Director: John Q. Trojanowski, M.D., Ph.D.
Title: Parkinson's Disease and Dementia
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 (ɑ-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 ɑ-syn (see Figure 1), the overarching goals of the Penn Udall Center are to elucidate mechanisms of disease progression and ɑ-syn transmission through synergistic collaborations between basic and translational research projects that work with each of the supportive cores to implement the mission of the Penn Udall Center.
The Penn Udall Center includes four Research Projects that build upon their well-developed and substantial basic and clinical research collaborations, plus support from the four integrated Cores:
Project 1: A multimodal biomarker approach to evaluating and predicting cognitive decline in Lewy Body diseases (Alice Chen-Plotkin, MD). These studies seek to replicate previously-reported candidate biomarkers (older age, greater motor severity, postural instability gait disorder features, presence of hallucinations, lower levels of CSF amyloid-beta 1-42, and regional pattern of atrophy reflecting changes seen in Alzheimer’s disease) of CI in a training cohort of Lewy Body Disorder (LBD) patients, to define relationships among candidate biomarkers and identify potential pathophysiological subtypes of CI in LBD, and to develop a multimodal predictive algorithm for cognitive decline in LBD and apply it to an independent test cohort of PD patients.
Project 2: Mechanisms of PD executive dysfunction in language (Murray Grossman, MD). This project is designed to find 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. More specifically, Project 2 aims to assess the cognitive and neural basis for coordination during conversations in PDD and DLB, the cognitive and neural basis for resolving lexical ambiguity in PDD and DLB, and the pathologic basis for cognitive deficits in PDD and DLB.
Project 3: Mechanisms of transmission of pathological ɑ-synuclein in neurons (Virginia M-Y Lee, PhD, MBA). This study tests the hypothesis that neurons from different CNS regions are selectively vulnerable to develop either Lewy Bodies/Lewy Neurites (LBs/LNs) alone or LBs/LNs with Alzheimer’s disease (AD)-like tau pathology and altered levels of secreted Amyloid Beta (Aβ) in response to treatment with distinct ɑ-synuclein (ɑ-syn) pre-formed fibril (PFF) strains. It also seeks to generate and characterize synthetic ɑ-syn PFF 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. This project also collaborates with Project 4 to identify anti- α-syn monoclonal antibodies (MAbs) that block transmission in neuron-based synucleinopathy models to be used for immunotherapy in α-syn transgenic mice of Project 4.
Project 4: Immunotherapy targeting PD transmission in animal models (John Q. Trojanowski, MD, PhD). This project investigates the seeded recruitment of endogenous alpha-synuclein (ɑ-syn) by pathological ɑ-syn species into Lewy bodies (LBs) and neurites (LNs) followed by the spread of these pathologies in Parkinson’s disease (PD) without and with dementia (PDD) as well as in dementia with LBs (DLB). The associated hypothesis is that these mechanisms underlie the progression of PD/ PDD/ DLB and that the relentless accumulation of pathological ɑ-syn mediates neurodegeneration in these and related LB disorders (LBDs) referred to as synucleinopathies. Based on prior studies in collaboration with Project 3 demonstrating the transmission of pathological ɑ-syn in a human mutant A53T ɑ-syn transgenic (Tg) mouse model (line M83) of LBD, Project 4 tests specific hypotheses on mechanisms of pathological ɑ-syn transmission and determines if passive immune therapy with ɑ-syn specific monoclonal antibodies (MAbs) abrogates the CNS spread of ɑ-syn pathologies. The rapid spread of ɑ-syn pathology throughout the CNS in young M83 mice injected with ɑ-syn PFFs or disease brain lysates months before disease onset in uninjected M83 mice supports our hypothesis that misfolded ɑ-syn is sufficient to transmit LBD. Further, in collaboration with Project 3, synthetic ɑ-syn PFF strains were identified that differentially seed endogenous ɑ-syn to form LBs/LNs in addition to tau inclusions similar to Alzheimer’s disease (AD) neurofibrillary tangles (NFTs). Hence, Project IV assesses the ability of ɑ-syn PFF strains to differentially seed ɑ-syn and cross-seed tau to form pathological ɑ-syn and tau inclusions, respectively, and it also investigates how ɑ-syn and tau interact and contribute to the progression of LBD. Finally, Project 4 examines the potential for ɑ-syn specific MAbs to halt ɑ-syn seeded LBD transmission.
Penn Udall Cores include: Administrative (Dr. Trojanowski); Clinical (Daniel Weintraub, MD); Neuropathology, Biomarker and Genetics (Dr. Trojanowski); Data Management, Biostatistics and Bioinformatics (Sharon Xie, PhD).
Ongoing research at the Penn Udall Center addresses several NINDS PD2014 research priorities, including:
Reagents and antibodies produced in the Center, ɑ-synuclein fibrils, human tissues and biofluid samples as well as DNA are available for use by other investigators. Assistance is also available for establishment of ɑ-synuclein transmission studies in other laboratories.
The mission of the Penn Udall is to conduct multidisciplinary clinical, translational, and basic research that improves understanding of and develops better treatments for patients with Parkinson's disease (PD) and related conditions. Major efforts of the Center are directed toward the understanding of cognitive changes in persons with PD, specifically the stages of progression from normal cognition to dementia in PD, PD with dementia (PDD), and dementia with Lewy bodies (DLB). Related basic and translational research studies are examining underlying causes of these changes, including brain degeneration mediated by progressive accumulations of pathological forms of the protein alpha–synuclein, and specific ways to prevent and treat this accumulation. 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.
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