Julie Ann Schneider, MD - US grants

This 5-year clinical scientist development award proposes the use of quantitative epidemiologic principles to relate post-mortem findings to neurologic conditions associated with aging. A spectrum of parkinsonian signs, including bradykinesia, rigidity, tremor, and gait imbalance are common in older persons without Parkinson's disease, and are associated with increased morbidity and mortality. The nigrostriatal system also shows a spectrum of change with age. Preliminary data suggest that nigral neurofibrillary pathology is more common than previously recognized and is related to parkinsonian signs in older persons with and without Alzheimer's disease. The proposed studies will relate nigral neurofibrillary pathology and biochemical nigrostriatal changes to quantitative measures of global and specific parkinsonian signs in older persons with and without Alzheimer's disease. We will test the hypotheses that neurofibrillary pathology, specifically within the pars compacta of the substantia nigra, rather than the ventral tegmental or retrorubral areas, accounts for parkinsonian signs in older persons with and without AD, and that the mechanism by which neurofibrillary pathology produces parkinsonian signs involves decreased gene expression of tyrosine hydroxylase and a reduction in striatal dopamine, but not neuronal loss. We will also determine the role of mitochondrial mutations in the pathogenesis of neurofibrillary pathology and parkinsonian signs. The proposed project will use brain tissue of 80 older persons, without Parkinson's disease, in The Religious Order Study, a longitudinal study of over 650 catholic clergy who have agreed to annual examinations and brain donation after death. The proposed study will provide the Candidate in the opportunity to work with senior colleagues and allow the development of a unique research area that integrates the clinical neurology and neuropathology training. Through the course of these studies and analyses, through didactic sessions with her sponsors and consultants, and related course work, the candidate will develop the skills necessary to become an independent investigator.

DESCRIPTION (provided by applicant): Dementia is most commonly caused by Alzheimer's disease (AD) pathology (plaques and tangles); however AD pathology is very commonly mixed with other pathologies which further lower cognition and increase the odds of dementia in older persons.TDP-43 pathology, a marker of an uncommon presenile dementia syndrome called Frontotemporal Lobar Degeneration (FTLD-TDP), has recently been identified in a large proportion of older brains especially those with AD pathology. The role of TDP-43 pathology in aging and AD is unknown but there is increasing evidence that it is detrimental. It is not known whether TDP-43 pathology represents a third pathology of AD or a separate coexisting disease. Our overarching hypothesis is that age-related TDP-43 pathology represents a separate pathologic process associated with a dementia syndrome with a distinct cognitive phenotype and specific genetic risk factors that are separate from AD. We propose to address these hypotheses by performing a epidemiologic study of TDP-43 pathology in aging and AD, by leveraging existing clinical, pathologic, and genetic data from 2 epidemiologic clinical-pathologic cohort studies, and collecting new TDP-43 pathology data on 1400 brains. First, using a series of analytic models, we propose to test whether TDP-43 pathology is a separate aging pathology or mediates the effects of AD pathology. Second, we propose to investigate whether TDP-43 pathology in aging is associated with a specific cognitive profile and separately increases the rate of cognitive decline. We also propose to examine the role of TDP-43 pathology in older persons without dementia, and separately examine TDP-43 in older persons without AD pathology. If TDP-43 pathology represents coexisting FTLD-TDP, the clinical profile may show early and prominent executive and language impairment rather than an AD phenotype in each of these groups. Third because the oldest-old are the fastest growing segment of the population and because AD pathology is not as relevant in this age-group, we propose to investigate the role of TDP-43 pathology in this important subgroup of older persons. Finally in the last two aims we propose to investigate the association of genetic polymorphisms (SNPs) with TDP-43 pathology and cognition. We propose that SNPs associated with FTLD are related to TDP-43 pathology in aging; whereas SNPs associated with clinical AD are related to AD pathology in aging. We present compelling preliminary data in the support of these aims. Results from these proposed studies will fill an important gap in scientific knowledge and are likely to impact future studies of prevention and treatment of cognitive impairment and dementia in aging.

ABSTRACT ? NEUROPATHOLOGY CORE The Neuropathology Core will play a pivotal role to help achieve the overall Rush ADRC goals by supporting, promoting and facilitating innovative translational research. Specifically, the Neuropathology Core will promote collaborative, transparent, and reproducible research by providing investigators with expertise, mentoring, and a comprehensive and unique resource of biospecimens and data using contemporary laboratory methods, state-of-the-art diagnostics, and sophisticated statistical support and data management. The Neuropathology Core will do this in participation with the Administrative, Data Management and Statistical, Biomarker and Neuroimaging, and Outreach, Recruitment and Engagement Cores, and the Research Education Component working with ADRC core leaders and other colleagues and focusing on our well-characterized subjects in the Clinical Core, Religious Orders Study (ROS) and Latino Cores. Specifically, the Neuropathology Core will (1) Use rapid autopsy and optimal biospecimen collection procedures to obtain antemortem (blood, lymphocytes, DNA) and postmortem (brain, cerebrospinal fluid) biospecimens (2) Preserve, process and store antemortem (blood, lymphocytes, DNA) and postmortem (brain and CSF) biospecimens for clinical-pathologic and innovative translational research by using uniform best practice procedures for research studies while maintaining flexibility to accommodate special needs of specific researchers, studies, and collaborations. (3) Perform state-of-the-art assessments on brain tissue using contemporary macroscopic and microscopic procedures and collect state-of-the-art neuropathologic data and diagnoses, including data on AD, Lewy body, TDP, and HS, and vascular (gross and microinfarcts, hemorrhages, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy) pathologies to support a wide range of studies. (4) Distribute antemortem and postmortem specimens and data, share expertise, and mentor junior researchers and faculty in neuropathology by making biospecimens, data, and expertise assessable to junior and established investigators within and across the ADRC community, and outside of the centers; also partaking in collaborative studies with other centers and projects funded by the National Institution Aging (e.g., NACC, ADGC) and other organizations seeking to advance research in AD/ADRD. (5) Catalogue all biospecimens, photography, neuropathologic data and diagnoses, digital slide images and tissue distribution, using modern and secure data management systems. These activities will support, promote and facilitate innovative translational research that will lead to effective prevention, diagnosis, and interventions for Alzheimer?s disease and Alzheimer?s Disease Related Disorders.

Principal Investigator/Program Director (Last, First, Middle): Morris, Martha Clare This R01 application, entitled ?Diet Patterns and Alzheimer's Disease and Other Dementia Neuropathologies? is a revised submission in response to PAR-15-356. By the year 2050 it is projected that there will be 13.5 million Americans with AD at a cost of $1.1 trillion. Currently there is no cure for AD and no effective treatments. Preventive therapies are thus crucial for heading off a public health crisis. It is estimated that delaying dementia onset by just 5 years will reduce the cost and prevalence of the disease by half. Lifestyle interventions are an excellent strategy for population- wide impact. There is considerable epidemiological evidence linking diet to AD prevention, supported by underlying biologic mechanisms in the disease etiology for individual nutrients. In addition, a large number of AD risk factors have a demonstrated dietary basis. Dietary patterns including the DASH and Mediterranean diets and a hybrid of these diets called MIND (Mediterranean-DASH Diet Intervention for Neurodegenerative Delay) have been related to slower rates of cognitive decline and decreased incidence of AD. To date there has not been a study that has related dietary patterns to Alzheimer disease brain neuropathology or other neuropathologies associated with dementia. The clinical-neuropathologic cohort study, the Rush Memory and Aging Project affords the unique opportunity to investigate the relation of these healthy diet patterns to brain neuropathologies and to brain health. The extensive clinical and dietary data obtained among 600 hundred study participants with autopsy data will allow for unprecedented examination of diet pattern relations to multiple neuropathologies associated with AD dementia (amyloid plaques, neurofibrillary tangles, and CERAD, Braak, and NIA Reagan scores), vascular dementia (macro- and micro-infarcts, TDP-43, atherosclerosis, arteriosclerosis, cerebral amyloid angiopathy), other dementias (Lewy bodies, hippocampal sclerosis) and presynaptic proteins, a measure of brain health and cognitive reserve. The study will also examine the potential mediating roles of brain neuropathologies and of presynaptic proteins on the MIND, DASH, and Mediterranean dietary pattern associations with decline in cognitive function and clinical dementia. The study will advance the science by identifying the neuropathologic biomechanisms underlying dietary relationships to cognitive decline, AD and other dementias. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page