2005 All Hands Meeting Multivariate assessment of a preclinical mouse model of Parkinson’s disease: “Connecting the dots” to the human disease state Diana L. Price, Ph.D. National Center for Microscopy and Imaging Research University of California, San Diego

Deliverables  mGluR5 manuscript: 2006  D1/D2 immuno: confirm. w/ larger N  MRI analyses: 2006 MRI analyses: T1 & T2: baseline measures

The alpha-synuclein project: A multi-site, multi- disciplinary collaboration NCMIR – UCSD (M.H. Ellisman) Advanced light and electron microscopy  Diana Price  Van Phung  Maryann Martone  Heather Nguyen  Andrea Thor Experimental Neuropathology Laboratory -UCSD (E. Masliah) Animal models & Parkinson’s strategy  Edward Rockenstein  Mike Mante Supported by The Branfman Family Foundation, NIH (NCRR, NIDA, NIA) and MJ Fox Foundation. Duke University – Center for In Vivo Microscopy (G.A. Johnson) Microscopic MRI   Anjum Ali   Mike Fehnel   Sally Gewalt Additional collaborators Harvard University J. Neumeyer Orally active apomorphine UICUC J. George Targeted nanoparticle delivery of small molecule therapeutics

Parkinson’s Disease & Alpha-synuclein  Neuronal cell death  Lewy Bodies  Alpha-synuclein protein (  -SYN)  Mouse model overexpressing  -SYN

Challenges in PD research  Disease heterogeneity  Complex etiology (genetics, environment)  Model systems  Connecting the dots

How well does the  -syn mouse recreate features of PD?  Widespread  -syn aggregates in CNS  Neurochemistry mGluR5 receptor expression Dopamine D1/D2 receptors  MRI studies: volume & composition  Cognitive and motor deficits

Multimodal studies of PD animal models Behavior Assessment of cognitive and motor function Chemistry & Genetics Protein analyses Web QTL Ligand binding studies Imaging Correlation of large-scale mapping of immunolabeling and MRI studies Ultrastructural studies using EM

Multiscale imaging studies at NCMIR  Electron microscopy  Multiphoton and confocal microscopy

New MRI imaging techniques for improved resolution and contrast  Clinical imaging limitations  Evaluation of preclinical models High resolution T1 weighted imaging High contrast T2 weighted imaging Correlation histological data  12 T1 weighted datasets (6 female & 6 males) and correlated T2 weighted datasets  Facilitation of processing procedures Pre-processing underway Volumetric analyses & regional intensities  Goal: Extension to non-invasive clinical imaging

High-resolution T1 weighted images Non-invasive MRI imaging of  -syn tg mice Non-transgenic Alpha-synuclein transgenic

High-contrast T2 weighted images Non-invasive MRI imaging of  -syn tg mice Non-transgenic Alpha-synuclein transgenic

Opportunities for evaluating potential therapies  Pharmacological Dopaminergic: Dopamine D1/D2 receptor agonists Glutamatergic: mGluR5 receptor antagonists  Immunization Passive immunization: clearing of protein aggregates Multivariate assessment allows us to evaluate these therapeutics on pathological and behavioral levels for correlation with clinical observations

Publications  D.L. Price, S.K. Chow, N.A.B. MacLean, H. Hakozaki, S. Peltier, M.E. Martone and M.H. Ellisman (In Press) High-Resolution Large-Scale Mosaic Imaging Using Multiphoton Microscopy to Characterize Transgenic Mouse Models of Human Neurological Disorders, Neuroinformatics, Special Issue: Integration and modeling of imaging in the phenotype-genotype problem  D.L. Price, E. Rockenstein, N.A.B. MacLean, M. Mante, V. Phung, D. Askay, E. Masliah, and M.H. Ellisman (In preparation)  Increased mGluR5 immunoreactivity and behavioral deficits in transgenic mice overexpressing alpha-synuclein