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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
1P50NS062684-01A1
Application #
7760246
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
1
Fiscal Year
2009
Total Cost
$168,163
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Blue, Elizabeth E; Bis, Joshua C; Dorschner, Michael O et al. (2018) Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project. Dement Geriatr Cogn Disord 45:1-17
Houser, Madelyn C; Chang, Jianjun; Factor, Stewart A et al. (2018) Stool Immune Profiles Evince Gastrointestinal Inflammation in Parkinson's Disease. Mov Disord 33:793-804
Flanagan, Margaret E; Cholerton, Brenna; Latimer, Caitlin S et al. (2018) TDP-43 Neuropathologic Associations in the Nun Study and the Honolulu-Asia Aging Study. J Alzheimers Dis 66:1549-1558
Gray, Shelly L; Anderson, Melissa L; Hanlon, Joseph T et al. (2018) Exposure to Strong Anticholinergic Medications and Dementia-Related Neuropathology in a Community-Based Autopsy Cohort. J Alzheimers Dis 65:607-616
Moreno, Monica A; Or-Geva, Noga; Aftab, Blake T et al. (2018) Molecular signature of Epstein-Barr virus infection in MS brain lesions. Neurol Neuroimmunol Neuroinflamm 5:e466
Condello, Carlo; Lemmin, Thomas; Stöhr, Jan et al. (2018) Structural heterogeneity and intersubject variability of A? in familial and sporadic Alzheimer's disease. Proc Natl Acad Sci U S A 115:E782-E791
Locke, Timothy M; Soden, Marta E; Miller, Samara M et al. (2018) Dopamine D1 Receptor-Positive Neurons in the Lateral Nucleus of the Cerebellum Contribute to Cognitive Behavior. Biol Psychiatry 84:401-412
Cholerton, Brenna; Johnson, Catherine O; Fish, Brian et al. (2018) Sex differences in progression to mild cognitive impairment and dementia in Parkinson's disease. Parkinsonism Relat Disord 50:29-36
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
Dublin, Sascha; Walker, Rod L; Gray, Shelly L et al. (2017) Use of Analgesics (Opioids and Nonsteroidal Anti-Inflammatory Drugs) and Dementia-Related Neuropathology in a Community-Based Autopsy Cohort. J Alzheimers Dis 58:435-448

Showing the most recent 10 out of 178 publications