Dementia occurs in up to 80% of people with idiopathic Parkinson disease (PD) and substantially increases morbidity, mortality and cost of care for these individuals. In fact, it may be the most important factor leading to residential care placement. Yet, treatment of dementia in PD remains nearly non-existent, making this one of the great unmet needs for the nearly one million people affected by PD in North America. A major roadblock in developing and testing new treatments for dementia in PD is identification of the cause of dementia in a given individual - critically important to test therapies in relatively homogenous groups. This is a particular challenge in PD since dementia may be caused by either underlying cortical a-synuclein (a-syn) pathology or co-existing Alzheimer's (AD) pathology that includes abnormal deposition of A? and tau proteins. Our recent studies suggest that this may be an oversimplification. A? may be an independent factor, not necessarily related to tauopathy in PD, producing 3 groups of PD dementia: 1) primarily cortical synucleinopathy, 2) primarily cortical synucleinopathy with abnormal A? and 3) much less commonly cortical synucleinopathy with abnormal A? and tauopathy. We will test the hypotheses that behavior, PET, MRI, genetic and CSF biomarkers will permit identification of these causes and help predict onset of dementia in PD. We propose to test these hypotheses with a longitudinal follow up of people with PD with and without dementia and matched healthy controls. The multidisciplinary team will do evaluations including standard clinical evaluation, clinical dementia ratings, neuropsychological testing, volumetric MRI based measures of regional atrophy, resting state functional connectivity MR of brain networks, PET PIB in vivo measures of amyloid, CSF measures of relevant proteins (a-syn, A?42 and tau), postmortem neuropathology and quantified analysis of a-syn, A? and tau in selected brain areas. The postmortem analyses of brains will permit validation of the biomarkers. This also will provide the opportunity to make connections between imaging findings, behavior and regional protein expression in the brain. This study will validate biomarkers of specific pathologies underlying dementia in PD and that predict dementia onset. Our approach, borrowed heavily from studies in AD, will provide the framework for testing to-be-developed measures such as new CSF proteins, imaging methods or genetic signatures to determine whether they are more reliable or earlier biomarkers of dementia in PD. The ultimate goal is to use these biomarkers to test the efficacy of new therapies that will prevent dementia in PD.

Public Health Relevance

Parkinson disease (PD) is a progressive neurologic degenerative disease affecting nearly one million people in North America. These people have very high risk for development of dementia that adds substantial morbidity, mortality and economic burden to patients, families and society. This proposal will investigate the clinical manifestations of different forms of dementia, clarify the underlying causes and develop biomarkers that herald the onset of dementia. These steps are critical for development of effective treatment of dementia associated with PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS075321-03
Application #
8462310
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Babcock, Debra J
Project Start
2011-05-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$675,484
Indirect Cost
$231,086
Name
Washington University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Norris, Scott A; Jinnah, H A; Espay, Alberto J et al. (2016) Clinical and demographic characteristics related to onset site and spread of cervical dystonia. Mov Disord 31:1874-1882
Eisenstein, Sarah A; Bogdan, Ryan; Love-Gregory, Latisha et al. (2016) Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status. Synapse 70:418-31
Benitez, Bruno A; Davis, Albert A; Jin, Sheng Chih et al. (2016) Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson's Disease. Mol Neurodegener 11:29
Davis, Albert A; Andruska, Kristin M; Benitez, Bruno A et al. (2016) Variants in GBA, SNCA, and MAPT influence Parkinson disease risk, age at onset, and progression. Neurobiol Aging 37:209.e1-7
Stewart, Stephanie B; Koller, Jonathan M; Campbell, Meghan C et al. (2015) Additive global cerebral blood flow normalization in arterial spin labeling perfusion imaging. PeerJ 3:e834
Buddhala, Chandana; Campbell, Meghan C; Perlmutter, Joel S et al. (2015) Correlation between decreased CSF α-synuclein and Aβ₁₋₄₂ in Parkinson disease. Neurobiol Aging 36:476-84
Karimi, Morvarid; Tu, Zhude; Yue, Xuyi et al. (2015) Radiation dosimetry of [(18)F]VAT in nonhuman primates. EJNMMI Res 5:73
Yan, Ling; Hicks, Matt; Winslow, Korey et al. (2015) Secured web-based video repository for multicenter studies. Parkinsonism Relat Disord 21:366-71
Lucero, Carolyn; Campbell, Meghan C; Flores, Hubert et al. (2015) Cognitive reserve and β-amyloid pathology in Parkinson disease. Parkinsonism Relat Disord 21:899-904
Campbell, Meghan C; Koller, Jonathan M; Snyder, Abraham Z et al. (2015) CSF proteins and resting-state functional connectivity in Parkinson disease. Neurology 84:2413-21

Showing the most recent 10 out of 57 publications