterized research participants, biological specimens, brain tissue, data provision and analytics; 4) contribute to the national research commons relevant to AD and related disorders; and 5) provide venues and mechanisms for education and training of new scientists, as well as educating and informing key stakeholders. The focus of the OADC?s Neuropathology Core on the transition from healthy aging to dementia has led to the accumulation of a large repository of tissue from cognitively intact brain donors and from those who develop dementia and milder impairments at a more advanced age, with pathologies that differ somewhat from those of ?classic? Alzheimer?s disease. Understanding these changes in the context of the clinical and imaging findings in these individuals is proposed as the scientific ?leitmotif? around which the Specific Aims are constructed. These are to: 1. Provide standardized research assessments while at the same time affording this diagnostic expertise to the population of OADC subjects by providing family members of the deceased and physicians involved in their care with timely autopsy reports based on the most current standardized diagnostic criteria. 2. Facilitate research by collecting, storing and distributing a highly accessible, but appropriately safeguarded, repository of well-prepared brain tissue and neuropathologic data from carefully and longitudinally characterized patients with mild cognitive impairment (MCI) or dementia as well as non-cognitively impaired individuals using a variety of methods that maximizes utility to scientists. 3. Teach trainees in pathology, neurology, psychology, psychiatry, and basic sciences the current methods of neuropathological classification of neurodegenerative diseases and age-related changes, and mentor faculty in NP. 4. Develop innovative new approaches to maximize achievements in Aims 1 to 3.
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0.958 |
2018 — 2021 |
Silbert, Lisa C Woltjer, Randall L |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
White Matter Hyperintensity-Associated Astrocytopathy in Alzheimers Disease and Vascular Cognitive Impairment a Targeted Histopathologic Study Using Postmortem 7t Mri @ Oregon Health & Science University
PROJECT SUMMARY Vascular disease is the largest single identifiable risk factor for dementia apart from age and the only one potentially preventable. Alzheimer's Disease (AD) pathology proportionately decreases with age in those with clinical dementia, implicating non-AD mechanisms as important determinants of older-onset dementia. These mechanisms are likely vascular in nature, as ?mixed vascular/AD? is more common than AD alone in older individuals. The hallmark of vascular cognitive impairment (VCI) is subcortical white matter disease, visualized on magnetic resonance imaging (MRI) as white matter hyperintensities (WMHs). WMHs are ubiquitous with age, increase the risk of dementia, stroke, and death, and are increased in AD. Our research shows WM damage extends beyond WMHs, within the immediately surrounding normal appearing white matter (NAWM). Recent studies suggest an important role of WM astrocytic dysfunction (?astrocytopathy?) in VCI. Our preliminary data support this association, and has identified changes in astrocyte phenotypes and increased tau pathology in the grey matter (GM) of cortex overlying WMHs compared with GM overlying NAWM, suggesting WMH-associated astrocytopathy contributes to both WM and GM dysfunction in both VCI and AD. We hypothesize that regional chronic cerebral ischemia results in astrocytic changes within the GM and WM, that alone and in combination with AD-associated pathologies potentiate CNS dysfunction and subsequent cognitive impairment and dementia in the elderly, and that WMHs may serve as a biomarker for these changes. We have developed a 7T postmortem MR protocol that allows for the identification and targeted sampling of WMHs and surrounding normal appearing tissue for histopathological examination that includes a detailed assessment of astrocytic changes, using brain tissue from a well-characterized cohort of Oregon Alzheimer's Disease Center subjects who come to autopsy. In Aim 1, we will identify the features of WM astrocytopathy associated with WMHs and areas in transition to becoming WMHs. In Aim 2, we will identify these changes in GM, associate these with AD-specific pathologic changes, and determine their spatial relationship to regional WMHs. In Aim 3, we will determine which regional WM and GM astrocyte abnormalities found in Aims 1 and 2 are associated with dementia status and global cognition, controlling for standard pathologies associated with neurodegenerative diseases, such as those of AD. We anticipate that the studies in human tissue will produce new insights into the relationship between VCI and AD, and suggest specific functions and functional losses of astrocytes in mediating these associations. We anticipate that treatments aimed at astrocytic protection and recovery from hypoxic injury could suggest a new spectrum of possibilities for therapeutic targets designed to prevent AD and related dementias.
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0.958 |