The Morris K. Udall Center for Parkinson’s Disease Research at The Feinstein Institute for Medical Research

Director: David Eidelberg, M.D.

Central Theme

The Udall Center at The Feinstein Institute for Medical Research focuses on a unique patient-oriented approach using validated functional brain networks to develop novel approaches/solutions to basic problems of diagnosis and management confronted each day by Parkinson’s disease (PD) patients, clinicians and caretakers. Findings from Center projects will shed light on the relationship between functional brain organization in the resting state (PET, rest state fMRI) and neural activation during cognitive processing (event-related fMRI), and provide unique information on how both interact to shape performance in PD patients and healthy people. Project 1 addresses the serious clinical problem of levodopa-induced dyskinesias, which ultimately affect nearly all PD patients. Project 2 examines the network basis for individual differences in the cognitive response to dopaminergic treatment with a view to predicting which patients will develop untoward cognitive side effects under different treatment conditions. Project 3 aims to establish the feasibility of a new network-based algorithm for providing earlier and more accurate differential diagnosis than is currently possible.

Center Structure

Six cores will support the research activities of three Projects: the Administrative, Clinical, Statistics and Data Management, Imaging, and Education and Training cores.  The activities of each core are independent. That said, these activities will be highly coordinated across the Clinical, Cognitive and Behavioral, and Imaging Cores in that the data output of these cores will be entered into the database created in the Statistics and Data Management core.

The specialized Udall Center mechanism allows Feinstein investigators to collaborate with scientific leaders in important translational research areas. For instance, the involvement of Dr. Angela Cenci-Nilsson at Lund University (Sweden) offers a true translational collaboration in the study of the role of the microvasculature in the pathogenesis of levodopa-induced dyskinesias (LID). Professor Cenci-Nilsson’s unique expertise provides the basis for a unique collaboration spanning the gap between experimental animal studies and human investigation in Parkinson’s disease.  Similarly, investigators in Dr. Eidelberg’s laboratory have developed a productive working relationship with Dr. Mark Gluck and his team at Rutgers University (Newark, NJ) in the area of cognitive processing in Parkinson’s disease. This collaboration will develop further in the course of the fMRI/behavioral studies of probabilistic category learning and neuro-economic decision making planned over the next five years.  Moreover, the proposed studies conducted at the sleep disorders centers at North Shore – LIJ Health System, Stanford University, and the University of Pennsylvania, overseen respectively by Drs. Harley Greenberg, Emmanuel Mignot and Howard Hurtig, will offer insights into the network abnormalities that appear in individuals at risk for PD prior to the onset of motor symptoms.  

Recent Significant Advances

Project 1 (David Eidelberg, MD; Angela Cenci-Nilsson, MD, PhD): The results obtained from Dr. Cenci's group thus far verify the main hypotheses of Project 1, namely: (1) that the administration of L-DOPA produces large transient increases in rCBF; (2) that the magnitude of rCBF changes correlates with dyskinesia; and (3) that the L-DOPA-induced increase in rCBF may be accompanied by blood-brain-barrier leakage. Taken together, these results show that the rat model of L-DOPA-induced dyskinesia is a valuable experimental tool to address mechanisms of altered neurovascular function during the pharmacotherapy of Parkinson's disease.

Project 2 (David Eidelberg, MD; Mark Gluck, PhD): The current studies have allowed for further refinement of predictive models of the impact on dopaminergic status to cognitive functioning in early stage non-demented PD patients. The ongoing experiments particularly those involving 11C-PIB PET imaging, will enhance the understanding of the mechanisms underlying cognitive non-response/deterioration in more advanced patients. Likewise, these data will also inform the fMRI studies of neuroeconomic decision making that are being conducted in these subjects.

Project 3 (Andrew Feigin, MD; Chris Tang, MD, PhD; Martin Lesser, PhD): Although Project 3 data are still being accrued, our international collaborations have helped expedite these studies. FDG PET data acquired in India have provided superb validation of the network-based classification technique that we have implemented for differential diagnosis. Moreover, in a collaborative imaging study of 24 RBD patients (in collaboration wth Dr. Jean-Jacques Montplaisir, University of Montreal, Canada), we have found that elevated disease-related network activity in patients with REM behavioral disturbance (RBD) predicted the onset of parkinsonism within three years. This study, along with the data currently being collected in our Udall Center, will help validate the use of networks as imaging biomarkers of prodromal disease.

Resources Available

Animal Models: Rat model of L-dopa-induced dyskinesia (LID) at Lund University.

Other Resources: Clinical ratings (off-state UPDRS), a standardized neuropsychological testing battery, off-state FDG PET data, off-state, routine anatomical MRI, DNA banking, and brain donation/banking.

Plans for the Coming Year

Project 1: (1) For specific aim 1, we continue enrollment and study of PD patients on levodopa therapy with levodopa-induced dyskinesias, and patients on chronic levodopa therapy with uncomplicated responses; (2) Continued enrollment and study of healthy controls; (3) Continued enrollment and study of drug-naïve patients for specific aim 2. Patients scanned in year 2 will return for the 12 month follow-up evaluation; (4) We will continue the animal studies.

Project 2: (1) We will continue enrollment and study of patients for all 3 aims; (2) Interim analyses will be performed

Project 3: (1) We will enroll 24 subjects for specific aim 1; (2) The subjects for specific aim 2 will return for clinical and neuropsychological evaluation; (3) Subjects for specific aim 3 will return for repeat evaluation including PET scan.

Select Recent Publications

1. Dhawan V, Tang CC, Ma Y, Spetsieris P, Eidelberg D. Abnormal network topographies and changes in global activity: absence of a causal relationship. NeuroImage, 2012: Aug 19 [Epub ahead of print]
2. Holtbernd F, Eidelberg D. Functional brain networks in movement disorders: recent advances. Curr Opin Neurol 2012 Jun 15 [Review] [Epub ahead of print]
3. Niethammer M, Eidelberg D. Metabolic brain networks in translational neurology: concepts and applications. Ann Neurol 2012 Apr 24. [Review] [Epub ahead of print]
4. Poston KL, Eidelberg D. Functional brain networks and abnormal connectivity in the movement disorders. Neuroimage,2012; 62(4):2261-70 [Review]
5. Ma Y, Peng S, Spetsieris PG, Sossi V, Eidelberg D, Doudet DJ. Abnormal metabolic brain networks in a nonhuman primate model of parkinsonism. J Cereb Blood Flow Metab 2012; 32: 633-42
6. Mure H, Tang CC, Argyelan M, Ghilardi MF, Kaplitt MG, Dhawan V, Eidelberg D. Improved sequence learning with subthalamic nucleus deep brain stimulation: evidence for treatment-specific network modulation. J Neurosci 2012; 32(8):2804-13
7. Poston KL, Tang CC, Eckert T, Dhawan V, Frucht S, Vonsattel JP, Fahn S, Eidelberg D. Network correlates of disease severity in multiple system atrophy. Neurology, 2012; 78(16): 1237-44
8. Niethammer M, Feigin A, Eidelberg D. Functional neuroimaging in Parkinson’s disease. Cold Spring Harb Perspect Med 2012; 2(5): a009274. [Review] [PMCID: PMC3331691]
9. Ohlin KE, Sebastianutto I, Adkins CE, Lundblad C, Lockman PR, Cenci MA. Impact of L-DOPA treatment on regional cerebral blood flow and metabolism in the basal ganglia in a rat model of Parkinson’s disease. NeuroImage, 2012; 61(1):228-39. [**Selected as “Article of the Month” at Lund Medical Faculty]
10. Mattis PJ, Tang CC, Ma Y, Dhawan V, Eidelberg D. Network correlates of the cognitive response to levodopa in Parkinson’s disease. Neurology, 2011; 77:858-65
11. Ohlin KE, Fancardo V, Lindgren HS, Sillivan SE, O’Sullivan SS, Luksik AS, Vassoler FM, Lees AJ, Konradi C, Cenci MA. Vascular endothelial growth factor is upregulated by L-dopa in the parkinsonian brain: implications for the development of dyskinesia. Brain 2011; 134(pt8): 2339-57

Public Health Statement

The Udall Center at The Feinstein Institute for Medical Research employs rigorously validated Parkinson’s disease (PD)-related networks to address vital issues that impact heavily on the care of today’s PD patients. Because dopaminergic treatment is generally so effective for the motor symptoms of PD, at least early on, it is easy to dismiss the very real problems that ultimately develop: levodopa-induced dyskinesias and cognitive and behavioral changes for some patients. Understanding these phenomena should not only help us improve the lives of patients, but will provide unique insight into the pathophysiology of PD and perhaps other neurodegenerative disorders. Likewise, the validation of an automated pattern-based method for early diagnosis will help streamline trials of new therapies for PD as well as for atypical parkinsonian syndromes.

Collaborations

1. We are participating in a collaborative study between the University of Washington, University of Pennsylvania, Mayo Clinic Jacksonville and The Feinstein Institute Udall Centers on “Genetic Risk Factors for Neuropsychiatric Symptoms in Parkinson’s disease”. The purpose of this study is to determine if genetic variation is associated with neuropsychiatric symptoms that occur during the course of Parkinson’s disease and to determine if these variations predict response to treatment.
2. We have established a collaboration with the Dr. Jacques Montplaisir at the University of Montreal in which we quantified Parkinson’s disease and Multiple Systems Atrophy network activity from SPECT data in their established REM-behavior disorder (RBD) cohort. Network analysis of perfusion SPECT data demonstrates that RBD exhibits a reliable metabolic prodrome. Moreover, ongoing analysis is providing valuable data to support of the use of network quantification to determine phenoconversion risk in preclinical RBD subjects.
3. We are working on a collaborative project with the University of Ljubljiana, Slovenia. Preliminary results of a small Slovenian Parkinson’s disease (PD) dataset showed a very good correlation between PD Cognitive Pattern and Motor-Related Pattern scores of PD images reconstructed with different brain reconstruction methods. The project will be extended to include additional PD images from both of our Centers and we will explore more detailed variation of iterative reconstruction parameters.
4. We have an ongoing collaboration with Dr. Madhavi Tripathi from Institute of Nuclear Medicine and Allied Sciences, New Delhi, India. Dr. Tripathi spent some time training with us at our Center as part of an Indo-US Science & Technology Forum fellowship (see Training section below). She has been working with our Imaging Core team to analyze FDG PET data that was acquired in India. Her work has provided superb validation of the network-based classification technique that we have implemented for differential diagnosis. Dr. Tripathi is currently preparing a manuscript of these results for publication.

Training/Education Activities

1. Dr. Eidelberg has just completed a grant sponsored by the New York State Empire Clinical Research Investigator Program to mentor Dr. Niethammer (Co-Investigator, Projects 1-3 and Clinical Core). This program encourages teaching hospitals and Graduate Medical Education (GME) consortia to train physicians as clinical researchers to advance biomedical research in New York's academic health centers. Under Dr. Eidelberg’s supervision, Dr. Niethammer’s work has led to first-authored peer-reviewed publications. He has additionally written two high level reviews relating to his work and has presented his findings at major scientific meetings. With this training in hand, Martin will be able to continue to grow as an independent clinical investigator.
2. The Indo-US Science & Technology Forum (IUSSTF) awarded the prestigious 2011 Indo-US Research Fellowship to Dr. Madhavi Tripathi from Institute of Nuclear Medicine and Allied Sciences, New Delhi, India to work in our Center for a period of three months. During her short time with us, Dr. Tripathi worked with our Imaging Core team to analyze FDG PET data that was acquired in India.
3. We had the pleasure of hosting three promising young investigators (Drs. Petra Tomse, Marko Grmek and Rok Berlot) from the University of Ljubjiana, Slovenia during the past year. Drs. Tomse and Grmek received awards from the International Atomic Energy Agency to visit to our Center. Most notably, Dr. Tomse received a Type 1 IAEA Fellowship, which allowed her to train with us for four months. She worked with Udall Imaging core members to study different brain image reconstruction methods. Her work has produced encouraging preliminary results and her institution has asked Dr. Eidelberg to collaborate with them by expanding the study and has invited Dr. Dhawan (Imaging Core Leader) to be a co-mentor on Dr. Tomse’s PhD thesis.
4. Three young investigators will be coming to visit us in the Fall 2012: Dr. Carsten Eggers from the University of Cologne, Germany, Dr. Therese Söderlund from the Institute of Nuclear Medicine at University College London Hospital, United Kingdom, and Ms. Sanne Meles from the University of Groningen, The Netherlands. They will all receive specialized training in brain imaging and data analysis through the Imaging Core.
5. We have two Feinstein Institute postdoctoral fellow trainees working on Udall Center projects. Dr. Ji Hyun Ko works with the Udall team on Project 1 and Dr. Florian Holtbernd is working on Project 3.
6. Drs. Eidelberg and Gluck have co-sponsored Dr. Jessie Simon, a postdoctoral fellow from Rutgers University  for an NRSA award. She has been working closely with Dr. Gluck on Project 2 and Cognitive and Behavioral core activities. If funded, Dr. Simon will study the effects of DAT1 genotype on cognitive sequence learning in Parkinson's disease.

Community Outreach

1. A Centricity Series Symposium on Parkinson's Disease at The Feinstein Institute was held on January 25, 2012. The topic was “Parkinson’s Disease: Improving Brain Function and Clinical Performance” and defined the disease through physical effects, cognitive issues, and identification of pathological characteristics. Udall Center investigators held discussions on imaging techniques and the role they play in diagnosis, as well as current treatments, surgical procedures, biochemical mechanisms, and rehabilitation. We were honored to have Amy Rick, CEO of the Parkinson’s Action Network (PAN) speak during the symposium. Audience members included patients, clinicians, health care workers, and local representatives from PAN and the American Parkinson’s Disease Association. A video link is posted online at www.centricityseries.org.
2. We held a Parkinson’s Support Group Meeting on June 22, 2012 at North Shore University Hospital. Dr. Feigin and other members of the Udall Clinical Core gave lectures to patients about Parkinson’s disease and discussed various treatment options including an emphasis on research projects available at our Udall Center. A Clinical Core Coordinator was on site as a research representative to give patients the opportunity to learn more about our projects.