Executive Difficulty in Parkinson's Disease with Dementia
The project will assess the cognitive and neural basis for coordination during conversations in PDD and DLB.
Our prior work found a deficit in narrative organization, worse in DLB than PDD, related to prefrontal gray matter (GM) disease. Narrative represents half of a conversation. We propose to extend this work to assess the organization of an entire conversation. Coordination is the ability to adjust a conversational narrative to optimize communication with a conversational partner. We extend our novel model of social cognition to conversational discourse, hypothesizing that coordination involves executive control in the form of mental flexibility and Theory of Mind (ToM), as well as core language processes. We will assess conversational comprehension and expression with measures we developed to examine coordination. We expect worse coordination deficits in DLB than PDD, and we will explore sensitivity for detecting early deficits in PD-MCI (mild cognitive impairment). Regression analyses will relate these deficits to executive measures of mental flexibility and ToM. Novel MRI analyses integrating GM atrophy and diffusion tensor imaging (DTI) tractography of white matter (WM) disease will relate these deficits to interruption of a large-scale neural network involving specific prefrontal GM regions and associated WM projections, showing greater prefrontal and striatal disease in DLB than PDD.
The project will assess the cognitive and neural basis for resolving lexical ambiguity in PDD and DLB.
Our prior work found a deficit in resolving ambiguous sentences, worse in DLB than PDD, that is related to prefrontal GM disease. We confront ambiguity daily in conversation, including very common words such as pronouns (e.g. “she”) and words with multiple meanings (e.g. homonyms such as “pitcher”). Based on our novel model of decision-making, we will design assessments of anaphora, defined as the assignment of a referent to a pronoun, and homonym meaning. We will manipulate the amount of information available to support identifying the ambiguous referent, and the risk associated with misinterpretation. We expect worse deficits in DLB than PDD, and will explore early detection in PD-MCI. Difficulty resolving the meaning of ambiguous words will be due in part to limited executivecontrol, including probability assessment and risk management. This deficit profile will be related to disease in prefrontal and striatal GM and associated WM projections that is worse in DLB than PDD.
The project will also assess the pathologic basis for cognitive deficits in PDD and DLB.
PDD and DLB pathology is well described, but few clinical-pathologic studies relate cognitive deficits to pathology in PDD and DLB. We propose a comparative clinical-pathological assessment of the pathologic basis for impaired cognition in Aims 1 and 2 in PDD and DLB. We expect alpha-syn pathology in PDD and DLB, and denserprefrontal pathology in DLB, particularly involving amyloid-beta and tau, in dorsolateral, ventral-orbital and medial frontal regions. Since imaging relates cognitive findings in Aims 1 and 2 to these prefrontal regions, we also expect this pathology will correlate with cognitive findings, reflecting differences in PDD and DLB. Additional analyses will group demented patients based on pathologic features, showing that a group with frontal A beta/tau pathology has executive-mediated language deficits. With Projects III and IV, we will relate novel lysate strains to DLB and PDD clinical-pathological profiles.
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- Yushkevich, PA, Avants, BB, Pluta, J, Minkoff, D, Detre, JA, Grossman, M, Gee, JC. Shape-based alignment of hippocampal subfields: Evolution in postmortem MRI. Medical Image Computing & Computer-Assisted Intervention, 11:510-517, 2008. PMC2680118
- Peelle, J E, Troiani, V, Grossman, M. Interaction between process and content in semantic memory: An fMRI study of noun feature knowledge. Neuropsychologia 47:995-1003, 2009. PMC2675540
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- Massimo, L, Anderson, C, Moore, P, Vesely, L, Avants, B, Libon, DJ, Grossman, M. Neuroanatomy of apathy and disinhibition in frontotemporal lobar degeneration. Demen Geriat Cogn Disord, 27:96-104, 2009. PMC2820577
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- Gross, RG, Ash, S, McMillan, CT, Gunawardena, D, Powers, C, Libon, DJ, Moore, P, Liang, T-W, Grossman, M. Impaired information integration contributes to communication difficulty in corticobasal syndrome. Cogn Behav Neurol, 23:1-7, 2010. PMC2930985
- Grossman, M, Troiani, V, Anderson, C, Avants, B, Gee, JC, McMillan, C, Massimo, L, Khan, A, Antani, S, Eslinger, P. The role of ventral medial prefrontal cortex in social decisions: Converging evidence from fMRI and frontotemporal lobar degeneration. Neuropsychol, 48;3505-3512, 2010. PMC2949451
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- Grossman, M. Primary progressive aphasia: Clinical-pathological correlations. Nat Rev Neurol, 6;88-97, 2010. PMC20139998
- Farag, C, Troiani, V, Bonner, M, Powers, C, Avants, B, Gee, J, Grossman, M. Hierarchical organization of scripts: Converging evidence from fMRI and frontotemporal degeneration. Cerebral Cortex 20;2453-2463, 2010. PMC2936800
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- Yu, C-E, Bird, TD, Bekris, LM, Leverenz, JB, Steinbart, E, Galloway, NM, Feldman, H, Woltjer, R, Miller, CA, Wood, EM, Grossman, M, McCluskey L, Clark CM, Neumann, M, Danek, A, Galasko, DR, Arnold, SE, Chen-Plotkin, A, Karydas, A, Miller, BL, Trojanowski, JQ, Lee, VM-Y, Schellenberg, GD, Van Deerlin, VM. The spectrum of mutations in progranulin: A collaborative study screening 545 cases of neurodegeneration. Arch Neurol, 67:161-170, 2010. PMC20142524
- Chen-Plotkin, AS, Hu, WT, Siderowf, A, Weintraub, D, Gross, RG, Hurtig, HI, Xie, SX, Arnold, SE, Grossman, M, Clark, CM, Shaw, LM, McCluskey, L, Elman, L, Van Deerlin, VM, Lee, VM-Y, Soares, H, Trojanowski, JQ. Plasma epidermal growth factor levels predict cognitive decline in Parkinson disease. Ann Neurol, 69:655-663, 2011. PMC3095216
- Eslinger, PJ, Moore, P, Anderson, C, Grossman, M. Social cognition, executive function and neuroimaging correlates of empathic deficits in frontotemporal dementia. J Neuropsych Clin Neurosc, 23:74-82, 2011. PMC 21304142
- Reilly, J, Peelle, JE, Antonucci, SM, Grossman, M. Anomia as a marker of distinct semantic memory impairment in Alzheimer’s diseae and semantic dementia. Neuropsychol, 25;413-426, 2011. PMC21443339
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- Reilly, JJ, Peelle, JE, Rodriguez, A, Grossman, M. Frontal lobe damage impairs process and content in semantic memory: Evidence from category-specific effects in progressive nonfluent aphasia. Cortex 47:645-658, 2011. PMC 20576258
- Xie, SX, Baek, Y, Grossman, M, Arnold, SE, Karlawish, J, Siderowf, A, Hurtig, H, Elman, L, McCluskey, L, Van Deerlin, V, Lee, VM-Y, Trojanowski, JQ. Building an integrated neurodegenerative disease database at an academic health center. Alzh & Dem, 7;e84-e93, 2011. PMC3145967
- Ash, S, McMillan, C, Gross, RG, Cook, P, Morgan, B, Boller, A, Dreyfuss, M, Siderowf, A, Grossman, M. The organization of narrative discourse in Lewy body spectrum disorder. Brain Lang, 119:30-41, 2011. PMC3163000
- McMillan, CT, Rascovsky, K, Khella, MC, Clark, R, Grossman, M. The neural basis for establishing a focal point in pure coordination games. Soc Cogn Affect Neurosci, In press, 2011. PMC22009019
- Ash, S, Xie, S, Gross, RG, Dreyfuss, M, Boller, A, Camp, E, Morgan, B, O-Shea, J, Grossman, M. The organization and anatomy of narrative comprehension and expression in Lewy body spectrum disorders. Neuropsychol, In press, 2012.
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- Libon, DJ, Rascovsky, K, Gross, RG, White, MT, Xie, SX, Dreyfuss, M, Boller, A, Massimo, L, Moore, P, Kitain, J, Coslett, HB, Chatterjee, A, Grossman, M. The Philadelphia Brief Assessment of Cognition (PBAC): A validated screening measure for dementia. Clin Neuropsychol, In press, 2012.
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