2010 Progress Report
Representative scientific advances from the four research projects in the Penn Udall Center are highlighted below in excerpts taken from the complete progress report submitted to the National Institute of Neurological Disorders and Stroke (NINDS).
The research projects are functional consequences in cognitive impairment, executive difficulty in Parkinson's dementia, animal models of Parkinson's disease, and interactions of protein aggregation of Parkinson's dementia.
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.
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.
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 Aß42 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).
Plans for the Coming Year - Project 1
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.
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.
Plans for the Coming Year - Project 2
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.
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 alpha-syn “transmission” hypothesis and for establishing a cell-based assay for the identification of potential therapies for PD.
Plans for the Coming Year - Project 3
To test the following hypotheses: 1) that the presence of alpha-syn neuropathology in hippocampus, limbic system and other cortical areas distinguishes PD from PDD and DLB; 2) that the presence of tau and/or Aß 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 alpha-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 Aß precursor proteins (APP) which forms tau tangles or Aß plaques in WT and A53T alpha-syn mice developed in Aim 3, enhances cognitive impairments in these TG mice.
Project 4: Interactions of Protein Aggregation in Parkinson’s Dementia
Benoit Giasson, PhD
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 alpha-syn amyloid formation.
Plans for the Coming Year - Project 4
To examine the hypotheses that: 1) the initiation of tau fibrillization by alpha-syn and the synergistic enhancement of tau and alpha-syn fibrillization requires specific domain interactions on both proteins and is modulated by specific amino acid residues and post-translation modifications in alpha-syn and tau; 2) minute quantities of amyloidogenic alpha-syn can initiate tau pathogenesis by investigating the biological and pathological consequences of alpha-syn and tau interaction in vivo using transgenic mice with pan-neuronal expression of wild-type tau and wild-type or A53T alpha-syn; and 3) some extracellular Aß peptide deposits can mediate intraneuronal aggregation of alpha-syn in transgenic mice and to determine the mechanism for this process.