Non-motor Symptoms: Unraveling the "Invisible" Face of Parkinson's Disease

Overview

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.

The spectrum of non-motor symptoms in Parkinson's disease is wide, and every person living with PD will have a unique set of concerns. This survey of approximately 200 physicians also highlights that many of the most frequently reported non-motor symptoms are also most detrimental to quality of life. (Image courtesy of Maurizio Facheris)

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.

A new hypothesis of PD is that it may develop as a prion-like disease that spreads from the gut to the central nervous system. Here, lysates from human PD patients were injected into rodent intestines and found to spread to the brain via the vagal nerve. (Image presented by Horacio Kaufmann courtesy of Holmqvist et al. Acta Neuropathol. 2014.)

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)

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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