Udall Center - UPenn, Perelman School of Medicine

University of Pennsylvania logo

Director: John Q. Trojanowski, M.D., Ph.D.

Title:  Parkinson's Disease and Dementia

Website: http://www.med.upenn.edu/udall/


Central Theme

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, 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 Cores to implement the mission of the Penn Udall Center.


Center Structure

To accomplish these goals, the Penn Udall Center includes 4 Projects and 4 Cores that build upon well-developed basic and clinical research collaborations. Center Research Projects include: Project 1: A multimodal biomarker approach to Evaluating and predicting cognitive cecline in Lewy Body spectrum disorders (Alice Chen-Plotkin); Project 2: Mechanisms of PD Executive Dysfunction In Language (Murray Grossman); Project 3: Mechanisms Of Transmission Of Pathological Alpha-synuclein In Neurons (Virginia M-Y Lee); Project 4: Immunotherapy targeting PD transmission in animal models (John Trojanowski). Center Cores include” Administrative Core (John Trojanowski); Clinical Core (Daniel Weintraub); Neuropathology, Biomarker and Genetics Core (John Trojanowski); and Data Management, Biostatistics and Bioinformatics Core (Sharon Xie). 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 Advances

Project 1:  Notable findings include the demonstration that a multimodal classifier based on AD-derived biomarkers performs with 80% accuracy in identifying PD patients with vs. without dementia and the demonstration that low levels of plasma epidermal growth factor (EGF) predict subsequent cognitive decline in both PD (236 PD patients from Penn including the pre-specified Udall cohort as well as additional subjects) and AD (396 MCI subjects from the Alzheimer’s Disease Neuroimaging Initiative cohort) patients followed longitudinally.

Project 2: Following up prior autopsy studies of clinically diagnosed PDD, a large autopsy series of PDD and DLB (n=213) cases was examined. A medium to high level of Alzheimer’s disease (AD) co-pathology was found in 51% of LBD. This also was associated with higher burden of α-syn pathology compared to patients with low levels of AD co-pathology. The presence of medium to high levels of tau and Aβ co-pathology each worsened cognitive functioning relative to patients with low levels of AD co-pathology, and shortened survival in a dose-dependent manner. While many with AD co-pathology have dementia as an early feature of disease, we could not identify clinical or neuropathological cutpoints to reliably distinguish PDD and DLB. PDD and DLB also share prodromal symptoms, biomarker changes and genetic risk factors. Thus, we contend that PDD and DLB exist on a clinical-pathological spectrum more meaningfully defined by the status of AD co-pathology. Notably, additional findings emphasize the important role of AD co-pathology in the Penn autopsy series, the use of PET and reliable CSF biomarkers of AD to examine progressive AD co-pathology in LBD in real time, and the potential scientific and clinical roles of this knowledge for the spreading/progression of disease pathology and precision-medicine approaches to treatment.

Project 3: Research tested the α-syn transmission and strain hypotheses of pathological α-syn which included studies showing: 1) cell-to-cell transmission of LB/LN-like pathology in wild type animals (including non-human primates) following CNS inoculation of mouse α-syn (Ms-α-syn) preformed fibrils (PFFs); 2) in cell-based systems, the characterization of induced LBs/LNs in cultured neurons following treatment with Ms-a-syn PFFs; 3) reduction in PD-like LB/LN pathology in our Ms-α-syn transmission neuron-based cell culture and WT mouse models following exposure to/injection of Ms-α-syn  and treatment with α-syn specific monoclonal antibodies (MAb); 4)  induction of distinct α-syn strains in vitro by human α-syn PFFs; 5) formation of distinct α-syn strains by LB-α-syn and glial cytoplasmic inclusion (GCI)-α-syn isolated from human post-mortem synucleinopathy brains including LBD and MSA brains; 6) neuropathology studies of α-syn positive LBs/LNs and other neuropathological lesions in PDD and subjects with co-incidental AD and LB pathology.

Project 4: This component made significant progress towards implementing its Aims by: 1) identifying  unique synthetic α-syn PFF strains A and B that differentially transmitted LBD and cross-seeded tau tangles following injection into the brains of PS19 tau transgenic mice; 2) developing a wildtype mouse model of α-syn transmission using synthetic Ms-α-syn PFFs; 3) showing that  LB-α-syn and GCI-α-syn are distinct α-syn strains; and 4) demonstrating efficacy of immunization with anti-α-syn MAbs in model systems of α-syn transmission.


Public Health Statement

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.

 

Budget End Date: 2018/06/30

NIH Grant Number: P50 NS053488