Age-related cognitive decline (ARCD) is a complex convergent phenotype that prominently involves impaired executive function (EF) likely through disruption of the dorsolateral prefrontal cortex (PFC) circuit;despite much speculation, the cellular and molecular mechanisms that underlie this presumed disruption have not been demonstrated in humans. Cognitive impairment (Cl) or dementia (D) is highly prevalent among patients with Parkinson's disease (PD) but remains an incompletely understood non- motor complication of this devastating illness. Indeed, many patients with PD have neuropsychologically determined "Cl, no dementia" (PD-CIND) at the time of initial 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 distribution of dopamine (DA), norepinephrine (NE), and serotonin (5HT) degeneration in neocortex and neostriatum, and their associations with cognitive function test results, from aged individuals without PD or dementia 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 neurodegenerative diseases, (ii) determine the magnitude, regional distribution, and associations with cognitive test results of neostriatal medium spiny neuron spinodendritic degeneration in the same people whose tissue was investigated in Aim 1, and (iii) determine if selective loss of DA neurotransmission without neurodegeneration leads to regionally restricted spinodendritic degeneration in mice from Project 1. Completion 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 cognitive 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 critically neurolmaging and therapeutic efforts, and it draws on existing NIH funded resources.
This project will provide rationale for new evidence-based interventions for cognitive impairment in PD beyond DA replacement strategies, including enhancing synaptic levels of other neurotransmitters, preventing death of selected neuron populations, or ameliorating the consequences of cell death.
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