Age-related cognitive decline (ARCD) is a complex convergent phenotype that prominenfiy involves impaired execufive funcfion (EF) likely through disrupfion of the dorsolateral prefrontal cortex (PFC) circuit;despite much speculafion, the cellular and molecular mechanisms that underiie this presumed disruption have not been demonstrated in humans. Cognifive impairment (Cl) or dementia (D) is highly prevalent among pafients with Parkinson's disease (PD) but remains an incompletely understood non- motor complication of this devastating illness. Indeed, many pafients with PD have neuropsychologically determined """"""""Cl, no demenfia"""""""" (PD-CIND) at the time of inifial diagnosis. Like ARCD, patients with PD- CIND or PD-D display prominently impairment of EF;however, also like ARCD, the cellular and molecular bases are not clear. We hypothesize that selective regional- and neurotransmitter-specific degeneration in PFC or anterior neostriatum contributes significantly to impaired EF in ARCD, PD-CI, and PD-D. In Project 2 we will test our hypothesis through the following Specific Aims: (i) determine the magnitude and regional distribufion of dopamine (DA), norepinephrine (NE), and serotonin (5HT) degeneration in neocortex and neostriatum, and their associafions with cognitive function test results, from aged individuals without PD or demenfia but varying levels of ARCD, aged individuals with pathologic changes of PD but not a clinical diagnosis of PD and varying levels of Cl, and patients with closely related neurodegenerafive diseases, (ii) determine the magnitude, regional distribufion, and associations with cognifive test results of neostriatal medium spiny neuron spinodendritic degeneration in the same people whose fissue was invesfigated in Aim 1, and (iii) determine if selective loss of DA neurotransmission without neurodegenerafion leads to regionally restricted spinodendrific degenerafion in mice from Project 1. Complefion of these Specific Aims will provide the first integrated clinical, behavioral, morphometric, and neurochemical analysis of PFC and neostriatum in ARCD and PD with and without cognifive impairment, as well as in novel transgenic mice. This project is responsive to several points in the NIH Blueprint: it is a direct response to the therapeutic imperative for PD, it is highly translational as it will inform crifically neurolmaging and therapeufic efforts, and it draws on existing NIH funded resources.

Public Health Relevance

This project will provide rafionale for new evidence-based intervenfions for cognifive impairment in PD beyond DA replacement strategies, including enhancing synaptic levels of other neurotransmitters, prevenfing death of selected neuron populafions, or ameliorafing the consequences of cell death.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
United States
Zip Code
Boord, Peter; Madhyastha, Tara M; Askren, Mary K et al. (2017) Executive attention networks show altered relationship with default mode network in PD. Neuroimage Clin 13:1-8
Hendershott, Taylor R; Zhu, Delphine; Llanes, Seoni et al. (2017) Domain-specific accuracy of the Montreal Cognitive Assessment subsections in Parkinson's disease. Parkinsonism Relat Disord 38:31-34
Cooper, Christine A; Jain, Nimansha; Gallagher, Michael D et al. (2017) Common variant rs356182 near SNCA defines a Parkinson's disease endophenotype. Ann Clin Transl Neurol 4:15-25
Wile, Daryl J; Agarwal, Pankaj A; Schulzer, Michael et al. (2017) Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies. Lancet Neurol 16:351-359
Irwin, David J; Grossman, Murray; Weintraub, Daniel et al. (2017) Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis. Lancet Neurol 16:55-65
Corces, M Ryan; Trevino, Alexandro E; Hamilton, Emily G et al. (2017) An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues. Nat Methods 14:959-962
Cholerton, Brenna; Omidpanah, Adam; Madhyastha, Tara M et al. (2017) Total Brain and Hippocampal Volumes and Cognition in Older American Indians: The Strong Heart Study. Alzheimer Dis Assoc Disord 31:94-100
Gatto, Emilia M; Allegri, Ricardo F; Da Prat, Gustavo et al. (2017) Intrafamilial variable phenotype including corticobasal syndrome in a family with p.P301L mutation in the MAPT gene: first report in South America. Neurobiol Aging 53:195.e11-195.e17
Hill-Burns, Erin M; Debelius, Justine W; Morton, James T et al. (2017) Parkinson's disease and Parkinson's disease medications have distinct signatures of the gut microbiome. Mov Disord 32:739-749
Postupna, Nadia; Latimer, Caitlin S; Larson, Eric B et al. (2017) Human Striatal Dopaminergic and Regional Serotonergic Synaptic Degeneration with Lewy Body Disease and Inheritance of APOE ?4. Am J Pathol 187:884-895

Showing the most recent 10 out of 165 publications