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) 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 of the Penn Udall Center 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 (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 four research projects and four Cores that build upon their well-developed and substantial basic and clinical research collaborations. 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.
Recent Significant Advances
Representative scientific advances the Penn Udall Center are highlighted below:
- Project I: A Multimodal Biomarker Approach to Evaluating and Predicting Cognitive Decline in Lewy Body Spectrum Disorders (Dr. Alice Chen-Plotkin)
- 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.
- Project II: Mechanisms of PD Executive Dysfunction In Language, Project Leader (Dr. Murray Grossman)
- Results from Project II studies suggest that DLB cases have higher burdens of both AD and Lewy pathology with a shorter disease duration compared with PD and PDD. Both DLB-AD and DLB+AD groups had similar short disease durations compared with PDD+AD and PDD-AD. Thus, the clinical diagnosis of DLB and distinction from PDD may have prognostic utility in clinical practice.
- Project Goals aligned with NINDS PD2014 Research Priorities:
- Projects I and II both address the following NINDS PD2014 Research Priorities:
- Clinical Research Recommendation 3: “Characterize the long-term progression of PD and understand the mechanisms that underlie its heterogeneity in clinical presentation and rates of progression. Factors related to disease heterogeneity may include clusters of clinical features as well as biological factors such as genotype and biomarkers.”
- Translational Research Recommendation 1: “Develop patient stratification tools that define disease signatures of more homogeneous cohorts with emphasis on slow vs. fast progressing PD, prodromal PD, and non-motor symptoms.”
- Project III: Mechanisms Of Transmission Of Pathological Alpha-synuclein In Neurons (Dr. Virginia M-Y Lee)
- Significant progress has been made in Project III in two major areas: 1) We used our primary neuron culture model with Lewy bodies (LBs)/neurites (LNs) to test the hypothesis if axonal α-syn pathology compromised axonal transport. 2) We used our non-transgenic mouse model of α-synucleinopathies to ask if immune therapy can retard the spread of α-syn pathology and if reduction of pathology leads to amelioration of movement disorder.
- Project IV: Immunotherapy Targeting PD Transmission in Animal Models, Project Leader (Dr. John Q. Trojanowski )
- The studies conducted in Project IV demonstrate a mechanistic link between the transmission of pathologic α-syn and the formation of LBs/LNs with the degeneration of substantia nigra pars compacta (SNpc) dopamine neurons similar to clinical PD as well as the potential of immunotherapy using anti-α-syn monoclonal antibodies for the treatment of Lewy Body Diseases (LBD).
- Project Goals aligned with NINDS PD2014 Research Priorities
The Penn Udall Center has a range of research resources, including antibodies, α-syn fibrils, tissues and biofluid samples, as well as DNA, for use by other investigators.
Plans for the Coming Year
- Project I:
- We and others have reported promising candidate biomarkers of CI in PD and other LBD. 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.
- There is ongoing controversy regarding the pathophysiological substrate of CI in LBD. We propose to evaluate relationships among markers in two distinct ways. To extend our prior work, we will first 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. We will then use unsupervised classification methods to unmask latent subtypes of CI in LBD distinguished by specific patterns of clinical and biological markers.
- Data obtained to date will be used to develop three types of multimodal models for assessing risk of significant cognitive decline in individual PD patients. These models will then be applied to a separate, independent test cohort (n=225) of PD patients and assessed regarding the ability 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:
Prior studies in Project II identified deficits that were worse in DLB than in PDD, and related to prefrontal grey matter (GM) disease, including narrative organization and resolving ambiguous sentences. Future studies will extend findings in these areas:
- Narrative organization: As 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 expect worse coordination deficits in DLB than PDD, and we will explore sensitivity for detecting early deficits in PD-MCI. Novel imaging approaches will relate these deficits to interruption of a large-scale neural network involving specific prefrontal GM regions and associated white matter (WM) projections
- Resolving ambiguous sentences: 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”). We will manipulate the amount of information available to support identifying the ambiguous referent, and the risk associated with misinterpretation. Difficulty resolving the meaning of ambiguous words will be due in part to limited executive control. We predict that this deficit profile will be related to disease in prefrontal and striatal GM and associated WM projections that is worse in DLB than PDD.
- PDD and DLB pathology is well described, but few clinical-pathologic studies relate cognitive deficits to pathology in those diseases. We therefore propose a comparative clinical-pathological assessment of the basis for impaired cognition in PDD and DLB. 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; we also expect this pathology will correlate with cognitive findings, reflecting disease-specific differences. Additional analyses will group demented patients based on pathologic features, to determine whether a group with frontal Aβ/tau pathology has executive-mediated language deficits. These studies will identify novel behavioral and imaging markers that distinguish among diseases, optimize current medication treatment and inform therapeutic development through detailed knowledge of the histopathologic basis of disease.
- Project III:
- 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 pre-formed fibril (PFF) strains.
- Generate and characterize synthetic α-Syn PFFs strains that differentially modulate the LBs/LNs and AD pathology.
- 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.
- 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 transgenic mice of Project IV.
- Project IV:
- 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.
- 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.
- Conduct proof of concept 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.
Select Recent Publications
Berlyand Y, Weintraub D, Xie SX, Mellis IA, Doshi J, Rick J, McBride J, Davatzikos C, Shaw LM, Hurtig H, Trojanowski JQ, Chen-Plotkin AS. An Alzheimer's Disease-Derived Biomarker Signature Identifies Parkinson's Disease Patients with Dementia. PLoS One. 2016 Jan 26;11(1):e0147319. PMID: 26812251
Toledo JB, Gopal P, Raible K, Irwin DJ, Brettschneider J, Sedor S, Waits K, Boluda S, Grossman M, Van Deerlin VM, Lee EB, Arnold SE, Duda JE, Hurtig H, Lee VM, Adler CH, Beach TG, Trojanowski JQ. Pathological α-synuclein distribution in subjects with coincident Alzheimer's and Lewy body pathology. Acta Neuropathol. 2015 Dec 31. [Epub ahead of print] PMID: 26721587
Pigott K, Rick J, Xie SX, Hurtig H, Chen-Plotkin A, Duda J, Morley JF, Chahine LM, Dahodwala N, Akhtar RS, Siderowf A, Trojanowski JQ, Weintraub D. Longitudinal study of normal cognition in Parkinson disease. Neurology. 85(15): 1276-82. PMCID: PMC4617168 [Available on 2016-10-13].
Kalia LV, Lang AE, Hazrati L, Fujioka S, Wszolek ZK, Dickson DW, Ross QA, Van Deerlin VM, Trojanowski JQ, Hurtig HI, Alcalay RN, Marder KS, Clark LN, Gaig C, Tolosa E, Ruiz-Martinez J, Marti Masso J, Ferrer I, Lopez de Munain A, Goldman SM, Schüle B, Langston J, Aasly J, Giordana MT, Bonifati V, Puschmann A, Canesi M, Pezzoli G, Maues de Paula A, Hasegawa K, Duyckaerts C, Brice A, Marras C. Clinical correlations with Lewy body pathology in LRRK2-related Parkinson’s disease. JAMA Neurol, 2015, 72:100-105. PMCID: PMC4399368
Public Health Statement
Recent studies by researchers at the Penn Udall Center suggest that the harmful accumulation of a protein, alpha-synuclein (α-syn), within the brain contributes to the progression of PD. The research team seeks to understand how the brain is affected by changes in the normal function of α-syn, and how these changes may cause alterations in thinking (cognition) and the development of memory loss (dementia) that occur in PD, as well as in Parkinson’s Disease with Dementia (PDD) and Dementia with Lewy Bodies (DLB) Their efforts will contribute to the development of new interventions and better diagnostics for PD/PDD/DLB.