Non-motor Symptoms: Unraveling the "Invisible" Face of Parkinson's Disease
Posted July 14, 2015
Non-motor symptoms of Parkinson's disease (PD) include gastrointestinal complications, autonomic dysfunction, impaired sleep, depression, psychosis, and cognitive problems, from mild impairment to dementia. "Non-motor symptoms are as important as motor symptoms in Parkinson's disease," said Anna Sauerbier of King's College London in her clinical overview of the topic. In a 2014 study published in Movement Disorders, only 2.5% of Parkinson's patients reported no non-motor symptoms, and most experienced multiple symptoms simultaneously, averaging 8–13 per patient. These symptoms are invisible in the sense that they are often not outwardly apparent—unlike resting tremor, muscle stiffness, bradykinesia, and postural instability, the motor hallmarks of PD. Furthermore, because of under-reporting by patients and lack of awareness among clinicians, non-motor symptoms are sometimes invisible in the clinical setting, which can lead to misdiagnosis and insufficient treatment, as Olivier Rascol of the University of Toulouse explained. "The 'why' we are here is very simple—actually not simple, but very straightforward," said organizer Nathalie Breysse of Lundbeck Research. "The impact of non-motor symptoms on patient quality of life is key."
Non-motor symptoms of PD frequently manifest early in disease progression, even before the onset of motor complications and an official diagnosis. Speakers at the Biochemical Pharmacology Discussion Group's April 27, 2014, symposium Non-Motor Symptoms: Unraveling the "Invisible" Face of Parkinson's Disease probed this conundrum. Why do complications emerge throughout the body in a disease traditionally thought to arise from cell-autonomous lesions within the motor control regions of the brain? Are there systematic diagnostic protocols that can distinguish patients exhibiting early non-motor PD symptoms who will later progress to classical Parkinsonism? Are there holistic therapeutic options, or do motor and non-motor symptoms have to be treated in a piecemeal fashion? Several themes emerged in response to these questions, including a call for standardized and detailed diagnostic tools in the face of complicated symptomologies like cognitive impairment. The presentations pointed to a new, surprising hypothesis of disease progression, which if corroborated could lead to earlier diagnoses and more comprehensive treatment plans.
At the core of this new paradigm is a growing appreciation that a common molecular pathology underlies the appearance of both motor and non-motor symptoms of PD: over-accumulation of the protein α-synuclein, aggregates of which form structures within cells called Lewy bodies. In healthy cells this protein may help regulate the normal release of neurotransmitters in synaptic vesicles, but its pathological accumulation leads to reduced neurotransmission and cell death. Parkinsonism, the collection of motor symptoms that includes resting tremor, muscle stiffness, bradykinesia, and postural instability, results from the loss of dopaminergic neurons in the substantia nigra of the midbrain. Defining where α-synuclein accumulates outside the central nervous system, and even in other peripheral cell types, should thus predict many non-motor symptoms of PD.
Lewy bodies have been observed in central regulatory regions of the autonomic nervous system, such as the hypothalamus, which contains dopaminergic neurons, as well as peripherally in the sympathetic and parasympathetic branches and in the organs they target. Dysautonomia in PD can include irregularities in cardiovascular, respiratory, gastrointestinal, thermoregulatory, pupillary, and urogenital control. Horacio Kaufmann of the NYU Langone Medical Center reviewed these symptoms, focusing on the cardiovascular autonomic nervous system, which is of particular interest because up to 58% of Parkinson's patients experience orthostatic hypotension. Kaufmann explained that inadequate vasoconstriction upon standing arises from inadequate noradrenergic neurotransmission; at the molecular level, reduced norepinephrine signaling to blood vessels is analogous to reduced dopamine neurotransmission, which underlies motor dysfunction in PD. This analogy is also applicable at the therapeutic level, because treating orthostatic hypotension requires stimulating or mimicking neurotransmission. Severe orthostatic hypotension is treated with the artificial amino acid droxidopa, which is taken up by sympathetic neurons and metabolized to norepinephrine, but also made available by conversion to active hormone outside the nervous system. Approved by the FDA as Northera in 2014, this drug is the first new treatment for orthostatic hypotension in nearly 20 years.
Kaufmann offered a hypothesis of PD pathogenesis in which α-synuclein accumulation might arise first in the viscera or peripheral nervous system and only later spread to the central nervous system. "If the vagal highway is where synuclein is transported to the brain, then perhaps all we have to do is close that highway," Kaufmann suggested. Therapeutically, "closing the highway" could mean physically cutting the vagal or sympathetic nerves. Kaufmann observed that while vagotomies are no longer performed, the procedures were once routinely used as a treatment for peptic ulcers. "My prediction is that those patients who had vagotomies will have a decreased risk of developing Parkinson's disease," he concluded.
Patrik Brundin of the Van Andel Institute, co-editor in chief of the Journal of Parkinson's Disease, elaborated on the involvement of the gut and echoed the characterization of PD as a prion-like disease. In these diseases, the appearance of misfolded prion protein nucleates the misfolding of normal protein and its eventual accumulation into large plaques. It is unclear if the α-synuclein in Lewy bodies is misfolded or just aberrantly accumulated. Arguing that α-synuclein is indeed susceptible to prion-like spread, Brundin highlighted several studies in which healthy donor neuronal tissue transplanted to Parkinson's patients later exhibited Lewy body formation. Brundin also speculated that this spread could follow a specific path in the body: "The aggregates start in the gut. Could there be spread of the aggregates—the misfolded synuclein—from the gut, up through the nervous system, up to the nigra?"
Parkinson's patients often report experiencing constipation, and in one recent study up to 50% of individuals retrospectively reported difficult bowel movements in the years preceding diagnosis. Brundin questioned whether this high frequency of constipation in the prodromal, or premotor, phase of the disease is not merely an early symptom but might be a key step in pathogenesis. Chronic constipation can lead to colitis, and either this constant inflammation or a failure to expel particular toxins could precipitate α-synuclein accumulation in the enteric neurons wrapping the intestine and colon. Strikingly, in one study men were 4 times more likely to develop PD when reporting average bowel movements of less than 1 per day, compared to those reporting 2 per day, after 12 years of follow-up. Moreover, biopsied colonic tissue from patients later diagnosed with PD exhibited α-synuclein accumulation.
After years of thinking of PD primarily as a movement disorder and as autonomous to dopaminergic neurons, the idea that it develops as protein accumulates and spreads from peripheral tissue to the central nervous system is perhaps unexpected. Nonetheless, it explains long-standing puzzles, such as how toxins associated with PD that do not appear to cross the blood–brain barrier might play a role in disease development. The prion-like hypothesis also offers new potential strategies for treatment and prevention.
Marie-Françoise Chesselet of the University of California, Los Angeles, reviewed the history of rodent models of PD as well as more recent efforts to recapitulate the proposed prion-like model of pathogenesis suggested in the clinical literature. Early mouse models used toxins or genetic lesions specifically targeting the dopaminergic neurons, but the mice frequently failed to exhibit non-motor symptoms. Forced overproduction of α-synuclein, however, produced phenotypic changes in mice reminiscent of the complete symptomology of PD in humans. Chesselet's group has since used the Thy1 promoter, expressed in mature neurons and certain stem cells, to overexpress full-length human α-synuclein in mice. These mice develop Lewy bodies in neuronal populations and eventually lose dopaminergic neurons, leading to Parkinson's-like motor symptoms, but not before developing non-motor deficits, including disturbed sleep, olfaction problems, constipation, and cardiovascular irregularities. The Thy1-α-synuclein mice also show cognitive deficits. Eric Sweet, a postdoctoral researcher at the Icahn School of Medicine at Mount Sinai, discussed his research in another mouse model, with a PD-associated LRRK2 mutation. He uses the LRRK2 mouse model to study progressive changes in hippocampal electrophysiology that could inform drug trials targeting LRRK2 kinase.
Traditionally, nonhuman primates have been the model of choice to study cognitive impairment. Erwan Bezard of the University of Bordeaux reviewed the now 30-year history of studies using the parkinsonian toxin MPTP in these animals. This model was important in the early testing of levodopa, the dopaminergic agonist and current most effective treatment for motor symptoms. Continued investigation has shown that MPTP-treated rhesus macaques also exhibit abnormal neuronal α-synuclein buildup. With recent advances allowing for genetic manipulations in macaques, there may soon also be a nonhuman primate model of PD that tests the prion-like spread hypothesis.
Daniel Weintraub of the University of Pennsylvania emphasized that cognitive concerns in PD are paramount to patients and caregivers. Particularly as therapeutic advances improve the treatment of motor symptoms, cognitive impairment takes on greater prominence. One study showed nearly 80% of Parkinson's patients without cognitive impairment progressed to dementia within 8 years. Studies also reveal a greater incidence of mild cognitive impairment in earlier phases of the disease than previously appreciated, with memory impairment the most frequent symptom. Moreover, patients diagnosed earlier with mild cognitive impairment almost always progress to dementia. Loss of both dopaminergic and noradrenergic neuron populations underlies this cognitive decline, and neurotransmitter agonists remain important therapeutic possibilities. The effectiveness of the noradrenergic agonist droxidopa, for example, is currently under clinical investigation for the treatment of cognitive deficits in PD. One therapeutic conclusion that has emerged in this field is that deep brain stimulation, while it may provide some correction for dyskinesias, is associated with a mild acceleration of cognitive decline in patients who undergo surgery. Weintraub acknowledged that non-pharmacologic interventions including exercise regimens and other lifestyle adjustments might appeal to patients and could help maintain cognitive abilities.
Measuring cognitive acuity is inherently difficult, and the improvement and standardization of assessment tools will play a role in therapeutic advances. Weintraub suggested the diagnoses Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) probably represent a continuum with a common pathology. He argued that failing to recognize these diagnoses as the same disease "complicates advocacy and research, and it really limits treatment advances." Maurizio Facheris of the Michael J. Fox Foundation echoed this idea that PD needs to be approached as a progressive disease. From this perspective, tools for the early detection of aberrant α-synuclein accumulation could be a breakthrough. The identification of early disease biomarkers and the improvement of imaging techniques are among the foundation's 2015 priorities. Shirley Lasch described the Parkinson's Progression Markers Initiative (PPMI), a large observational trial to find biomarkers for clinical trials. In a prodromal cohort it has identified hyposmia and REM sleep behavior disorder (RBD) as markers of later progression to PD.
Advocating the patient perspective, Diane Cook of the Parkinson's Disease Foundation emphasized that PD symptoms are both variable and progressive. "The result is that each person with Parkinson's needs a complicated and ever-changing support system to maximize their quality of life at every stage of the disease," she said. Further studying non-motor symptoms in Parkinson's disease is key to providing diagnostic and therapeutic tools that can be used in these support systems.
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Presentations available from:
Erwan Bezard, PhD (University of Bordeaux, France)
Nathalie Breysse, PhD (Lundbeck Research USA)
Marie-Françoise Chesselet, MD, PhD (University of California, Los Angeles)
Diane Cook (Parkinson's Disease Foundation)
Maurizio Facheris, MD (The Michael J. Fox Foundation for Parkinson's Research)
Horacio Kaufmann, MD (NYU Langone Medical Center)
Shirley Lasch, MBA (Parkinson's Progression Markers Initiative)
Anna Sauerbier, MD (King's College London, UK)
Eric Sweet, PhD (Icahn School of Medicine at Mount Sinai)
Daniel Weintraub, MD (University of Pennsylvania)
The Biochemical Pharmacology Discussion Group is proudly supported by
Mission Partner support for the Frontiers of Science program provided by
How to cite this eBriefing
The New York Academy of Sciences. Non-motor Symptoms: Unraveling the "Invisible" Face of Parkinson's Disease. Academy eBriefings. 2015. Available at: www.nyas.org/ParkinsonsNMS-eB
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Chesselet MF, Richter F, Zhu C, et al. A progressive mouse model of Parkinson's disease: the Thy1-aSyn ("Line 61") mice. Neurotherapeutics. 2012;9(2):297-314.
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The Michael J. Fox Foundation for Parkinson's Research
A foundation dedicated to finding a cure for Parkinson's disease through an aggressively funded research agenda and to ensuring the development of improved therapies for those living with Parkinson's today.
Parkinson's Disease Foundation
A national nonprofit dedicated to Parkinson's disease research, education, and advocacy.
Parkinson's Progression Markers Initiative
An observational clinical study to evaluate cohorts of interest using advanced imaging, biologic sampling, and clinical and behavioral assessments to identify biomarkers of Parkinson's disease progression.
Nathalie Breysse, PhD
Lundbeck Research USA
Nathalie Breysse received her PhD at the University of Luminy, France. Her studies in neuroscience were related to the functional involvement of metabotropic glutamate receptors in the basal ganglia circuitry in normal and pathological conditions, particularly the potential of mGluR5 receptors as a therapeutic target in treating Parkinson's disease. She joined the Wallenberg Neuroscience Center in Sweden as postdoctoral fellow, focused on the use of cell and gene therapy in the treatment of Parkinson's disease. She has since worked in the pharmaceutical industry at NPS Pharmaceuticals, Wyeth/Pfizer, and Lundbeck, where she is now the global Parkinson's disease therapeutic biology lead. She is focused on drug discovery and development programs related to neuropsychiatric and neurodegenerative disorders.
Elena Dale, PhD
Lundbeck Research USA
Elena Dale received her PhD from New York University Medical School. Her graduate work focused on studying ensemble properties of neuronal activity in the cerebellum and thalamo-cortical systems using imaging and electrophysiology techniques. Dale completed postdoctoral training at Columbia University, where she investigated the role of posttranslational modifications in the regulation of synaptic plasticity. She joined Lundbeck Research USA in 2009, establishing 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
Sonya Dougal is the director of Life Sciences Discussion Groups at the New York Academy of Sciences. She develops an annual portfolio of scientific symposia on life sciences and biomedical research. Dougal has over 14 years of experience in scientific research and program management in academia, industry, and nonprofits. She holds a PhD in cognitive psychology from the University of Pittsburgh. She was the recipient of a Ruth L. Kirschstein National Research Service Award from the National Institutes of Health for her postdoctoral training as a cognitive neuroscientist in the laboratory of Dr. Elizabeth Phelps at New York University.
Erwan Bezard, PhD
Erwan Bezard is the director the Institute of Neurodegenerative Diseases at INSERM, France, and a visiting professor at the China Academy of Medical Sciences. His work focuses on the compensatory mechanisms that mask the progression of Parkinson's disease, the pathophysiology of levodopa-induced dyskinesia, and the mechanisms of neurodegeneration in synucleopathies. He serves on the boards of organizations including the Michael J. Fox Foundation and Parkinson's UK. He is an associate editor of Neurobiology of Disease and serves on the editorial boards of several other neurobiology journals. He also consults for several drug companies and is a non-executive director of Plenitudes Sarl, France, and chief scientific officer of Motac Neuroscience, UK.
Patrik Brundin, MD, PhD
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. He obtained his MD and PhD degrees at Lund University, Sweden, where he was a professor of neuroscience from 2000 to 2014. He was involved in some of the first clinical neural transplantation trials and has coordinated several multidisciplinary research networks specializing in Parkinson's research. He is an ISI highly cited scientist in his area. His current research focuses on the α-synuclein prion-like hypothesis, on drug repurposing, and on the development of disease-modifying therapies in Parkinson's disease. He is co-editor-in-chief of the Journal of Parkinson's Disease.
Marie-Françoise Chesselet, MD, PhD
Marie-Françoise Chesselet is the Charles H. Markham Professor of Neurology, a distinguished professor in the Departments of Neurology and Neurobiology, and interim chair of the Department of Neurology at UCLA. After receiving MD and PhD degrees in Paris, France, she held research positions in France and faculty positions at the Medical College of Pennsylvania and the University of Pennsylvania. She now directs the Integrative Center for Neural Repair at UCLA. Her laboratory researches the molecular mechanisms of disorders of the basal ganglia and new treatments for Parkinson's and Huntington's diseases. Chesselet is a fellow of the American Association for the Advancement of Science and currently chairs its section on neuroscience. She recently completed a 4-year term on the National Advisory Environmental Health Sciences Council.
Parkinson's Disease Foundation
Diane Cook is a management consultant focused on leadership development and training. Since being diagnosed with Parkinson's disease (PD) in 2008, she has been an active research advocate and member of the Parkinson's community, founding and facilitating support groups for over 175 newly diagnosed Parkinson's patients in the Denver area and pioneering 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. Cook serves on the advisory board of the University of Colorado Movement Disorders Center and on the People with Parkinson's Advisory Council of the Parkinson's Disease Foundation (PDF). She is also a patient representative to the FDA, recently elected to the steering committee of the Clinical Trials Transformation Initiative.
Maurizio Facheris, MD
Maurizio Facheris earned his MD from the University of Brescia, Italy, and completed specialization in neurology at the University of Milano-Bicocca, Italy. He holds a Master's degree in clinical research from the Mayo Clinic College of Medicine. Facheris previously worked as a consultant for the movement disorders outpatients' clinic at the Central Hospital of Bolzano, Italy, and as a senior researcher at the Center for Biomedicine at EURAC. He joined the Michael J. Fox Foundation for Parkinson's Research in 2011 as senior associate director for research programs, overseeing the symptomatic strategies area, the scientific program for the clinical portfolio, and the clinical activities related to LRRK2, a major genetic form of parkinsonism.
Horacio Kaufmann, MD
Horacio Kaufmann is a professor of neurology and medicine at New York University. He holds the Axelrod Chair for dysautonomia research and directs the Dysautonomia Center. Kaufmann received his MD from the National University of Buenos Aires, Argentina, and completed a neurology residency and fellowship at Mount Sinai School of Medicine. He is board certified in neurology and autonomic disorders. His research looks at the function of the autonomic nervous system and its abnormalities in neurological disorders. He has focused on pure autonomic failure as a synucleinopathy related to Parkinson's disease, the vestibular sympathetic reflex in humans, and 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. Kaufmann serves as editor-in-chief of Clinical Autonomic Research.
Shirley Lasch, MBA
Parkinson's Progression Markers Initiative
Shirley Lasch is a senior director of project management at the Institute for Neurodegenerative Disorders (IND) and at Molecular NeuroImaging, LLC, focusing on the identification of biomarkers for early detection, disease progression assessment, and treatment development for Parkinson's disease and other related neurodegenerative disorders. She has been global project manager of the Parkinson's Progression Marker Initiative (PPMI), a multicenter, longitudinal PD biomarker study, since 2010. She previously worked in the pharmaceutical industry at Bayer Healthcare Pharmaceuticals and Bristol-Myers Squibb Pharmaceutical Research Institute. She holds an MBA from Quinnipiac University.
Olivier Rascol, MD, PhD
Olivier Rascol is a professor of clinical pharmacology at the Toulouse University Hospital. He obtained his MD in neurology from Toulouse University and his PhD in neurosciences in Paris. Rascol has directed the Toulouse Clinical Investigation Center since 1994 and the Toulouse European Space Clinic since 1998. He also directs a Research Group on Motricity in the Research Unit INSERM U825 and coordinates the French Reference Center for Multiple System Atrophy (Atypical Parkinsonism). Rascol chairs the national network of 56 Clinical Investigation Centers in France and the NS-Park Neurosciences Network of the French CIC. He also coordinates the French Clinical Research Infrastructure Network, F-CRIN.
Anna Sauerbier, MD
Anna Sauerbier is a clinical research fellow at the National Parkinson Foundation International Centre of Excellence at King's College Hospital. She received her MD from the Justus-Liebig University in Germany. Her research interests are the non-motor aspects of movement disorders (clinical and imaging), with a focus on the effect of ethnicity on the expression of non-motor symptoms in Parkinson's disease. She is currently working on her PhD 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), and a coordinator of the IPMDS Non-Motor PD Study Group.
Eric Sweet, PhD
Icahn School of Medicine at Mount Sinai
Eric Sweet is a postdoctoral fellow in the laboratories of Drs. Zhenyu Yue and Robert Blitzer at the Icahn School of Medicine at Mount Sinai. 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. He is using BAC transgenic mice to study the role of LRRK2 in the hippocampus and how LRRK2 affects neuronal function.
Daniel Weintraub, MD
Daniel Weintraub is an associate professor of psychiatry and neurology at the University of Pennsylvania and a 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 and Alzheimer's diseases. He completed a National Institute of Mental Health Career Development Award related to depression in Parkinson's disease and has been a principal investigator on grants from the Department of Veterans Affairs, the Institute of Aging at the University of Pennsylvania, and the Fox Foundation for Parkinson's Research. He has also worked on several industry-sponsored studies and on the clinical core of the Penn Udall Center, focused on cognitive impairment in PD. His research has focused on the epidemiology, neural substrate, assessment, and treatment of depression, psychosis, cognitive impairment, and impulse control disorders in PD. He is an associate editor of Movement Disorders.
Paul Riccio is a postdoctoral research scientist at Columbia University. He has a broad interest in the genetic regulation of development and is currently using new genetic techniques to study kidney patterning and regeneration.
The Biochemical Pharmacology Discussion Group is proudly supported by
Mission Partner support for the Frontiers of Science program provided by
This program was supported in part by a grant from Biogen.
The educational portion of this Program was supported, in part, by an independent educational grant from AstraZeneca.