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, A42 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 #
5R01NS075321-05
Application #
8836599
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
2015-05-01
Budget End
2016-04-30
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Washington University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Milchenko, Mikhail; Snyder, Abraham Z; Campbell, Meghan C et al. (2018) ESM-CT: a precise method for localization of DBS electrodes in CT images. J Neurosci Methods 308:366-376
Hardt, Joshua I; Perlmutter, Joel S; Smith, Christopher J et al. (2018) Pharmacokinetics and Toxicology of the Neuroprotective e,e,e-Methanofullerene(60)-63-tris Malonic Acid [C3] in Mice and Primates. Eur J Drug Metab Pharmacokinet 43:543-554
Jin, Hongjun; Han, Junbin; Resing, Derek et al. (2018) Synthesis and in vitro characterization of a P2X7 radioligand [123I]TZ6019 and its response to neuroinflammation in a mouse model of Alzheimer disease. Eur J Pharmacol 820:8-17
Maiti, Baijayanta; Perlmutter, Joel S (2018) PET Imaging in Movement Disorders. Semin Nucl Med 48:513-524
Gratton, Caterina; Koller, Jonathan M; Shannon, William et al. (2018) Emergent Functional Network Effects in Parkinson Disease. Cereb Cortex :
Jinnah, H A; Comella, Cynthia L; Perlmutter, Joel et al. (2018) Longitudinal studies of botulinum toxin in cervical dystonia: Why do patients discontinue therapy? Toxicon 147:89-95
Duncan, Ryan P; Van Dillen, Linda R; Garbutt, Jane M et al. (2018) Physical therapy and deep brain stimulation in Parkinson's Disease: protocol for a pilot randomized controlled trial. Pilot Feasibility Stud 4:54
Ibanez, Laura; Dube, Umber; Davis, Albert A et al. (2018) Pleiotropic Effects of Variants in Dementia Genes in Parkinson Disease. Front Neurosci 12:230
Milchenko, Mikhail; Norris, Scott A; Poston, Kathleen et al. (2018) 7T MRI subthalamic nucleus atlas for use with 3T MRI. J Med Imaging (Bellingham) 5:015002
Liu, Hui; Jin, Hongjun; Luo, Zonghua et al. (2018) In Vivo Characterization of Two 18F-Labeled PDE10A PET Radioligands in Nonhuman Primate Brains. ACS Chem Neurosci 9:1066-1073

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