Non-Motor Symptoms: Unraveling the "Invisible" Face of Parkinson’s Disease

Non-Motor Symptoms: Unraveling the "Invisible" Face of Parkinson’s Disease

Monday, April 27, 2015

The New York Academy of Sciences

Presented By

 

Non-motor symptoms of Parkinson's disease cause suffering in a significant number of patients and represent a critical unmet need that has not yet been adequately addressed. Non-motor symptoms include cognitive problems, mood disorders, psychosis, depression, dementia, sleep disturbances, pain, hyposmia, and autonomic dysfunction. Speakers in this symposium will review clinical tools for the diagnosis and treatment of these symptoms, discuss their underlying neurobiological basis, and address current and emerging preclinical models available for the development of new therapies.

*Reception to follow.

This event will also be broadcast as a webinar.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City when possible.

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The Biochemical Pharmacology Discussion Group is proudly supported by


  • Merck
  • WilmerHale

Mission Partner support for the Frontiers of Science program provided by Pfizer

Agenda

* Presentation titles and times are subject to change.


April 27, 2015

8:30 AM

Registration and Continental Breakfast

9:00 AM

Introductory Remarks
Sonya Dougal, PhD, New York Academy of Sciences
Nathalie Breysse, PhD, Lundbeck Research

9:15 AM

Living with the Hidden Parkinson's
Diane G. Cook, Parkinson's Disease Foundation

9:35 AM

Losing Autonomy: The Dark Side of Parkinson's Disease
Maurizio Facheris, MD, The Michael J. Fox Foundation for Parkinson's Research

10:05 AM

Non-Motor Symptoms in Parkinson’s Disease: Spectrum Complexity, Frequency and Clinical Scales for Assessment
Anna Sauerbier, MD, NPF International Centre of Excellence, Kings College London

10:35 AM

Autonomic Dysfunction in Parkinson Disease
Horacio Kaufmann, MD, NYU Langone Medical Center

11:05 AM

Networking Coffee Break

11:35 AM

Cognitive Impairment in Parkinson’s Disease
Daniel Weintraub, MD, University of Pennsylvania

12:05 PM

Management of Non-motor Symptoms in Parkinson Disease
Olivier Rascol, MD, PhD, University of Toulouse

12:40 PM

Networking Lunch Break and Poster Session

2:00 PM *

Do We Need More "Guts" in Parkinson’s Disease Research?
Patrik Brundin, MD, PhD, Van Andel Institute

* The 2:00 pm talk will not be broadcast as part of the live webinar.

2:30 PM

Animal Models of Non-Motor Deficits in Parkinson’s disease
Marie-Francoise Chesselet, MD, PhD, UCLA

3:00 PM

Networking Coffee Break

3:30 PM

Overview of Non-motor Symptoms in Non-human Primate Models of Parkinson's Disease
Erwan Bezard, PhD, University of Bordeaux

4:00 PM

Parkinson’s Progression Markers Initiative (PPMI) Prodromal Cohort of REM Behavior Disorder (RBD) with DAT Deficit
Shirley Lasch, MBA, The Parkinson’s Progression Markers Initiative (PPMI)

4:20 PM

The Parkinson’s Disease Associated Mutation LRRK2-G2019S Impairs Synaptic Plasticity in the Mouse Hippocampus
Eric Sweet, PhD, Icahn School of Medicine at Mount Sinai

4:40 PM

Closing Remarks
Nathalie Breysse, PhD, Lundbeck Research

4:45 PM

Networking Reception

5:45 PM

Adjourn

Speakers

Organizers

Nathalie Breysse, PhD

Lundbeck Research, USA

Nathalie Breysse is a Neuroscientist who received her PhD in France at University of Luminy. Her studies were related to the functional involvement of metabotropic glutamate receptors within the basal ganglia circuitry in normal and pathological conditions. Nathalie’s original research gave rise to manuscripts on the potential of mGluR5 receptors as a therapeutic target in treating Parkinson’s disease. Nathalie then joined the Wallenberg Neuroscience Center (Lund, Sweden) as post-doctoral fellow under Prof. Anders Bjorklund’s mentorship. The work conducted was focused on the use of cell- and gene therapy in the treatment of Parkinson’s disease. In the last ten years, Nathalie has worked in the pharmaceutical industry, NPS Pharmaceuticals (Canada), Wyeth/Pfizer (USA) and Lundbeck (USA and Denmark), in drug discovery and development programs related to neuropsychiatric as well as neurodegenerative disorders. Nathalie’s is currently global Parkinson’s Disease therapeutic biology lead at Lundbeck.

Elena Dale, PhD

Lundbeck Research, USA

Elena Dale received her PhD from New York University Medical School under the supervision of Dr. Rodolfo Llinas. Her graduate work focused on studying ensemble properties of neuronal activity in the cerebellum and thalamo-cortical systems using imaging and electrophysiology techniques. After completing her PhD, Elena did postdoctoral training in the laboratory of Dr. Ottavio Arancio at Columbia University where she investigated the role of post-translational modifications in the regulation of synaptic plasticity. Elena joined Lundbeck Research USA in 2009 where she established an in vitro electrophysiology laboratory. She is currently a Senior Research Scientist working on several drug discovery projects related to depression, pain and Parkinson’s Disease.

Sonya Dougal, PhD

The New York Academy of Sciences

Speakers

Erwan Bezard, PhD

University of Bordeaux

Bezard, INSERM Research Director, has authored or co-authored over 195 professional publications in the field of neurobiology, most of which are on Parkinson's disease and related disorders. Listed in the Top 1% of the most cited neuroscientists (H factor=47; Source: Scopus), he is known for his work (i) on the compensatory mechanisms that mask the progression of Parkinson's disease, (ii) on the pathophysiology of levodopa-induced dyskinesia and (iii) on the mechanisms of neurodegeneration in synucleopathies. His current research interests include the study of the levodopa-induced dyskinesia, the intimate mechanisms of cell death in Parkinson’s disease, the modelling of disease progression and the development of new strategies to alleviate symptoms and/or to slow disease progression. Bezard is the director of a CNRS research unit located in Bordeaux, the Institute of Neurodegenerative Diseases, which features preclinical and clinical researchers working towards development of therapeutic solutions. He is also a Visiting Professor at the China Academy of Medical Sciences (Beijing, China) where he has set-up and manages a non-human primate facility dedicated to Movement Disorders. He serves on the board of international organizations such as the Michael J. Fox Foundation and Parkinson’s UK. He is Associate Editor of Neurobiology of Disease, a leading journal in the field. He serves on the editorial boards of several other neurobiology journals. Besides consulting for several drug companies in the field of movement disorders, he is a non-executive director of Plenitudes Sarl (France) and Chief Scientific Officer of Motac Neuroscience (UK).

Patrik Brundin, MD, PhD

Van Andel Institute

Since 2012, Dr. Patrik Brundin is the Director of the Center for Neurodegenerative Science and the inaugural holder of the Jay Van Andel Endowed Chair in Parkinson Research at the Van Andel Research Institute, Grand Rapids, Michigan, USA. Dr. Brundin is an internationally renowned expert in the field of Parkinson’s and neurodegenerative disease research with a career in this area that spans over 30 years, including key involvement in some of the first clinical neural transplantation trials. He obtained his M.D. (1992) and Ph.D. (1988) at Lund University in Sweden where he was Professor of Neuroscience in 2000-2014. He has published over 300 papers, coordinated several multidisciplinary research networks specializing in Parkinson’s research and was identified as a ISI Highly Cited Scientist in his area. His main current research interests are the alpha-synuclein prion-like hypothesis, drug repurposing and development of disease-modifying therapies in Parkinson's disease. He is co-Editor-in-chief of the Journal of Parkinson’s Disease.

Marie-Francoise Chesselet, MD, PhD

UCLA

Marie-Françoise Chesselet is the Charles H. Markham Professor of Neurology, Distinguished Professor in the Departments of Neurology and Neurobiology, and Interim Chair of the Department of Neurology at UCLA. After receiving the M.D. and Ph.D. degrees in Paris, France, she held research positions in France and faculty positions at the Medical College of Pennsylvania and the University of Pennsylvania, before joining UCLA in 1996. At UCLA, Dr. Chesselet chaired the Department of Neurobiology from 2002 to 2013 and is currently the Director of the Integrative Center for Neural Repair, which includes the Center for the Study of Parkinson’s Disease at UCLA she created in 1998. She has directed the NINDS-funded UCLA UDALL Center for Parkinson’s disease research from 1998 to 2013, the NIEHS-funded UCLA Center for Gene Environment in Parkinson’s Disease from 2002 to 2014, and the UCLA Advanced Center for Parkinson’s Disease Research of the American Parkinson Disease Association since 1998. Dr. Chesselet has directed graduate programs at the University of Pennsylvania and UCLA and has directed the NINDS-funded Training Program in Neural Repair from 1998 to 2014. Her laboratory conducts research on the molecular mechanisms of disorders of the basal ganglia and new treatments for Parkinson’s and Huntington’s diseases. Her work has been extensively supported by the NIH, the Michael J. Fox Foundation, Cure HD Initiative, and several bio pharmaceutical companies. She currently holds grants from the Department of Defense, CIRM, and Tsumura Inc. Dr. Chesselet is a Fellow of the American Association for the Advancement of Science and currently chairs its section on Neuroscience. She just completed a 4 years term on the National Advisory Environmental Health Sciences Council.

Diane G. Cook

Parkinson's Disease Foundation

Diane Cook is a management consultant and community leaders who focuses on leadership development and training.  Since being diagnosed with Parkinson’s disease (PD) in 2008, Diane has been an active member of the local, national and international Parkinson’s community. She has founded and facilitated 4 support groups for over 175 newly diagnosed Parkinson’s patients in the Denver area and has pioneered the application of self-efficacy skills to Parkinson’s disease management, in part as the result of a research study sponsored by the Colorado Neurological Institute. Diane serves on the Advisory Board of the University of Colorado Movement Disorders Center, on the People with Parkinson’s Advisory Council of the Parkinson’s Disease Foundation (PDF) and as an active Research Advocate.  Diane is also a Patient Representative to the FDA and has just been elected to the Steering Committee of the Clinical Trials Transformation Initiative.

Maurizio Facheris, MD

The Michael J. Fox Foundation for Parkinson's Research

Maurizio Facheris earned his Medical Degree from the University of Brescia, Italy and his specialization in Neurology from the University of Milano-Bicocca, Milano, Italy. His thesis work focused on the role of lipid peroxidation and oxidative stress in neurodegenerative disorders. He then completed a master’s degree in Clinical Research at the Mayo Clinic College of Medicine in Rochester, MN, deepening his knowledge in the genetic epidemiology of Parkinson’s disease. Upon returning to Italy, Dr. Facheris worked both as a consultant for the movement disorders outpatients’ clinic at the Central Hospital of Bolzano, Italy, and as senior researcher at the Center for Biomedicine at EURAC, Bolzano, Italy, where he was in charge of the scientific coordination of a broad population-based prospective epidemiological study. Through his work both at the hospital and the research institute, Dr. Facheris earned a broad understanding of all aspects of clinical research. Dr. Facheris joined the Michael J. fox Foundation for Parkinson’s Research in 2011 as. As Senior Associate Director, Research Programs, Maurizio stays closely linked to the Parkinson's research community in order to develop an aggressive and innovative agenda for accelerating research and drug development for Parkinson's disease. Regularly meeting with academic and industry researchers around the world to identify promising proposals to support, providing troubleshooting and ongoing management of projects as they go forward, Dr. Facheris oversees the symptomatic strategies at the Foundation, the scientific program for the clinical portfolio, and the clinical activities related to LRRK2, a major genetic form of parkinsonism.

Horacio Kaufmann, MD

NYU Langone Medical Center

Horacio Kaufmann, MD is Professor of Neurology and Medicine at New York University. He holds the Axelrod Chair for dysautonomia research and directs the Dysautonomia Center. Dr. Kaufmann received his medical degree from the National University of Buenos Aires in Argentina. He completed his Neurology residency and fellowship at Mount Sinai School of Medicine in New York. He is board certified in neurology and autonomic disorders. His research has focused on the function of the autonomic nervous system and its abnormalities in neurological disorders. He has been funded by the National Aeronautics and Space Administration (NASA), the National Institute of Health, the US Food and Drug Administration (FDA), the Dana Foundation and the Dysautonomia Foundation, Inc.  Dr. Kaufmann published the first complete autopsy findings in patients with pure autonomic failure, establishing this disorder as a synucleinopathy related to Parkinson disease. He described the vestibular sympathetic reflex in humans as a feed forward mechanism that helps maintain blood pressure during movement. Recently, he defined the autonomic phenotype of Riley Day syndrome as a developmental disorder of the afferent neurons of the baroreceptor reflex. He was the principal investigator in the largest multinational clinical trials using norepinephrine precursor therapy as a treatment for neurogenic orthostatic hypotension. Dr. Kaufmann serves as the Editor-in-Chief of Clinical Autonomic Research. He lives in New York City with his wife, Lucy and his children, George, age 8, and Dolores, age 4.

Shirley Lasch, MBA

The Parkinson’s Progression Markers Initiative (PPMI)

Shirley Lasch is a Senior Director of Project Management at the Institute for Neurodegenerative Disorders (IND); Molecular NeuroImaging, LLC (MNI) located in New Haven CT. Shirley is responsible for managing multiple studies focused on the identification of biomarkers for early detection, the assessment of disease progression and the development of new treatments for Parkinson disease and other related neurodegenerative disorders. As Global Project Manager of the Parkinson’s Progression Marker Initiative (PPMI) since 2010, Shirley has closely supported the leadership in the implantation of this multicenter, longitudinal PD biomarker study. Prior to joining IND and MNI Shirley worked in the pharmaceutical industry at Bayer Healthcare Pharmaceuticals as well as the Bristol-Myers Squibb Pharmaceutical Research Institute in the area of drug discovery, and translational medicine. Severing in several roles including Research Investigator, Shirley has proposed, launched and managed numerous research projects. Regarding Educational background, Shirley has received her MBA from Quinnipiac University after earning her Bachelor of Science in biology from Eastern Connecticut State University.

Olivier Rascol, MD, PhD

University of Toulouse

Doctor Olivier Rascol is Professor of Clinical Pharmacology at the Toulouse University Hospital since 1993. He obtained his MD in Neurology (Toulouse, 1985) and his PhD in Neurosciences (Paris, 1992). Dr Rascol is running the Toulouse Clinical Investigation Centre since 1994 and the Toulouse European Space Clinic since 1998. He is also running a Research Group on Motricity in the Research Unit INSERM U825 and is the coordinator of the French Reference Center for Multiple System Atrophy (Atypical Parkinsonism). Dr Rascol is the chair of the national network of the 56 French Clinical Investigation Centers since 2008 and the chair of the NS-Park Neurosciences Network of the French CIC since 2010. From 2011, Dr Rascol is now coordinating the National French Clinical Research Infrastructure Network F-CRIN.

Anna Sauerbier, MD

NPF International Centre of Excellence, Kings College London

Dr. Anna Sauerbier is a clinical research fellow at the National Parkinson Foundation  International Centre of Excellence, King’s College Hospital, London having received her medical degree from the Justus-Liebig University in Gießen, Germany. Her research interests are the non- motor aspects of movement disorders (clinical and imaging), with a focus on the impact of ethnicity on the expression of non-motor symptoms in Parkinson’s disease. She has published several peer-reviewed papers and book chapters and has presented at international meetings. She is currently working on her PhD project titled: “Range and nature of non-motor symptoms in people with Parkinson's: exploring possible ethnic differences between white Caucasian, black African/Caribbean and South Asian population in London, UK.” at King’s College London. She is the treasurer of the European Association of Young Neurologists and Trainees (EAYNT), an associate member of the International Parkinson and Movement Disorder Society (IPMDS) as well as one of the coordinators of the IPMDS Non-Motor PD Study Group (NM-PD-SG).

Eric Sweet, PhD

Icahn School of Medicine at Mount Sinai

Eric Sweet is a Postdocotoral Fellow in the labs of Dr. Zhenyu Yue and Dr. Robert Blitzer. He obtained his PhD from Rutgers University studying the role of large scaffolding proteins in dendrite branching. He is interested in exploring the changes in cellular function that occur in the non-motor areas of the brain during the progression of Parkinson’s disease. At Mount Sinai his work focuses on the role of LRRK2 in the hippocampus and its impact on neuronal function using BAC transgenic mice.

Daniel Weintraub, MD

University of Pennsylvania

Dr. Weintraub is Associate Professor of Psychiatry and Neurology at the University of Pennsylvania and Psychiatrist at the Parkinson’s Disease Research, Education and Clinical Center (PADRECC) at the Philadelphia Veterans Affairs Medical Center.  A board-certified geriatric psychiatrist, he conducts clinical research in the psychiatric and cognitive complications of Parkinson’s disease (PD) and Alzheimer's disease.  He completed a NIMH Career Development Award related to depression in Parkinson’s disease, and has also been Principal Investigator on grants from the VA, the Institute of Aging at Penn, the Fox Foundation for Parkinson’s Research, and several industry-sponsored studies, as well as Principal Investigator on the Clinical Core of the Penn Udall Center focused on cognitive impairment in PD.  His research has primarily focused on the epidemiology, neural substrate, assessment and treatment of depression, psychosis, cognitive impairment and impulse control disorders in PD.  He also is Associate Editor of Movement Disorders Journal.

Sponsors

For sponsorship opportunities please contact Perri Wisotsky at pwisotsky@nyas.org or 212.298.8642.

Grant Support

This program is supported in part by a grant from Biogen.

The educational portion of this Program is supported, in part, by an independent educational grant from AstraZeneca.

Speaker Sponsorship

Travel for Marie-Francoise Chesselet, MD, PhD, David Geffen School of Medicine at UCLA, is supported in part by a sponsorship from Charles River.

Promotional Partners

ALZForum

American Federation for Aging Research (AFAR)

College of Staten Island

The Dana Foundation

Elsevier

GTCBio

Journal of Alzheimer's Disease

The Michael J. Fox Foundation

Nature

New York Local Section of the American Chemical Society

Parkinson's Disease Foundation

Parkinson's Unity Walk


The Biochemical Pharmacology Discussion Group is proudly supported by

 

  • Merck
  • WilmerHale

Mission Partner support for the Frontiers of Science program provided by Pfizer

Abstracts

Losing Autonomy: The Dark Side of Parkinson’s Disease
Maurizio F. Facheris, MD, MSc, The Michael J. Fox Foundation for Parkinson’s Research

Parkinson’s disease (PD) remains to date a “movement disorder”. Many doctors rely only on motor symptoms to diagnose and therapeutically manage PD, neglecting nonmotor or non-dopaminergic responsive symptoms such as constipation, orthostatic hypotension, depression, pain, apathy, fatigue, sleep problems, sexual, and bladder problems. Nonmotor symptoms (NMS) can emerge in patients who may have very early motor PD or sometimes even before they show any cardinal sign of motor PD. NMS can also become prevalent in subjects with optimal control of motor symptoms. In all the above cases everyday activities can be severely impacted, ultimately reducing overall quality of life. The etiology and pathophysiology of NMS in PD have not been completely unveiled, despite the availability of preclinical models. Prevalence and severity of NMS varies based on the source of information: neurologists and even movement disorders specialists tend to underestimate the impact of NMS on PD patients; conversely several patients don’t recognize those symptoms being related to PD and omit to speak about them with their health provider. Researchers have proposed to assess and stage NMS as part of the standard neurological visit and have suggested including them in decisions for proper care and treatment. Scales have been developed and proposed but somehow remain largely unused or undervalued. The Michael J. Fox Foundation continues to seek solutions to these questions and help solve remaining unmet needs.
 

Non-Motor Symptoms in Parkinson’s Disease: Spectrum Complexity, Frequency and Clinical Scales for Assessment
Anna Sauerbier, National Parkinson Foundation International Centre of Excellence, King’s College London and Kings College Hospital NHS Foundation Trust, London, United Kingdom

Non-motor symptoms (NMS) have emerged as a key feature of Parkinson’s disease (PD), from the pre-motor phase of PD as a potential clinical biomarker, to the advanced stages of the disease, causing complications that lead to hospitalisations and substantially increased costs of care. NMS pose one of the greatest challenges in the management of PD. Recognition of the prevalence of NMS and their significant burden on the patient’s quality of life has led to the development of validated tools such as the Non-Motor Symptoms Scale (NMSS) and the Non-Motor Symptoms Questionnaire (NMSQuest) which now allow better assessment of NMS. Despite the unmet need in NMS as recognized by the UK National Institute for Clinical Excellence, they continue to be regarded as peripheral concerns compared to the motor symptomatology of PD.1,2 This session aims to provide an introduction to the concepts, clinical issues and evidence pertaining to a holistic assessment of NMS in PD. In particular, definitions of non-motor Parkinson’s and new methods of grading the non-motor burden of PD, the non-motor symptom burden (NMSB) classification will be addressed in this session.2-4
 
Coauthor: K Ray Chaudhuri, National Parkinson Foundation International Centre of Excellence, King’s College London and Kings College Hospital NHS Foundation Trust, London, United Kingdom
 
References:
1 Chaudhuri and Schapira. Lancet Neurology. 2009;8:464-474
2 Chaudhuri KR, Sauerbier A, Rojo JM et al. Parkinsonism Relat Disord. 2015;21:287-91
3 Sauerbier A and Ray Chaudhuri Br J Hosp Med (Lond). 2014;75:18-24
4 Ray Chaudhuri K, Rojo JM, Schapira AH et al. PloS one. 2013;8:1-7.
 

Autonomic Dysfunction in Parkinson Disease
Horacio Kaufmann, MD FAAN, New York University School of Medicine

Parkinson disease (PD) not only affects catecholaminergic neurons in the CNS but also peripheral autonomic neurons. Abnormal intracellular deposits of alpha-synuclein and degeneration of sympathetic and enteric fibers impairs cardiovascular, gastrointestinal, bladder and sexual function. The severity of autonomic symptoms in PD patients varies markedly. There is converging evidence to indicate that a “peripheral” autonomic/ enteric neuropathy stage precedes the classic motor deficits – sometimes for many years. Data in experimental animal models show that both afferent vagal and sympathetic fibers transport abnormal synuclein from gut and heart to the CNS, strengthening the hypothesis of a triggering event outside the brain that sets off the neurodegeneration cycle. In many patients with PD, degeneration of post-ganglionic sympathetic neurons results in a deficiency in norepinephrine release. This causes neurogenic orthostatic hypotension (nOH), a postural drop in blood pressure with sometimes disabling symptoms of cerebral hypoperfusion. The orally active artificial amino-acid L-threo-dihydroxyphenylserine (droxidopa) is a norepinephrine precursor that improves symptomatic nOH by raising blood pressure. The pharmacological strategy is similar to dopamine replacement with levodopa, and both precursor drugs are converted into biologically active catecholamines by the ubiquitously expressed enzyme dopa-decarboxylase. High doses of carbidopa, a peripheral dopa-decarboxylase inhibitor, block the pressor effect of droxidopa, but enhances its CNS penetration. Recent phase 3 clinical trials led to the approval of droxidopa for the treatment of nOH in the US. Combining droxidopa with inhibitors of other enzymes/transporters involved in catecholamine metabolism, as has been tried with levodopa, is an attractive potential therapeutic strategy to explore. 
 

Cognitive Impairment in Parkinson’s Disease
Daniel Weintraub, MD1,2
1 Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States
2 Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania, United States

Significant advances in our understanding of the epidemiology of cognitive impairment in Parkinson’s disease (PD) have been recognition that: (1) impairments occur in a range of cognitive domains; (2) dementia (PDD) is common, affecting up to 80% of patients; and (3) approximately 25% of non-demented patients have mild cognitive impairment (PD-MCI). Some of the emerging conclusions to be drawn from this recent neurobiological research include: (1) diffuse subcortical Lewy body disease pathology appears to be the major contributing pathology to cognitive decline in PD; (2) in addition, a significant percentage of PD patients also have Alzheimer’s-related neuropathological changes; (3) a range of neurotransmitter deficits are associated with cognitive impairment; (4) impairments in the cortico-striatal neural circuitry likely contribute to cognitive impairment; (5) a range of genetic influences for specific cognitive impairments or decline have been identified; and (6) diffuse gray and white matter neurodegeneration and metabolic deficits are associated with cognitive decline. A major step forward has been recently proposed clinical criteria for the diagnosis of PDD and PD-MCI. In parallel work, several cognitive assessment instruments for different purposes have now been validated for use in PD. The need for improved treatments remain a huge unmet need, as only one large positive controlled cholinesterase inhibitor study in PDD has been published, and two recent controlled memantine studies that included PDD patients were inconclusive or negative.
 

Management of Non-motor Symptoms in Parkinson Disease
Olivier Rascol, MD, PhD, University of Toulouse, France

Non-motor parkinsonian symptoms (NMPS) are common in Parkinson disease (PD), including autonomic dysfunction, pain, cognitive impairment, psychiatric problems, sleep abnormalities and others. They significantly impair patient’s quality of life. Unfortunately, the importance of their management is under-estimated by most physicians and clinical practice relies on empirical experience supported by poor evidence. There are many reasons for such a situation. Pathophysiological mechanisms are poorly understood and convincing therapeutic targets are often lacking. Animal models have been rarely used and preclinical data are scarce. Many NMPS are heterogeneous, with controversial classifications and inconsistent definitions. Most NMPS fluctuate like or with motor symptoms, and the clinical importance of this phenomenon remains unclear. Some NMPS respond, at least partly, to dopaminergic medications while other can worsen. Several NMPS often coexisting in the same patient, a strategy aiming at improving a given one can thus worsen another. It is intuitively assumed that nondopaminergic treatments should improve NMPS, on the model of what has been shown in non-PD populations. However, this has not been tested specifically in PD, both regarding efficacy and safety. Randomized placebo-controlled trials are dramatically lacking in this field. Properly validated clinical scales are to be developed, and if an effect is observed, its clinical importance should be defined. The growing interest into non- motor symptoms in PD is improving patients’ and physicians’ awareness. We now need to increase the number and quality of trials assessing pharmacological and non- pharmacological interventions to improve this major aspect of the care of PD patients.
 

Do We Need More Guts in Parkinson’s Disease Research?
Patrik Brundin, MD, PhD, Laboratory of Translational Parkinson’s Disease Research, Center for Neurodegenerative Science, Van Andel Research Institute

Dr. Brundin will review emerging evidence that the gut is important in Parkinson’s disease (PD). Although PD traditionally was viewed as primarily a movement disorder, recent research shows that the gut might play a crucial role. First, it is clear the constipation is a common and troubling non-motor symptom in PD and that it frequently precedes the onset of the movement disorder by several years. Second, several studies indicate that enteric nerves exhibit alpha-synuclein aggregates in PD and the suggestion has been made that they even develop before motor symptoms are apparent. While these observations first need to be reproduced in large patient cohorts, it has been speculated that biopsies from the gastrointestinal tract might be used to predict who is at increased risk of PD. The idea that the gastrointestinal tract is affected early in the disease is in part based on the notion that synucleinopathy in PD progresses according to the Braak stages. Adding the concept that alpha-synuclein can spread from one neuron to another in a prion-like manner, the model proposes that alpha-synuclein aggregates propagate from enteric nerves to the dorsal motor nucleus of the vagal nerve and thereafter on to other brain regions. Third, inflammation in the gastrointestinal has tentatively been proposed as a possible trigger of alpha-synuclein aggregation. In this context, it is particularly interesting to consider recent reports that PD patients exhibit alterations in the gut microbiome, and that environmental risk modifiers such as coffee and smoking both are known to modify the intestinal flora.
 

Animal Models of Non-Motor Deficits in Parkinson’s Disease
Marie-Francoise Chesselet, MD, PhD, UCLA

The emergence of many non-motor deficits associated with Parkinson’s disease (PD) before the onset of motor deficits and their poor response to dopaminergic agents raises the strong possibility that they are at least in part mediated by mechanisms independent from nigrostriatal degeneration. Indeed, the discovery of widespread alpha-synuclein pathology in brain regions mediating functions that are altered early in PD suggests a link between this pathology and non-motor deficits. We tested this hypothesis directly by examining non-motor behaviors in mice that over-express human wildtype alpha-synuclein under the Thy1 promoter (Thy1-aSyn mice). These mice have proteinase K-resistant aggregates of alpha-synuclein in brain regions and show loss of striatal dopamine and hypokinesia at older ages. This model shows robust deficits in olfaction, gut and cardiac function, cognition, EEG pattern, and sleep many months before the onset of dopamine loss, supporting a role of alpha-synuclein in non-motor deficits in PD. However, a more thorough examination of models in which a selective loss of dopamine is induced by toxins has recently revealed that nigrostriatal dopamine may also contribute to these deficits. Overall, several animal models of non-motor deficits associated with PD are now available, thus providing translatable end-points for studies of novel therapeutic strategies for PD.
 

Overview of Non-motor Symptoms in Non-human Primate Models of Parkinson’s Disease
Erwan Bezard, PhD, Institute of Neurodegenerative Diseases, University of Bordeaux

Aside from motor symptoms, Parkinson’s disease is associated with a number of non-motor symptoms, some of them arising many years before motor signs. Modeling those symptoms into experimental models is key for (i) our understanding of their pathophysiology, (ii) for the subsequent therapeutic target identification and (iii) for the preclinical proof of concept demonstration of efficacy of a therapeutic strategy. In that context, the speaker will review the non-human primate models of parkinsonian non-motor symptoms. The most investigated non-motor symptoms include cognitive impairment, diurnal sleepiness, REM sleep behaviour disorder (RBD), gastro-intestinal dysfunction, orthostatic hypotension. Gait issues will also be covered. Finally, recent developments in Parkinson’s disease modeling in non-human primates such as prion-like models and transgenesis will be covered. Emphasis will be put upon the translational nature of the investigational endpoints that are in these primate species exactly the same than in Parkinson’s disease patients.
 

Parkinson’s Progression Markers Initiative (PPMI) Prodromal Cohort of REM Behavior Disorder (RBD) with DAT Deficit
Shirley Lasch, MBA, The Parkinson’s Progression Markers Initiative (PPMI)

A cohort of prodromal subjects, with REM behavior disorder (RBD) and a dopamine transporter (DAT) binding deficit where enrolled within the Parkinson’s Progression Markers Initiative (PPMI) to examine progression biomarkers during prodromal PD and establish the time course for phenoconversion to motor Parkinson’s Disease (PD). PPMI is longitudinal study to identify clinical, imaging and biospecimen biomarkers of PD onset and progression. PPMI has established standardized methods of acquisition and analysis of biomarker data in a multi-center study. PPMI sites with a collaborative relationship with a local sleep centers recruited patients with polysomnograms (PSG) from recent sleep studies. Patients with evidence for RBD based on their PSG as determined by REM sleep without atonia (RSWA), using the Montplaisir 2010 or Frauscher 2012 criteria assessed by a central reading lab and who also had a DAT deficit (compared to healthy subjects) as determined by the PPMI imaging core lab using standardized visual and quantitative outcomes were enrolled and will be assessed longitudinally on a schedule similar to existing PPMI cohorts. To date 115 RBD subjects with PSGs where recruited, 97(84%) met evidence of RBD by central reading lab 16(14%) did not meet criteria (2/1.8% not readable). DaTSCAN imaging was completed on 82(65%) subjects with 41(50%) meeting criteria of DAT deficit. Longitudinal follow-up is on-going. PPMI has established the feasibility of utilizing a central PSG read as eligibility criteria for a multi-center PD prodromal RBD cohort.  Continued follow-up of this cohort is required to understand the prodromal PD biomarker signature for RBD subjects.
 

The Parkinson’s Disease Associated Mutation LRRK2-G2019S Impairs Synaptic Plasticity in the Mouse Hippocampus
Eric Sweet, PhD, Icahn School of Medicine at Mount Sinai

Parkinson’s disease (PD) is a major movement disorder characterized pathologically by the loss of the dopamine neurons and formation of Lewy bodies. In addition to motor abnormalities, PD patients display a variety of non-motor symptoms, including executive function and memory loss. These non-motor symptoms are not treated well by current dopamine replacement or brain stimulation therapies. In order to explore the mechanisms that produce these symptoms we used a BAC transgenic mouse model of the PARK8 gene encoding leucine-rich repeat kinase (LRRK2). Mutations in the LRRK2 gene are the most common genetic factors associated with PD; among these mutations is G2019S, which increases LRRK2 kinase activity. LRRK2 is highly expressed in brain regions that are involved with non-motor functions, including the frontal cortex and the hippocampus, and thus is likely to play a role in non-motor PD symptoms. We used electrophysiological method to study the pathogenic role that the LRRK2 G2019S mutation, associated with increased kinase activity, plays in Schaffer collateral-CA1 synapse of the dorsal hippocampus. In field and whole-cell patch recordings, we studied basal synaptic function and synaptically-induced forms of plasticity, including PPF, LTP and LTD. Our results show that an increase in kinase activity due to the LRRK2-G2019S mutation is associated with altered short- and long-term changes in synaptic function. We conclude that LRRK2 may play a role in normal hippocampal function and in some of the non-motor deficits seen in PD.
 

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