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) 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 6, 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 (a-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 a-syn (see Figure 1), the overarching goals of the Penn Udall Center are to elucidate mechanisms of disease progression and a-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 years 1-5 are highlighted below.
The goal of Project I was to create a new rating scale for measuring Instrumental Activities of Daily Living (IADLs) in patients with PD and a range of cognitive functions. The new scale is called the Functional Independence Index for Parkinson’s Disease (FII-PD). We collected preliminary data on the relationship between IADL function and cognition. The item bank was developed and calibrated, test-retest reliability was demonstrated, construct validity was shown by comparison to measures of cognition, existing daily function scales and direct observation of daily functional ability. A 15-item short form was validated which can be administered on paper or on a tablet computer.
We also generated significant preliminary data relevant to the new proposal for Project I. Using longitudinal clinical data collected in the Clinical Core and working with Core B, we assessed the relationship between several biological markers and change in cognitive function over time. We performed studies using imaging markers, particularly volumetric MRI and showed relationships between two distinct patterns of brain atrophy. In one study, we showed that a pattern of brain atrophy that is a marker for AD predicts cognitive decline in non-demented PD patients. In another study we identified a novel atrophy pattern that differentiates patients with PD and normal cognitive status from those with PD and dementia. We conducted studies showing the relationship between cognitive decline and CSF Abeta42, a biomarker associated with AD. We assessed the relationship between ApoE4 carrier status and risk of PD dementia and found an approximately 3 fold increased risk of cognitive decline among ApoE4 carriers in our cohort. Finally, we identified a novel plasma biomarker for cognitive decline. Dr. Siderowf has joined Avid Radiopharmaceuticals as of July, 2012.
Project II Investigators were the first to systematically study higher-level measures of linguistic functioning in PDD and DLB and suggest that these linguistic measures appear to be markers that distinguish PDD from DLB. Specifically, we discovered a deficit in sentence processing in comprehension and expression, as well as a deficit in conversational discourse in both comprehension and expression. Moreover, we studied the neurolinguistic basis for this impairment. Thus, we found that these linguistic deficits were due in large part to limitations in executive resources like working memory and top-down organization. This emerged from experimental manipulations of linguistic stimuli. For example, there is significantly greater difficulty understanding sentences that are lengthened by the strategic placement of an adjectival phrase, and this is most evident in grammatically complex sentences. Likewise, there is significantly greater difficulty understanding events in a story that are inter-related by a complex, hierarchical association compared to events that are related serially. Correlation analyses related performance on these linguistic measures to performance on neuropsychological measures of executive functioning. We also found comparable deficits in direct comparisons of comprehension and expression, suggesting a single source of executive impairment regardless of modality. Additional validation of this pattern of impairment comes from quantitative neuroimaging which shows that high resolution MRI is beginning to define the neuroanatomic basis for these cognitive difficulties. Significant gray matter thinning in PDD and DLB is seen in frontal, temporal and parietal cerebral regions and regression analyses related executive-mediated language difficulties to gray matter thinning in prefrontal regions. Converging evidence to support the anatomic basis for these findings comes from fMRI studies of healthy adults, including measures of discourse comprehension and expression, as well as sentence comprehension. Further, Dr. Rachel Gross is co-PI on a collaborative supplement with Dr. David Eidelberg and his colleagues at the Feinstein Institute Udall Center to explore the use of imaging as a marker of CI in LBD, which has implications for patient care and treatment trials. Her study related areas of gray matter atrophy to severity of CI in several prefrontal regions, temporal lobe including the hippocampus, and parietal lobe including the precuneus. Moreover, the set of atrophied regions was related to deficits in specific executive, memory, and visuospatial measures. Finally, we demonstrated that patients with PDD and DLB are significantly impaired in decision-making, an executive process crucial for interpreting ambiguous sentences. These detailed neurolinguistic assessments are critically informative because performance on these measures distinguishes patients with DLB who are more impaired relative to patients with PDD. This is important because there may be different a-syn strains and histopathologic abnormalities underlying DLB and PDD, and these conditions may be optimally treated by different medication regimens.
Project III made significant progress in the development of in vitro and in vivo models of PD/PDD/DLB in Years 1-5. We were the first to develop cell-based models of Lewy body (LB)/ Lewy neurite (LN) a-syn pathology in non-neuronal cells and primary neurons. To accomplish this, we treated HEK-293 non-neuronal cells stably expressing a-syn with a-syn pre-formed fibrils (PFFs) using liposome-mediated transduction, and showed that cells developed large a-syn inclusions that were insoluble, misfolded, hyperphosphorylated and ubiquitinated similar to authentic LBs in PD. Thus, a-syn PFFs can “seed” the recruitment of endogenous a-syn and convert them into pathological inclusions. We next showed that synthetic a-syn PFFs are readily internalized by primary neurons generated from the hippocampus, cortex and midbrain neurons of wild type (WT) non-transgenic (non-Tg) rodents (mouse or rat) wherein they recruit and convert soluble endogenous mouse a-syn proteins into insoluble LB/LN-like inclusions which leads to decreases in selective synaptic proteins, progressive loss of neuronal excitability and connectivity, followed by neuron death. The simplicity of our neuronal model system of LBs/LNs will spur future research on the mechanisms of pathogenesis in PD and other synucleinopathies. Finally, the results of these cell-based studies support a recent provocative hypothesis that a-syn is capable of “spreading” between cells in the CNS when misfolded a-syn conformers released by affected neurons initiate recruitment of endogenous a-syn to form LNs/LBs once taken up by hitherto unaffected neurons. Indeed, the neuron-based models will be used in Project III in the renewal period to study mechanisms of a-syn transmission.
Another major accomplishment is the development of a mouse model wherein a-syn pathology is transmitted and propagated throughout the CNS. Briefly, we used a previously characterized transgenic (Tg) mice line (M83) which constitutively express human A53T mutant a-syn and inoculated a-syn PFFs into the striatum and/or cortex of young M83 mice months before they develop a-syn pathology or show evidence of neurological deficits. Significantly, injections of a-syn PFFs accelerated LB/LN formation and dramatically reduced survival. Since a-syn pathologies were widely disseminated throughout the brain far beyond the injection sites, transynaptic transmission of a-syn pathology likely occurs. Thus, a-syn PFFs are sufficient to induce PD-like pathology and transmit disease in vivo. This model opens up new avenues for understanding the progression of PD/PDD/DLB and related synucleinopathies, and may aid the development of novel therapeutic strategies to block progression of LBD. Establishment of a-syn transmission mouse model forms the basis of the new Project IV in the Udall Center competing renewal, and allows us to test hypotheses about the cell-to-cell spreading of pathological a-syn to induce formation of LBs/LNs in cultured neurons and in Tg mice as well as develop novel immune therapies for PD/PDD/DLB.
Finally, we generated Tg mouse models of LBD by creating forebrain-specific conditional Tg mice that overexpress human WT or A53T mutant a-syn. Induction of a-syn expression in mature A53T a-syn Tg mice resulted in age-dependent learning and memory deficits concomitant with loss of synaptic proteins. Moreover, the distribution of a-syn pathology in these inducible A53T a-syn mice is similar to human DLB/PDD and the extent of a-syn pathology in the limbic system correlated with memory impairment. Remarkably, when a-syn expression was suppressed in these mice, we observed partial clearing of pre-existing a-syn pathology and reversal of synaptic defects which was associated with improved memory function. These results suggest that drugs that reduce a-syn levels or reduce LB/LN burden could be used to treat established PD/PDD/DLB.
Project IV conducted extensive structure/function studies to understand the molecular mechanism driving the polymerization of a-syn. The analyses of the various regions/residues in the middle hydrophobic region of a-syn involved in the polymerization of a-syn itself showed that even one as short as 2 amino acid residues (A76 and V77), dramatically impaired the ability of a-syn to polymerize into amyloid fibrils. However, this inhibition of amyloid assembly was clearly complex since other deletions within this hydrophobic region reduced the rate of fibrillization without abrogating filament assembly. Furthermore, residue E83 was shown to play an important role in negatively regulating a-syn amyloid formation since the mutation of residue E83 to an A rescued the ability of several a-syn mutants to polymerize.
Other studies examined the ability of mutant a-syn to cross-seed tau. Deletion of the N- and C-terminus of a-syn did not impair the ability of a-syn to induce tau fibrillization, but all a-syn mutants with alterations in the hydrophobic region were unable to induce tau fibrillization suggesting that the key region of interaction with tau is within the a-syn hydrophobic region of a-syn. To further study a-syn-induced tau polymerization in cultured cells, Project IV used a cellular model, in which recombinant, a-syn PFFs cross-seeded tau to promote the formation of neurofibrillary tangle (NFT)-like aggregates thus supporting the notion that minute amounts of aggregated a-syn are sufficient to induce tau amyloid inclusion formation. Next, Project IV investigated the ability of a-syn to induce tau fibrillization in vivo by cross-breeding WT tau (T40) and WT or A53T a-syn Tg mice. These studies revealed significant NFT-like tau pathology in the hippocampus of bigenic mice that was not seen in the monogenic Tg mice. These findings were observed in the absence of a-syn inclusions, suggesting that a-syn can induce the formation of tau inclusions in vivo without forming a-syn inclusions. Thus, it is plausible that small amounts of biochemically detectable pathological a-syn seed formation of NFT-like pathology. We also generated and studied Tg mice expressing E46K human a-syn and these mice developed a-syn inclusions that recapitulate all the properties of human LBs in addition to NFT-like tau inclusions. Hence, these data support the view that pathological a-syn can induce formation of the tau inclusions in vivo.
We also characterized the pathological features in PD patients with leucine-repeat rich kinase-2 (LRRK2) mutations and we observed that most patients showed typical PD LB/LN pathology. We also have established a novel system to purify active recombinant LRRK2 and we used this enzyme to identify small inhibitors of this kinase which enabled us to demonstrate unique enzymatic properties of LRRK2 including some that are altered by specific disease causing mutations. Significantly, although both Mg2+ and Mn2+ serve as an ATP cofactor in activating LRRK2, LRRK2 mutations alter metal cation binding and regulate LRRK2 activities. Therefore, we proposed that the enzymatic kinetic properties of LRRK2 may reflect important characteristics of this enzyme. Finally, protein microarrays were used to screen over 9,000 human proteins by radiometric protein microarray and identified 28 substrates phosphorylated by LRRK2. This included proteins involved in actin-cytoskeleton dynamics, intracellular signaling, and synaptic transmission that undergo LRRK2-mediated phosphorylation and may represent promising targets that could lead to therapeutic applications. Dr. Giasson joined the faculty of the University of Florida at Gainesville as of January, 2012.
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.
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.
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 gray 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, hypothesizing 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 (mild cognitive impairment). 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. 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 novel lysate strains to DLB and PDD clinical-pathological profiles.
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 Abeta in response to treatment with distinct a-syn PFF strains.
Specific Aim 2: Generate and characterize synthetic a-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 a-syn and tau into insoluble aggregates in primary neurons, thus reflecting strain-like properties.
Specific Aim 4: Collaborate with Project IV to identify anti-a-syn monoclonal antibodies (MAbs) that block a-syn transmission in neuron-based synucleinopathy models to be used for immunotherapy in a-syn Tg mice of Project IV.
Specific Aim 1: Determine if unique synthetic a-syn PFF strains characterized by Project III differentially transmit LBD and cross-seed tau 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 a-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 a-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 a-syn to determine if immunization with monoclonal antibodies (MAbs), identified by Project III to neutralize a-syn transmission, abrogates induction and spread of a-syn pathology in vivo.
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.
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.
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.
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 (a-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.
Of the 212 publications in this period, 32 had 2 or more Udall Center co-authors, 22 had 3 or more Udall Center co-authors and 20 had 4-10 Udall Center co-authors. Thus, Due to extensive collaborations in this Center, a number of papers are listed in more than one Core/Project. Most recent publications are listed bellow.
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 updated March 20, 2013