Director: John Q. Trojanowski, M.D., Ph.D.
Title: Parkinson's Disease and Dementia
Budget End Date: 6/30/2017
The purpose of the Morris K. Udall Center of Excellence for Parkinson’s Disease Research at the Perelman School of Medicine (PSOM) of the University of Pennsylvania (Penn) during its renewal period for years 6-10 is to advance understanding of the etiology of Parkinson’s disease (PD) without and with dementia (PDD) as well as dementia with Lewy bodies (DLB), and to improve the diagnosis and treatment of PD/PDD/DLB.
The vision statement of the Penn Udall Center, now in Year 8, is to build on its recent progress to elucidate the progression of PD from normal cognition to cognitive impairment (CI), executive dysfunction and dementia in PDD, as well as disease progression in DLB in addition to the associated central nervous system (CNS) degeneration mediated by progressive accumulations of pathological alpha-synuclein (α-syn). Because recent Penn Udall Center studies raise the provocative, but highly plausible possibility that the progression of PD/PDD/DLB is linked to the cell-to-cell spread of pathological α-syn, the overarching goals of the Penn Udall Center are to elucidate mechanisms of disease progression and α-syn transmission through synergistic collaborations between basic and translational research Projects that work with each of the Cores to implement the mission of the Penn Udall Center.
To accomplish these goals in its renewal period, the Penn Udall Center includes 4 Cores and 4 Projects that build upon their well developed and substantial basic and clinical research collaborations in the following Cores and Projects: Administrative Core A: Core Leader (CL) - J.Q. Trojanowski; Clinical Core B: CL - H. Hurtig; Co-Investigator (Co-I) – D. Weintraub; Co-I - N. Dahodwala*; Neuropathology, Biomarker and Genetics Core C: CL - J.Q. Trojanowski; Co-CL - V. Van Deerlin; Co-I - E.B. Lee*; Data Management, Biostatistics and Bioinformatics Core D: CL - S. Xie; Co-Investigator – L.-S. Wang*; Project I: “A Multimodal Biomarker Approach to Evaluating and Predicting Cognitive Decline in Lewy Body Spectrum Disorders”: Project Leader (PL) - A. Chen-Plotkin*; Co-Investigator – D. Weintraub; Project II: “Mechanisms Of PD Executive Dysfunction In Language”: PL - M. Grossman; Project III: “Mechanisms Of Transmission Of Pathological Alpha-synuclein In Neurons”: PL - V.M.-Y. Lee; Project IV: “Immunotherapy Targeting PD Transmission in Animal Models”: PL - J.Q. Trojanowski; Co-investigator – K. Luk*. Notably, the participation of 5 new Penn faculty (marked by *) in the Udall Center renewal attests to the vigor of the Center’s commitment to train the next generation of PD researchers. The Penn Udall Center investigators work in a seamlessly interdisciplinary manner, as well as collaborate with other Udall Centers. Thus, the Penn Udall Center team will contribute to advancing efforts to develop new interventions and better diagnostics for PD/PDD/DLB..
Representative scientific advances from 4 Projects in the Penn Udall Center for year 7 are highlighted below.
Project I: A Multimodal Biomarker Approach to Evaluating and Predicting Cognitive Decline in Lewy Body Spectrum Disorders, Project Leader – Alice Chen-Plotkin, M.D.; Co-Investigator – Daniel Weintraub, M.D.
Cognitive impairment (CI) and dementia occur in up to 80% of PD patients during the course of their illness, and these non-motor features are a major cause of disability and burden to caregivers and to the health care system. Project 1 seeks to understand the relationships among various measures reported to associate with CI in PD and to create a tool for predicting significant cognitive decline in the near term – such a tool would have high impact in identifying appropriate subjects for therapeutic trials. In Year 7 we found that in univariate analyses, CSF Amyloid-beta 1-42 and SPARE-AD scores are cross-sectionally correlated with consensus clinical determination of cognitive status. In addition, SPARE-AD scores are correlated with age-adjusted Mattis Dementia Rating Scale Scores, suggesting that a significant part of PD-associated CI may be due to regional patterns of atrophy reminiscent of those seen in AD, since the SPARE-AD model is in fact trained on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort.
This progress in year 7 from Project I addresses the following two NINDS PD2014 Research Recommendations:
Project II: Mechanisms Of PD Executive Dysfunction In Language, Project Leader – Murray Grossman, M.D.
Patients with PD spectrum disorders have difficulty regulating their responses to rewarding situations such as gambling. We sought to evaluate patients’ responses to reinforcing situations in language. PD (n=12) patients and healthy seniors (n=11) were presented with randomly-ordered sentences that were either Direct (e.g. "The king chased the queen. She fell") or were fully Ambiguous (e.g. "The visitor chased the client. She fell.") since neither noun is gender-biased. Sentences were distributed across 4 blocks. In all blocks, the Direct items were positively reinforced with 5 monetary units if participants selected the correct response, and were awarded no points for an incorrect response. In the second block, we reinforced responses to the first noun of Ambiguous sentences, and in the fourth block we reinforced responses to the second noun of Ambiguous sentences. The first and third blocks contained random reinforcement of the Ambiguous sentences. On reinforced trials of Ambiguous sentences, PD patients were insensitive to positive feedback. An evaluation of the last quarter of stimulus materials in Block 2 and Block 4 revealed that PD patients (M=81%) respond accurately to the reinforced item significantly less often than Controls (M=96%; U=20.0; p=0.004).
Additionally, we performed preliminary analyses on 26 cases of probable DLB from our autopsy cohort. This shows that DLB cases have higher degrees of neurofibrillary tangles and senile plaques compared to our PDD cohort, although they have a similar burden of Lewy body pathology as we find in PDD. We have agreements from collaborators at University of Washington, Oregon Health Sciences Center, University of California in San Diego, Rush College of Medicine and University of Pittsburgh to contribute cases of DLB, totaling more than 100 cases.
This progress in year 7 from Project II addresses the following two NINDS PD2014 Research Recommendations:
Project III: Mechanisms of Transmission of Pathological Alpha-Synuclein in Neurons, Project Leader – Virginia M-Y Lee, Ph.D.
The most significant accomplishment from Project III during the past year is our demonstration that different synthetic α-syn strains can be created from monomeric recombinant α-syn protein with different biological properties that could explain the potential heterogeneity of α-syn pathology found among the different synucleinopathies.
This progress in year 7 from Project III addresses the following NINDS PD2014 Research Recommendation:
Project IV: Immunotherapy Targeting PD Transmission in Animal Models, Project Leader – John Q. Trojanowski, M.D., Ph.D.; Co-investigator – Kelvin Luk, Ph.D.
Studies undertaken in Year 7 in collaboration with Project III demonstrate a mechanistic link between transmission of pathologic a-syn, the formation of Lewy bodies(LBs)/Lewy neurites (LNs) and the degeneration of substantia nigra (SN) pars compacta (SNpc) neurons similar to authentic PD thereby opening up new avenues for developing immunotherapy for PD and providing model systems in which to test these therapies.
This progress in year 7 from Project IV addresses the following NINDS PD2014 Research Recommendation:
The Penn Udall Center has antibodies produced in the Center, α-syn fibrils, other reagents, CVS tissues and biofluid samples as well as DNA available for use by other investigators. The Penn Udall Center themselves are resources for the PD research community within and beyond the Udall Center network as exemplified by the work Dr. Kelvin Luk does now with many investigators interested in setting up α-syn transmission studies as well as his work with the Michael J. Fox Foundation (MJFF) to help them establish a core facility to provide α-syn fibrils to interested investigators which aligns with NINDS PD2014 Basic Research Recommendation #1: Develop transmission models of pathologic α-synuclein and tau, and determine the mechanisms of propagation, release, and uptake of misfolded α-synuclein and tau including the role of “strains.”
Project I: A Multimodal Biomarker Approach to Evaluating and Predicting Cognitive Decline in Lewy Body Diseases, Alice Chen-Plotkin, M.D.
Specific Aim 1: To replicate previously-reported candidate biomarkers of CI in a training cohort of LB Disease (LBD) patients. We and others have reported promising candidate biomarkers of CI in PD and other LBD. These candidate markers encompass multiple modalities: (1) clinical features, (2) genetic markers, (3) biochemical markers, and (4) imaging markers. We propose to evaluate a set of 20 candidate markers that have been previously reported in the literature for association with cognitive performance in a training cohort (n=375) of LBD patients. The goal of this aim is to replicate previously-reported findings in our cohort, thereby demonstrating the generalizability of the markers and the relevance of our cohort to other LBD populations.
Specific Aim 2: To define relationships among candidate biomarkers in Aim 1 and identify potential pathophysiological subtypes of CI in LBD. There is ongoing controversy regarding the pathophysiological substrate of CI in LBD. We propose to evaluate relationships among markers in two distinct ways. First, in an extension of our prior work, we will conduct a hypothesis-driven analysis to determine whether markers associated with Alzheimer’s disease (AD) correlate with each other, defining a subgroup of patients in whom CI is substantially due to co-existing AD pathology. Second, we will use unsupervised classification methods to unmask latent subtypes of CI in LBD distinguished by specific patterns of clinical and biological markers.
Specific Aim 3: To develop a multimodal predictive algorithm for cognitive decline in LBD and apply it to an independent test cohort of PD patients. We will use data from Aims 1 and 2 to develop three types of multimodal models for assessing risk of significant cognitive decline in individual PD patients. We will then apply these models to a separate, independent test cohort (n=225) of PD patients. In this cohort, we will assess the ability of each type of model to identify those individuals most at risk for cognitive decline in a 2-year window. Finally, we will construct a user-friendly web-based clinical tool for stratifying near-term dementia risk in patients with PD.
Project II: Mechanisms of PD Executive Dysfunction in Language, Murray Grossman, M.D.
Specific Aim 1: 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 grey 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 and thereby test our hypothesis 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. 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.
Specific Aim 2: 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 executive control, 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.
Specific Aim 3: 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 through collaborations with Cores B and C. We expect α-syn pathology in PDD and DLB, and denser prefrontal pathology in DLB, particularly involving amyloid-beta (Aβ) 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 Aβ/tau pathology has executive-mediated language deficits. With Projects III and IV, we will relate features of novel α-syn strains in brain lysates to DLB and PDD clinical-pathological profiles.
This work will lead to novel behavioral and imaging markers that distinguish DLB from PDD and detect PD-MCI, optimize current medication treatment and prepare us for disease-modifying treatments for each condition through detailed knowledge of the histopathologic basis for disease, and will advance cognitive neuroscience.
Project III: Mechanisms of Transmission of Pathological Alpha-Synuclein in Neurons, Virginia M-Y Lee, Ph.D.
Specific Aim 1: Test the hypothesis that neurons from different CNS regions are selectively vulnerable to develop either LBs/LNs alone or LBs/LNs with AD-like tau pathology and altered levels of secreted Aβ in response to treatment with distinct α-Syn PFF strains.
Specific Aim 2: Generate and characterize synthetic α-Syn PFFs strains that differentially modulate the LBs/LNs and AD pathology.
Specific Aim 3: Determine if enriched LBs/LNs fractions isolated from different regions of PD/PDD/DLB brains, will differentially “seed” and “cross-seed” the recruitment of endogenous α-Syn and tau into insoluble aggregates in primary neurons, thus reflecting strain-like properties.
Specific Aim 4: Collaborate with Project IV to identify anti- α-Syn monoclonal antibodies (MAbs) that block α-Syn transmission in neuron-based synucleinopathy models to be used for immunotherapy in α-Syn Tg mice of Project IV.
The Specific Aims of Project III are most closely related to the following NINDS PD2014 Research Recommendations:
Project IV: Immunotherapy Targeting Parkinson’s Disease Transmission in Animal Models, John Q. Trojanowski, M.D., Ph.D.
Specific Aim 1: Determine if unique synthetic a-syn PFF strains characterized by Project III differentially transmit Lewy body disease (LBD) and cross-seed tau neurofibrillary tangles (NFTs) following injection into the brains of M83 mice, using methods established in our laboratory to assess behavior, neuropathology and cerebrospinal fluid (CSF) levels of α-Syn and tau in these mice.
Specific Aim 2: Determine if enriched fractions of LBs/LNs from PD substantia nigra (SN) versus PDD/DLB cingulate cortex (CC) contain distinct α-Syn strains that differentially transmit LBD and cross-seed tau NFTs following injection into the brains of M83 mice using the same methods as in Aim 1.
Specific Aim 3: Conduct proof of concept (POC) studies in M83 mice injected with pathological α-Syn to determine if immunization with monoclonal antibodies (MAbs), identified by Project III to neutralize α-Syn transmission, abrogates induction and spread of α-Syn pathology in vivo.
The Specific Aims of Project IV are most closely related to NINDS PD2014 Basic Research Recommendation #1: Develop transmission models of pathologic α-synuclein and tau, and determine the mechanisms of propagation, release, and uptake of misfolded α-synuclein and tau including the role of “strains.”
In addition the Cores (Administrative; Clinical; Neuropathology, Biomarker and Genetics; Data Management, Biostatistics and Bioinformatics) continue to pursue the Core Aims.
Guo JL, Lee VM. Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat Med. 2014 Feb; 20(2):130-8. PMCID: PMC4011661.
Nuytemans K, Inchausti V, Beecham GW, Wang L, Dickson DW, Trojanowski JQ, Lee VM, Mash DC, Frosch MP, Foroud TM, Honig LS, Montine TJ, Dawson TM, Martin ER, Scott WK, Vance JM. Absence of C9ORF72 expanded or intermediate repeats in autopsy-confirmed Parkinson's disease. Mov Disord. 2014 Feb 26; PMCID: PMC4022044.
Avants BB, Libon DJ, Rascovsky K, Boller A, McMillan CT, Massimo L, Coslett HB, Chatterjee A, Gross RG, Grossman M. Sparse canonical correlation analysis relates network-level atrophy to multivariate cognitive measures in a neurodegenerative population. Neuroimage. 2014 Jan 1;84:698-711. PMCID: PMC3911786.
Toledo JB, Van Deerlin VM, Lee EB, Suh E, Baek Y, Robinson JL, Xie SX, McBride J, Wood EM, Schuck T, Irwin DJ, Gross RG, Hurtig H, McCluskey L, Elman L, Karlawish J, Schellenberg G, Chen-Plotkin A, Wolk D, Grossman M, Arnold SE, Shaw LM, Lee VM, Trojanowski JQ. A platform for discovery: The University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Alzheimers Dement. 2013 Aug 23; PMCID: PMC3933464.
The Penn Udall Center investigators work in a seamlessly interdisciplinary manner, as well as collaborate with other Udall Centers. Thus, the Penn Udall Center team will contribute to advancing efforts to develop new interventions and better diagnostics for PD/PDD/DLB.
Last Modified February 10, 2015