The Morris K. Udall Center of Excellence for Parkinson's Disease Research at the University of Pennsylvania School of Medicine

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

Title:  Parkinson's Disease and Dimentia

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

Central Theme

The Udall Center at the University of Pennsylvania School of Medicine (PENN) builds on the continuing momentum of a team of PENN clinical and basic scientists to accomplish the overarching goals of this multidisciplinary Parkinson’s disease (PD) research program. Briefly, the goals of the PENN Udall Center are to elucidate mechanisms of brain degeneration in patients with PD, especially those underlying poorly understood neuropsychiatric impairments. PD with dementia (PDD), which may be pathologically and clinically indistinguishable from dementia with Lewy bodies (DLB), frequently co-occurs with Alzheimer’s disease (AD), and the Lewy body (LB) variant of AD (LBVAD) is the most common subtype of AD. However, the reasons for the convergence of LBs and AD pathologies remain enigmatic. Here, we hypothesize that accumulations of oligomeric/fibrillar species of alpha-synuclein (α-syn) lead to neurodegeneration and neuropsychiatric deficits in addition to parkinsonism, which may be compounded by tau and amyloid beta (Aβ) pathologies seeded by α-syn oligomers/fibrils.

Center Structure

To accomplish the goals of the PENN Udall Center, Projects 1 and 2 are patient-oriented studies designed to develop: 1) a disease-specific rating scale to assess the impact of cognitive impairment on daily function in PDD; and 2) a functional imaging study to better define the anatomic substrate of cognitive impairment in PD and PDD.  Projects 3 and 4 bridge patient-oriented studies by pursuing research on novel animal models of PD/PDD to clarify how the misfolding, fibrillization and aggregation of α-syn, tau and Aβ contribute to the neuron dysfunction and degeneration that result in cognitive impairments in PDD. These four highly integrated and synergistic Projects are supported by an Administrative Core (A), a Clinical and Education Core (B), a Neuropathology and Genetics Core (C) and a Data Management and Biostatistics Core (D). 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 improving the diagnosis and management of patients with PD, PDD, DLB and related disorders.

Recent Significant Advances

Representative scientific advances from the four research projects in the Penn Udall Center are highlighted below.  

Project 1: Functional Consequences in Cognitive Impairment in PD, Andrew Siderowf, M.D.

We have continued to analyze data collected from Udall Core B participants to understand the relationship between cognitive impairment and daily function in PD patients.  One study, showing that mild cognitive difficulties are associated with declines in daily function in non-demented as well as demented subjects, has been accepted for publication.  A follow-up study showing that this relationship is much stronger in patients with more severe motor impairment is in preparation.  

There has also been substantial progress in developing a new tool for measuring the impact of cognitive dysfunction on daily function in PD. We combined the Neuro-QOL “Adult Cognition Item Bank”  group of 42 items with an additional 56 items developed through consultation with patients and expert clinicians to create a bank of 98 items that are currently being tested in phase II of this project. The survey is accessed through the Penn Udall Center website.  We have conducted analyses on the first wave of respondents (patients = 193; caregivers = 113).  This analysis has revealed several interesting findings.

• Mean response score for all items are more correlated with measures of cognitive impairment than motor impairment (0.45 vs 0.39).  

• Correlation with cognitive impairment is slightly higher for non-NeuroQOL items (#43-98 r=0.46) than for items from the NeuroQOL adult cognition battery (#1-42; r=0.42).  

• In preliminary factor analysis, there appears to be one dominant factor for both patients and caregivers.  However,

• Factor structure differs substantially between patients and caregivers. These findings will require further analysis involving larger numbers of responses and careful matching of patients to caregivers.

Finally, a recent study showed that the CSF Aβ42 cut point that is diagnostic for AD- based on studies done in the AD Neuroimaging Initiative (ADNI), is predictive of cognitive decline in PD (Siderowf et al). Moreover, we recently interrogated PD plasma samples with the Rules Based Medicine (RBM) panel of >150 analytes (including trophic factors, signaling molecules and cytokines) which showed that plasma levels of epidermal growth factor (EGF) correlate with cognition and risk for cognitive impairment (Chen-Plotkin et al). These RBM biomarker studies of PD and other neurodegenerative diseases were recently reviewed (Hu et al.) and plans are underway to confirm and extend these RBM studies in additional Udall subjects. Further, plasma RBM studies are in progress on ADNI subjects so there will be a rich database for teasing out biomarkers that are specific for cognitive impairment in PD versus other dementias (Hu et al.).

Select Recent Publications

Siderowf, A., Xie, S.X., Hurtig, H., Weintraub, D., Duda, J., Chen-Plotkin, A., Shaw, L.M., Van Deerlin, V., Trojanowski, J.Q., and Clark, C.M. CSF amyloid β 1-42 predicts cognitive decline in Parkinson’s disease. Neurol., 75:1055-1061, 2010.

Chen-Plotkin, A., Hu,W.T., Siderowf, A., Weintraub, D, Goldmann Gross, R., Hurtig, H.I., Xie, S., Arnold, S.E., Grossman,M., Clark, C.M., Shaw, L.M., McCluskey, L., Elman, L.,Karlawish, J., Van Deerlin, V.M., Lee, V.M.-Y., Soares, H., and Trojanowski, J.Q. Plasma EGF levels correlate with cognitive performance and predict cognitive impairment in Parkinson’s disease. Ann. Neurol., In press, 2010.

Hu,W.T., Chen-Plotkin, A., Arnold, S.E., Grossman,M., Clark, C.M., Shaw, L.M., McCluskey, L., Elman, L., Karlawish, J., Hurtig, H.I., Siderowf, A., Lee, V.M.-Y., Soares, H., and Trojanowski, J.Q. Biomarker discovery for Alzheimer’s disease, frontotemporal lobar degeneration, and Parkinson’s disease. Acta Neuropathol., 120:385-399, 2010.

Project 2: Executive Difficulty in Parkinson’s Dementia, Murray Grossman, M.D.

The results from the past year illustrate the specific cognitive deficits in PDD/DLB that are likely to interfere with activities of daily living.  From a cognitive neuroscience perspective, they also point out the critical collaboration between executive and language resources that is necessary to optimize language functioning.  

Select Recent Publications

Peelle, J. E., Troiani, V., Grossman, M.: Interaction between process and content in semantic memory: An fMRI study of noun feature knowledge.  Neuropsychologia 47:995-1003, 2009. PMC2675540

Peelle, J.E., Troiani, V., Gee, J., Moore, P., McMillan, C., Vesely, L., Grossman, M.: Sentence comprehension and voxel-based morphometry in progressive nonfluent aphasia, semantic dementia, and nonaphasic frontotemporal dementia.  Journal of Neurolinguistics 21:418-432, 2008. PMC2598754

Ash, S., Moore, P., Vesely, L., Gunawardena, D., McMillan, C., Anderson, C., Avants, B., Grossman, M.: Non-fluent speech in frontotemporal lobar degeneration.  Journal of Neurolinguistics 22:370-383, 2009. PMC20074786

Listerud, J., Anderson, C., Moore, P., Libon, D.J., Grossman, M.: Neuropsychological patterns in MRI-defined subgroups of patients with degenerative dementia.  Journal of the International Neuropsychological Society 15:459-470, 2009.

Das, S.R., Avants, B.B., Grossman, M., Gee, J.C.: Registration-based cortical thickness measurement.  NeuroImage 45:867-879, 2009. PMC19150502

Whitney, C., Weis, S., Krings, T., Huber, W., Grossman, M., Kircher, T.: Task-dependent modulations of prefrontal and hippocampal activity during intrinsic word production.  Journal of Cognitive Neuroscience 21:697-712, 2009.

Grossman, M.: Primary progressive aphasia: Clinical-pathological correlations.  Nature Reviews Neurology 6;88-97, 2010. PMC20139998

Avants, B., Cook, P.A., Ungar, L., Gee, J.C., Grossman, M.: Dementia induces correlated reductions in white matter integrity and cortical thickness: A multivariate neuroimaging study with sparse canonical correlation analysis.  NeuroImage 50;1004-1016, 2010. PMC20083207

Yu, C.-E., Bird, T.D., Bekris, L.M., Leverenz, J.B., Steinbart, E., Galloway, N.M., Feldman, H., Woltjer, R., Miller, C.A., Wood, E.M.,, Grossman, M.,  McCluskey L., Clark C.M., Neumann, M., Danek, A., Galasko, D.R., Arnold, S.E., Chen-Plotkin, A., Karydas, A., Miller, B.L., Trojanowski, J.Q., Lee, V.M.-Y.,  Schellenberg, G.D., Van Deerlin, V.M. The spectrum of mutations in progranulin: A collaborative study screening 545 cases of neurodegeneration. Arch. Neurol., 67:161-170, 2010. PMC20142524

Project 3: Models of Parkinson’s Dementia, Virginia M-Y Lee, Ph.D.

The studies from the past funding year advanced understanding of mechanisms underlying neurodegenerative synucleinopathies. Moreover, our novel cell-based models of synucleinopathies will be extremely useful for testing the α-syn “transmission” hypothesis and for establishing a cell-based assay for the identification of potential therapies for PD.

Select Recent Publications

Luk, K.C., Song, C., O’Brien, P., Stieber, A., Branch, J., Brunden, K.R., Trojanowski, J.Q., and Lee, V.M.-Y. Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc. Nat. Acad. Sci., 106:20051-20056, 2009. PMC2785290

Lim, Y., Kehm, V., Li, C., Trojanowski, J.Q., and Lee, V. M.-Y. Forebrain overexpression of alpha-synuclein leads to early postnatal hippocampal neuron loss and synaptic disruption. Exper. Neurol., 221:86-97, 2010. PMC2812632

Roy, S., Lee, V.M.-Y., and Trojanowski, J.Q. Axonal transport and neurodegenerative diseases. In: Handbook Of The Neuroscience Of Aging, P.R. Hof, and C.V. Mobbs (Eds.), Elsevier Academic Press, pp. 107-112, 2009.

Project 4: Interactions of Protein Aggregation in Parkinson’s Dementia, Benoit Giasson, Ph.D.

Findings from this past funding year support the notion that while both the location and hydrophobicity of protein segments are important elements that affect the propensity to form amyloid fibrils, the intrinsic ability of a polypeptide to structurally fold into amyloid is also critical. These findings provide important insights in the planning of therapeutic agents that may be capable of preventing α-syn amyloid formation.

Select Recent Publications

Waxman, E.A., Covy, J.P., Bukh, I., Li, X., Dawson, T.M., Giasson B.I. Overexpression of leucine-rich repeat kinase 2 leads to aggresome-like formation, but it is not associated with α-synuclein aggregation or pathological inclusions.  J. Neuropath. Exp. Neurol. 68, 785-96, 2009. PMC2722758

Waxman, E.A., Mazzulli, J.R., Giasson, B.I. Characterization of hydrophobic residue requirements for α-synuclein fibrillization. Biochemistry, 48, 9427-9436, 2009. PMC2758333

Waxman, E.A., Emmer, K.L., Giasson, B.I. Residues Glu83 plays a major role in negatively regulating α-synuclein amyloid formation. Biochem. Biophys. Res. Commun. 391, 1415-1420, 2010. PMC2812690

Available Resources

The Penn Udall Center has a highly developed and integrated database that captures all of the clinical, genetic and neuropathological data that is collected. This database information is available to investigators from other Udall Centers, as well as to other investigators at PENN.  In addition, the PENN Udall Center has reagents, tissue samples and DNA available for use by other investigators.

Plans for the Coming Year

Project 1 (Siderowf): To conduct psychometric evaluations of the new rating instrument, and to assess the validity of scores on the new instrument in a longitudinal cohort study.

Project 2 (Grossman): To assess the cognitive and neural basis for: 1) impaired script processing, 2) difficulty interpreting structurally ambiguous sentences and 3) impaired story narratives in mild PDD/DLB.

Project 3 (Lee): To test the following hypotheses: 1) that the presence of α-syn neuropathology in hippocampus, limbic system and other cortical areas distinguishes PD from PDD and DLB; 2) that the presence of tau and/or Aβ lesions exacerbate the clinical phenotypes of movement disorder, dementia and other behavior abnormalities in PD, PDD and DLB; 3) that the presence of WT or mutant α-syn neuropathology in hippocampus, limbic system and other cortical areas in TG mouse models leads to cognitive impairments; and 4) that the regulated overexpression of tau or Aβ precursor proteins (APP) which forms tau tangles or Aβ plaques in WT and A53T α-syn mice developed in Aim 3, enhances cognitive impairments in these TG mice

Project 4 (Giasson): To examine the hypotheses that: 1) the initiation of tau fibrillization by α-syn and the synergistic enhancement of tau and α-syn fibrillization requires specific domain interactions on both proteins and is modulated by specific amino acid residues and post-translation modifications in α-syn and tau; 2) minute quantities of amyloidogenic α-syn can initiate tau pathogenesis by investigating the biological and pathological consequences of α-syn and tau interaction in vivo using transgenic mice with pan-neuronal expression of wild-type tau and wild-type or A53T α-syn; and 3) some extracellular Aβ peptide deposits can mediate intraneuronal aggregation of α-syn in transgenic mice and to determine the mechanism for this process.

The associated Cores (Administrative, Clinical and Education, Neuropathology and Genetics Core, and Data Management and Biostatistics) will continue to pursue their Aims and provide support for Projects 1-4.

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 improving the diagnosis and management of patients with PD, PDD, DLB and related disorders.