Director: John Q. Trojanowski, M.D., Ph.D.
Title: Parkinson's Disease and Dementia
The Penn Udall Center investigators work in a seamlessly interdisciplinary manner, as well as collaborates with other Udall Centers. Thus, the Penn Udall Center team will contribute to advancing efforts to develop new interventions and better diagnostics for Parkinson’s Disease (PD), Parkinson’s Disease with Dementia (PDD) and Dementia with Lewy Bodies (DLB).
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 7, 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 alpha-synuclein (α-syn; see Figure 1), 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 (see Figure 2): Administrative Core A: Core Leader (CL) - J.Q. Trojanowski; Clinical Core B: CL - H. Hurtig; Co-Investigator (Co-I) – R. Gross*; Co-I - N. Dahodwala*; Co-I - D. Weintraub; 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; Co-Investigator - R. Gross*; 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 6 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 the health care system. Project I's overall goal is to create tools for predicting significant cognitive decline in the near term -- such tools would have high impact in identifying appropriate subjects for therapeutic trials. We believe we will be able to achieve this goal based on the dataset collected to date. In addition, our early analyses suggest that current ways of assessing the association of various factors with CI in PD are limited in their largely uni-dimensional approach. Thus, our multimodal approach has the potential to define and clarify the most significant underlying signals, which may shed considerable light on the pathogenesis of CI in PD.
Project II: Mechanisms Of PD Executive Dysfunction In Language, Project Leader – Murray Grossman, M.D.
For Aim 1, assess the cognitive and neural basis for coordination during conversations in PDD and DLB, Year 6 findings are consistent with the hypothesis that patients with PDD and DLB have significant difficulty with coordination, an essential element in conversational discourse, and that this is related to a prefrontal area of atrophy crucial for coordination during discourse. Findings from Year 6 for Aim 2 assess the cognitive and neural basis for resolving lexical ambiguity in PDD and DLB, suggest that sentence comprehension limitations are related to executive measures and not due to language-related limitations, and disease is in non-language areas implicated in our model of decision-making. For Aim 3, assess the pathologic basis for cognitive deficits in PDD and DLB, we have performed preliminary analyses on 26 cases of probable DLB from our autopsy cohort at University of Pennsylvania. 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.
Project III: Mechanisms of Transmission of Pathological Alpha-Synuclein in Neurons, Project Leader – Virginia M-Y Lee, Ph.D.
During Year 6, we showed that synthetic α-Syn preformed fibrils (PFFs) are capable of templated recruitment of endogenous α-Syn to form Lewy bodies (LBs) and Lewy neurites (LNs), the characteristic hallmark neuropathology that characterize PD and DLB in both transgenic mice overexpressing mutant α-Syn and wildtype non-transgenic mice. Our data point to a prion-like cascade in synucleinopathies whereby cell-to-cell transmission and propagation of misfolded α-Syn underlie the central nervous system (CNS) spread of LBs/LNs. These findings open up new avenues for understanding the progression of PD and for developing novel therapeutics.
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 6 demonstrate a mechanistic link between transmission of pathologic α-Syn, the formation of LBs/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. In addition, to determining if transmission of α-Syn might result in iatrogenic infectivity of pathological α-Syn in human subjects, we examined a large cohort of individuals treated with cadaver derived human growth hormone in which there were 22 subjects who previously were reported to have developed a prion disease, but this study showed there were no subjects who developed AD or PD despite the fact that pathological tau, Aβ, and α-Syn are found in the pituitaries of elderly subjects and those with AD or PD. Thus, unlike prions, pathological α-Syn appears to be transmissible but not infectious.
The Penn Udall Center has reagents, tissue and biofluid samples as well as DNA available for use by other investigators.
Future plans are highlighted below.
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 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 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.
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 α-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.
In addition the Cores continue to pursue the Core Aims.
Core A: Administration, John Q. Trojanowski, M.D., Ph.D.
Specific Aim 1: Oversee administrative, fiscal and budgetary aspects of the Udall Center, and conduct regular meetings of the Udall Center
Executive Committee (EC) comprised of Core/Project Leaders to monitor and review the progress and accomplishments of each
Core and Project.
Specific Aim 2: Conduct annual reviews of the Udall Center by an External Advisory Panel (EAP) comprised of 5 scientists from outside Penn with expertise relevant to the research conducted in the Penn Udall Center.
Specific Aim 3: Foster the exchange and dissemination of research findings from Core/Project investigators by participating in annual retreats and caregiver meetings held by the Udall Center Clinical Resource Core B, Institute on Aging (IOA), the Center for Neurodegenerative Disease Research (CNDR), the Mahoney Institute of Neurological Sciences (MINS)/Comprehensive Neuroscience Center (CNC), the Institute for Translational Medicine and Therapeutics (ITMAT)/Clinical Translational Science Award (CTSA), the Parkinson’s Disease and Movement Disorder Center (PD&MDC) and the Penn-affiliated Philadelphia Veterans Administration Medical Center Parkinson’s Disease Research, Education and Clinical Center (PADRECC).
Specific Aim 4: Oversee and implement data/reagent/resource sharing by all Udall Center Core/Project investigators according to NIH/NINDS policies including the distribution of data to the NINDS PD-DOC or its equivalent when re-established.
Specific Aim 5: Promote participation of Penn Udall Center investigators in the annual Udall Center meetings.
Specific Aim 6: Promote training of basic and clinical scientists in the Udall Center with mentoring by Core/Project investigators.
Core B: Clinical, Howard Hurtig, M.D.
Specific Aim 1: To recruit and characterize research subjects and obtain research material:
1a. To establish and characterize with regular physical, functional and neuropsychological assessments, a cohort of properly consented patients and controls who will: 1) Participate in studies of PD, PDD and DLB; 2) Donate blood for DNA extraction, plasma and CSF for chemical biomarker testing; and 3) Promote brain donation from Udall participants to the Udall Center Core C. Patients will be recruited to the Udall cohort from the PD&MDC as well as other sources, including contacts made through outreach activities; control subjects will be recruited from families of patients, from senior centers in the Philadelphia area, and from other investigators in the affiliated Center for Neurodegenerative Disease Research (CNDR) research projects. Particular emphasis will be placed on recruiting women and minorities. These research subjects, their clinical data, biofluids and brain tissue will be utilized to conduct Projects I-IV of the Udall Center.
1b. To collaborate with Core C to investigate genetic factors in families of patients with at least one affected first degree relative with PD, and to offer genetic counseling as described in Core C to all families who participate in the Udall Center’s programs.
Specific Aim 2: To collaborate with Core A to educate lay and professional referral sources on PD, PDD, DLB and related dementias in pursuit of recruiting a diverse patient population to participate in research as well as to train the next generation of PD researchers. Outreach efforts will include education for physicians and other healthcare providers, the regional PD community, and traditionally underserved minorities in the Philadelphia region at health fairs, senior centers and long-term care facilities. We also will collaborate with Core A and other Udall Center investigators to provide training in clinical research methods to post-doctoral fellows, residents and medical students.
Specific Aim 3: To contribute data to the clinical and tissue databases in cooperation with Core D, to resolve questions related to clinical data, and to facilitate the sharing of data with investigators in the Penn Udall Center and other Udall Centers. The Penn Udall Center database serves as the repository for all clinical, genetic, pathological and summarized imaging data collected at the Penn Udall Center. Core B will contribute these data to Core D and will work closely with Core D to resolve any questions related to data collection and storage. Likewise, Core B will provide all clinical data to Core C and Projects I-IV.
Specific Aim 4: To facilitate collaborations with other Udall Centers on standardization of sample collection and clinical characterization. We will continue and expand ongoing efforts, begun in collaboration with the University of Washington (UW) Udall Center, to develop and promulgate standardized clinical assessments of cognitive impairments (CI) and dementia in PD/PDD/DLB across the Udall network.
Core C: Neuropathology, Biomarker and Genetics, John Q. Trojanowski, M.D., Ph.D.
Specific Aim 1: Conduct a postmortem examination on Udall Center patients with clinical PD, PDD or DLB and normal controls (NC) followed
in Core B to establish a neuropathology (NP) diagnosis in each case.
Specific Aim 2: Collect and bank biosamples, including postmortem CNS tissues, DNA, plasma and CSF for NP, biomarker (BMKR) and genetic studies on living and deceased NC and patients followed in Core B and studied in Projects I-IV of this Udall Center.
Specific Aim 3: Maintain the Udall Center bank of biosamples from NC and PD/PDD/DLB patients, and distribute samples to investigators approved by the Executive Committee (EC) described in Core A.
Specific Aim 4: Archive NP, BMKR and genetics findings, and monitor all biosamples in a database in collaboration with Core D and the Udall Center’s PD Data Organizing Center (PD-DOC) or the equivalent when re-established.
Specific Aim 5: Provide advice and technical support to facilitate studies by Udall Center investigators and other scientists who use Core C resources.
Core D: Data Management, Biostatistics and Bioinformatics, Sharon Xie, Ph.D.
Specific Aim 1: Data Management and Computing Support: (a) to develop and maintain a relational database of demographic, clinical, genetic, biomarker, imaging and neuropathological
data gathered and used by Clinical Core (Core B), Neuropathology, Biomarker and Genetics Core (Core C), and Projects I-IV;
and (b) to support the network and associated computing facilities for the database and data analysis operations of the Udall Center.
Specific Aim 2: Biostatistical Support: (a) to advise investigators on study design for all Projects and Cores; (b) to assist investigators in the analysis of their data using rigorous statistical methods; (c) to assist in the preparation of reports, abstracts, and manuscripts; (d) to assist investigators in conducting exploratory analyses that may lead to the generation of new hypotheses for future research; (e) to develop new statistical methodologies and extend existing methodologies where needed for analysis of Udall Center data; and (f) to provide bioinformatics support for analysis of large complex data sets such as those that will come from ongoing GWAS and epigenetic studies described in Core C as well as to correlate deep phenotyping data on Udall subjects with alpha-synuclein (α-syn) strain data to link the characteristics of these strains to distinct clinical-pathologically defined phenotypes of PD without and with dementia (PDD) and dementia with Lewy bodies (DLB).
Specific Aim 3: Maintain and curate the Penn Udall website (http://www.med.upenn.edu/udall/) to educate the public about PD/PDD/DLB as well to partner with Core B for outreach and recruitment and retention of subjects in Udall Center research studies.
Parkinson's disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies. Irwin DJ, Lee VM, Trojanowski JQ. Nat Rev Neurosci. 2013 Sep;14(9):626-36. PMID: 23900411
Distinct α-synuclein strains differentially promote tau inclusions in neurons.
Guo JL, Covell DJ, Daniels JP, Iba M, Stieber A, Zhang B, Riddle DM, Kwong LK, Xu Y, Trojanowski JQ, Lee VM. Cell. 2013 Jul 3;154(1):103-17. PMID: 23827677
Clinical and biochemical differences in patients having Parkinson disease with vs without GBA mutations. Chahine LM, Qiang J, Ashbridge E, Minger J, Yearout D, Horn S, Colcher A, Hurtig HI, Lee VM, Van Deerlin VM, Leverenz JB,
Siderowf AD, Trojanowski JQ, Zabetian CP, Chen-Plotkin A. JAMA Neurol. 2013 Jul;70(7):852-8. PMID:
Lewy body-like α-synuclein aggregates resist degradation and impair macroautophagy.
Tanik SA, Schultheiss CE, Volpicelli-Daley LA, Brunden KR, Lee VM. J Biol Chem. 2013 May 24;288(21):15194-210. PMID: 23532841
Evaluation of potential infectivity of Alzheimer and Parkinson disease proteins in recipients of cadaver-derived human growth
hormone. Irwin DJ, Abrams JY, Schonberger LB, Leschek EW, Mills JL, Lee VM, Trojanowski JQ.
JAMA Neurol. 2013 Apr;70(4):462-8. PMID: 23380910 Free PMC Article
Plasma apolipoprotein A1 as a biomarker for Parkinson disease. Qiang JK, Wong YC, Siderowf A, Hurtig HI, Xie SX, Lee VM, Trojanowski JQ, Yearout D, B Leverenz J, Montine TJ, Stern M, Mendick
S, Jennings D, Zabetian C, Marek K, Chen-Plotkin AS.
Ann Neurol. 2013 Jul; 74(1):119-27. PMID: 23447138
APOE ε4 increases risk for dementia in pure synucleinopathies.Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, Buchman AS, Larson EB, Crane PK, Kaye JA, Kramer P, Woltjer R, Trojanowski JQ, Weintraub D, Chen-Plotkin AS, Irwin DJ, Rick J, Schellenberg GD, Watson GS, Kukull W, Nelson PT, Jicha GA, Neltner JH, Galasko D, Masliah E, Quinn JF, Chung KA, Yearout D, Mata IF, Wan JY, Edwards KL, Montine TJ, Zabetian CP. JAMA Neurol. 2013 Feb;70(2):223-8. PMID: 23407718
Last updated November 6, 2013