The initial funding period showed that patients with Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) have impaired executive control that interferes with processing crucial aspects of language such as narrative conversation and sentence ambiguity. These fine-grained measures showed greater deficits in DLB than PDD, and performance was related to gray matter (GM) atrophy of specific frontal regions, overlapping relevant measures of executive control. In addition to diagnostic specificity that promises to help differentiate DLB from PDD, these language measures have face validity since they are correlated with functional measures of daily living (ADLs). In this competing renewal, we build on initial findings with cognitive, imaging, biomarker and clinical-pathological studies that will lead to improved diagnostic accuracy.
Specific Aim 1 will assess the complex cognitive and neural basis for conversational narrative in PDD/DLB. We focus on coordination, or the ability to adjust a conversational narrative to optimize communication with a conversational partner.
Specific Aim 2 will assess the cognitive and neural basis for processing lexical ambiguity in PDD/DLB. We will evaluate anaphora, or the assignment of a referent to a pronoun, and homonym meaning. We expect significant deficits in these executive-mediated aspects of language, with worse performance in DLB than PDD, and both worse than PD. Regression analyses will relate these deficits to executive measures such as mental flexibility. Theory of Mind, and decision-making. Novel MRI analyses of GM atrophy and diffusion tensor imaging tractography studies of white matter (WM) disease will relate these deficits to interruption of a large-scale neural network involving several prefrontal GM regions and associated WM frontal-striatal projections. We will relate performance to functional status from Project 1, to cognitive measures from Core B, biofluid biomarkers from Core C, and novel lysates of alpha-synuclein (AS) strains from Projects 3 and 4.
Specific Aim 3 will assess the pathologic basis for these cognitive deficits in a comparative, clinical-pathological assessment of PDD and DLB. We expect significant prefrontal disease with neuronal loss and gliosis. Relative to PDD, denser histopathologic abnormalities involving AS, Beta-amyloid (AB) and tau will be seen in dorsolateral, ventral-orbital and medial frontal regions in DLB. This work will lead to novel behavioral and imaging markers of disease that distinguish PDD from DLB, and can potentially serve as targets for behavioral intervention while also advancing cognitive neuroscience.

Public Health Relevance

Parkinson's disease dementia (PDD) and Lewy body disease (DLB) appear to be distinct conditions that may have differing histopathologic abnormalities, although these distinctions have proven very elusive. The proposed studies will use fine-grained, executive-mediated language measures, novel measures of gray matter and white matter MRI imaging, and analytes from other cores and projects in this Udall program to define distinctions between PDD and DLB, and these will be validated in clinical-pathological studies of these cases. This work will lead to improved diagnostic accuracy, and help develop novel measures that may be useful as endpoints in clinical trials.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
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Special Emphasis Panel (ZNS1-SRB-J)
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University of Pennsylvania
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