The Administrative Core's goals are to set the overall direction for the Center, ensure optimal utilization of Center resources, and provide a sense of "Centerness". The Massachusetts ADRC's goals are to provide the infrastructure and environment to enhance and facilitate cutting-edge basic, translational, and clinical research in Alzheimer disease and related disorders, as well as provide a unique and exciting training environment for the next generation of clinicians and scientists working in these arenas. Our aims are outlined in the RFA, and include creating an administrative structure and infrastructure to facilitate the work of the Center. This includes administrative support for the Mass. ADRC's Clinical, Data Management and Statistics, Neuropathology, Education and Information Transfer Cores and research projects. We provide formal mechanisms to augment collaborative activities with the scientific and lay communities, and to enhance collaborations across departments, units, local institutions, and national efforts to create an energetic multi- and cross-disciplinary approach to understanding AD. The Administrative Core will also provide fiscal accountability and business management expertise for the Center, and ensure compliance with institutional, NIH and HIPAA policies and requirements related to human subjects and animal research. A second major effort of the Administrative Core is to organize 4 major Committee programs: An Executive Committee consisting of Core and Project leaders and additional Key Personnel, to advise the Director on scientific and administrative matters; an External Advisory Board to provide guidance to the Center on an annual basis; a Pilot Project Review Committee to recommend 3 pilot projects on an annual basis; and an Internal Advisory Board consisting of senior scientists, clinicians, and administrators from our constituent institutions to coordinate ADRC efforts with local resources. Additional committees and infrastructure are described to recruit pilot projects, to co-ordinate IRB approvals for projects, to coordinate recruitment of subjects for studies, and to monitor the scientific and administrative functions of the Center. RELEVANCE (See instructions): The Administrative Core of the Massachusetts ADRC provides the infrastructure and management of resources to enhance the training environment for clinical research in Alzheimer's disease and related disorders.
The amyloid p-protein (Afi) is closely linked to the pathophysiological processes that lead to Alzheimer disease (AD), and likely are ultimately responsible for the neural system collapse that causes the clinical syndrome of dementia. However the mechanistic role of Afi and the form in which it is toxic remain controversial. One hypothesis is that the insoluble amyloid plaque itself is deleterious to the brain. Contrasting this argument is the hypothesis that the damage is caused by soluble Aft oligomers. The overall goal of his Project is to examine these two competing hypotheses critically and determine whether one or both are more likely. In this research plan, we propose three specific aims built around advances in biochemical and morphological techniques. To learn whether and how soluble A(3oligomers, monomers and/or plaque cores correlate with the histopathological changes (gliosis, Ap deposits, neurofibrillary tangles), we will quantify the levels of soluble oligomers and monomers by new Size Exclusion Chromatography and sensitive IP/Western techniques and correlate these findings with each subject's detailed neuropathological phenotype and with clinical information. A second approach to these questions will utilize a newly developed histological preparation that allows visualization of individual synaptic elements, fibrillar Ap, and oligomeric Ap simultaneously. We have observed that oligomeric Ap-directed antibodies reveal a "halo" around plaques that corresponds to the region around plaques that have diminished dendritic spine density. Furthermore, oligomeric Ap-directed antibodies demonstrate puncta that co-localize with PSD95 positive dendritic spines. These observations motivate an analysis of oligomeric Apand synaptic change that will take aim at fundamental mechanisms of Ap-associated synaptic loss. These studies will address a central unresolved question: how do soluble oligomeric forms relate to the fibrillar, histologically detected forms of Ap. Moreover, our experiments will also directly address whether Ap in cognitively normal controls who have Ap deposits differ from those in subjects with AD. By taking advantage of well characterized material from the MADRC Neuropathology Core's Brain Bank, Clinical Core evaluations, and Statistical Core expertise, we plan to test hypotheses directed at the relationship of Ap to cognitive impairment and neuronal toxicity. RELEVANCE (See instructions): Project 3 of the Massachusetts ADRC will test the competing hypotheses of the role of Ap protein and the form in which its toxicity is associated with cognitive dysfunction and Alzheimer's disease neuropathology.
The overarching objective of the Massachusetts Alzheimer's Disease Research Center (MADRC) is to stimulate and support research of the highest quality in aging, Alzheimer's disease (AD), and related disorders. The specific goals are: To propose and support new research directed toward uncovering the etiology and pathogenetic mechanisms of AD and related dementias; to enhance collaborative research funded outside of the MADRC; and to catalyze education, training and information transfer related to dementia. Administrative, Clinical, Data and Statistical, Neuropathology, and Education Cores support 3 R01 style 5 year projects and 3 pilot projects/year. The Clinical Core has established a Longitudinal Cohort that follows ~600 individuals who are cognitively normal, have mild impairments, mild AD or other dementias. These subjects undergo full Uniform Data Set evaluations and data are submitted to NACC. Our retention rate to date (93% 1 year; 97% 2 year) shows that these individuals are committed to participate in longitudinal studies. Over 60% of these individuals have already also contributed to at least one other research project related to aging and cognition, including 7 different neuroimaging studies and a major Biomarkers program. The Neuropathology Core has tissues on nearly 1400 subjects, and in the last 4 years supplied 3 dozen separate investigators with over 10,000 slides or specimens. The Data and Statistics Core has built a new state of the art data repository. The Education Core has continued its mission of outstanding community involvement, and has enhanced recruitment for MADRC programs. Three R01 style applications are closely linked to Core activities, and focus on the relationship between amyloid, clinical symptoms, and neurotoxicity: Two relate to longitudinal studies in MADRC subjects. The first asks what does positive PIB amyloid imaging mean in the setting of normal cognition? The second, led by a junior investigator, examines whether amyloid deposition in vessels (CAA) alters the course of dementia. The third project utilizes MADRC brain bank material to examine whether oligomeric forms of amyloid - in addition to, or instead of, fibrillar forms - are neurotoxic. The MADRC provides infrastructure to support local and national efforts in AD research: In the current grant period 44 investigators used MADRC resources to support 76 NIH funded projects; an additional 68 projects supported by non-Federal sources relied in part on MADRC for subjects or other resources. Going forward, the MADRC will continue to expand its clinical and neuropathological resources, its innovative training and scientific programs directed toward AD research.
