This project investigates the cognitive and neural basis of impaired cognition in patients with mild Parkinson's disease dementia (PDD) and Dementia with Lewy bodies (DLB). We propose a detailed characterization of limited executive resources in PDD/DLB. By focusing on three domains of daily functioning that depend on planning and mental organization, we will test the hypothesis that limited organization in PDD/DLB is due to a breakdown of hierarchical, top-down, goal-oriented planning. Our powerful method links modern approaches to neurodegenerative diseases and cognitive neuroscience, while providing converging evidence from multiple sources to advance our appreciation of both areas with greater validity and reliability.
Specific Aim 1 examines comprehension of scripts or routine activities such as """"""""going to a restaurant."""""""" We hypothesize that mild PDD/DLB patients have difficulty understanding scripts because of impaired script organization. We will correlate cognitive deficits with MRI structural atrophy in PDD/DLB, and perform fMRI studies of healthy adults and PDD/DLB patients. This work will relate script organization to dorsolateral prefrontal cortex (dIPFC).
Specific Aim 2 examines executive resources like planning that contribute to the comprehension of sentences with a temporary structural ambiguity (e.g. """"""""While the mother walked the baby was crying""""""""). We hypothesize that disambiguating these sentences is difficult in mild PDD/DLB because of limited planning, and imaging studies will relate this to dIPFC.
Specific Aim 3 assesses PDD/DLB patients' organization of a narrative telling the wordless children's picture story """"""""Frog, Where Are You?"""""""". We expect that mild PDD/DLB patients will be able to describe each story event, but will have difficulty synthesizing these events into an organized narrative. Imaging studies will relate this to dIPFC. Our unique approach will improve diagnostic accuracy through converging evidence from multiple sources that show a deficit in planning and mental organization in PDD/DLB, and will underline the critical role of dIPFC in this impairment. Using a within-patient design, we will compare performance across studies to assess the various forms of planning. We will investigate the role of dementia in mild PDD/DLB through comparative work with non- demented PD patients. This work will lead to novel strategies for.improving lADLs in PDD/DLB by augmenting top-down planning and goal-oriented organization in these patients. We will also contribute to unraveling an elusive element of cognitive neuroscience - the contribution of dIPFC to planning and higher cognition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS053488-04
Application #
8101871
Study Section
Special Emphasis Panel (ZNS1)
Project Start
Project End
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$338,456
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Olm, Christopher A; McMillan, Corey T; Irwin, David J et al. (2018) Longitudinal structural gray matter and white matter MRI changes in presymptomatic progranulin mutation carriers. Neuroimage Clin 19:497-506
Sandelius, Åsa; Portelius, Erik; Källén, Åsa et al. (2018) Elevated CSF GAP-43 is Alzheimer's disease specific and associated with tau and amyloid pathology. Alzheimers Dement :
Henderson, Michael X; Peng, Chao; Trojanowski, John Q et al. (2018) LRRK2 activity does not dramatically alter ?-synuclein pathology in primary neurons. Acta Neuropathol Commun 6:45
Chahine, L M; Dos Santos, C; Fullard, M et al. (2018) Modifiable vascular risk factors, white matter disease and cognition in early Parkinson's disease. Eur J Neurol :
Cousins, Katheryn A Q; Ash, Sharon; Grossman, Murray (2018) Production of verbs related to body movement in amyotrophic lateral sclerosis (ALS) and Parkinson's Disease (PD). Cortex 100:127-139
Guerreiro, Rita; Ross, Owen A; Kun-Rodrigues, Celia et al. (2018) Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol 17:64-74
Shi, Min; Tang, Lu; Toledo, Jon B et al. (2018) Cerebrospinal fluid ?-synuclein contributes to the differential diagnosis of Alzheimer's disease. Alzheimers Dement 14:1052-1062
Tropea, Thomas F; Xie, Sharon X; Rick, Jacqueline et al. (2018) APOE, thought disorder, and SPARE-AD predict cognitive decline in established Parkinson's disease. Mov Disord 33:289-297
Portelius, Erik; Olsson, Bob; Höglund, Kina et al. (2018) Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology. Acta Neuropathol 136:363-376
Polinski, Nicole K; Volpicelli-Daley, Laura A; Sortwell, Caryl E et al. (2018) Best Practices for Generating and Using Alpha-Synuclein Pre-Formed Fibrils to Model Parkinson's Disease in Rodents. J Parkinsons Dis 8:303-322

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