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Environmental Factor, July 2012

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Connecting the dots in Parkinson’s disease

By Ernie Hood

Honglei Chen, M.D., Ph.D.

According to Chen, at least one million Americans currently have PD, with an annual cost of $25 billion. “If we identify a potential combination of premotor symptoms that is highly predictive of the disease, we can study the environmental factors that are related to either disease development or disease progression,” (Photo courtesy of Steve McCaw)

Linda Birnbaum, Ph.D.

“This is kind of a new field of research,” said NIEHS/NTP Director Linda Birnbaum, Ph.D., as she welcomed participants to the symposium. “It’s really just evolving, and we’re happy to have this minisymposium to lay out the research priorities and strategies that need to be looked at.” (Photo courtesy of Steve McCaw)

The first image that comes to mind about Parkinson’s disease (PD) is likely to be the classic muscular tremors associated with famous patients such as Michael J. Fox and Muhammad Ali. But the condition actually begins to manifest itself much earlier than the onset of those motor symptoms, with a variety of nonmotor or premotor symptoms that may appear decades prior to the motor features. Scientific understanding of the role of premotor symptoms in the etiology, development, and progression of PD is at an early stage, but the existing research is intriguing and the potential for important new knowledge to emerge is enormous. 


The potential is what led approximately twenty leading experts in the field to gather June 7-8 at the Parkinson’s Disease Premotor Symptom Symposium. The meeting was co-organized by NIEHS epidemiologist Honglei Chen, M.D., Ph.D., and program administrator Cindy Lawler, Ph.D. “We were interested in organizing this symposium because, first, by studying the premotor symptoms, we may get a window to identify the disease early, and equally important, we may learn more about early disease etiology,” said Chen.

“We need to be looking more broadly at Parkinson’s disease as a systemic illness,” explained Lawler. “There has been a focus on the motor symptoms and the dopamine system in the substantia nigra, effects that occur later in the disease process. If we really want to have a chance to alter the progression of the disease, we need to look earlier at this broader constellation of signs and symptoms that are very important in terms of quality of life and, at least in some cases, appear to precede the onset of motor symptoms.”

According to research findings presented at the symposium, that broader constellation of signs and symptoms includes constipation, loss of sense of smell, excessive daytime sleepiness, and mood or anxiety disorders, as well as REM sleep behavior disorder, characterized by kicking or other jerky movements during deep sleep. Some of the conditions, particularly in combination, can be quite debilitating and may appear up to twenty years prior to the development of the classic motor symptoms.

Three areas of research

The symposium devoted three main sessions to the topics of clinical research and epidemiology; animal models and mechanisms; and neuroimaging, pathology, and biomarkers. As the meeting progressed, it was clear the researchers were excited by what they were learning from their colleagues and eager to pursue new types of collaborations to explore the role of PD premotor symptoms.

Although the findings are tantalizing, the speakers agreed that none of the symptoms by themselves are specific or sensitive enough to be definitively considered predictive precursors to PD. Identifying combinations of premotor symptoms that would be reliably predictive would enable earlier detection and intervention, with a goal of halting or at least slowing progression of the disease.

“Because there is such a long preclinical phase of Parkinson’s, when people have some nonmotor symptoms, but have not developed motor symptoms, that would be the time to intervene with neuroprotective strategies,” said Lawler. “If you could find a way to even keep them at that level of functioning, it would have a tremendous impact on quality of life.”

New directions

Addressing the gaps in the research will be very challenging, but the opportunity to elucidate PD etiology and enhance prevention or provide clinical treatment, will encourage researchers to continue to analyze premotor symptoms, incorporating some of the new ideas they heard at the meeting. The results of the meeting will be used to help define high priority areas for future extramural investments in NIEHS Parkinson’s disease research, said Lawler.  “This is going to take a lot of effort in thinking of, and planning for, the best strategy to work on the premotor symptoms,” said Chen. “The symposium gave me a lot of ideas about which premotor symptoms I should focus on, what kind of planning work I need to think about, and what are the important questions I need to address.”

(Ernie Hood is a contract writer for the NIEHS Office of Communications and Public Liaison.)

Cindy Lawler, Ph.D.

Lawler moderated the second of the meeting’s three sessions, which was devoted to animal models and mechanisms. She noted that NIEHS would encourage researchers to submit applications that focus on PD premotor symptoms, an area currently under-represented in the Institute’s research portfolio. (Photo courtesy of Steve McCaw)

G. Webster Ross, M.D.

G. Webster Ross, M.D., presented findings from the Honolulu-Asia Aging Study cohort. His team of researchers found a three-fold risk for PD among people with constipation. Premotor symptoms, he said, appeared as early as 24 years before clinical diagnosis. (Photo courtesy of Steve McCaw)

Jau-Shyong Hong, Ph.D.

NIEHS researcher Jau-Shyong Hong, Ph.D., who is head of the NIEHS Neuropharmacology Group, spoke on “Inflammation-mediated neurodegenerative animal models for studying mechanisms and therapy of Parkinson’s disease.” (Photo courtesy of Steve McCaw)

Rodolfo Savica, M.D.

Discussions among the investigators in attendance were lively and enthusiastic. Rodolfo Savica, M.D., presented findings from Mayo Clinic research on PD premotor symptoms, using electronic databases to tease out possible associations and timelines. (Photo courtesy of Steve McCaw)

Amy Rick

Amy Rick, of the Parkinson’s Action Networks, represented the patient advocacy community at the symposium. “What you learn is also hugely relevant to the current generation of people with Parkinson’s… [to] help people who now have these nonmotor symptoms that are incredibly disruptive.” (Photo courtesy of Steve McCaw)

Robert Nussbaum, M.D., Jing Zhang, M.D., Ph.D., Alberto Ascherio, M.D., Dr. P.H.

Shown left to right, researchers Robert Nussbaum, M.D., of the University of California, San Francisco; Jing Zhang, M.D., Ph.D., of the University of Washington; and Alberto Ascherio, M.D., Dr. P.H., of the Harvard School of Public Health, were among the presenters at the symposium. (Photo courtesy of Steve McCaw)

Parkinson’s Disease Premotor Symptom Symposium organizers and attendees

To commemorate the occasion, symposium organizers and attendees gathered on the NIEHS patio for a group portrait. (Photo courtesy of Steve McCaw)

The dual-hit hypothesis

Growing interest in exploring how premotor research can improve our understanding on PD etiology, at least partially, arises from the hypothesis put forward in 2003 by German anatomist Heiko Braak, M.D., and colleagues. Braak and the others expanded on the hypothesis in a 2007 paper titled “Parkinson’s disease: a dual-hit hypothesis,” in which the researchers posit a viral PD etiology, with the virus entering different regions of the brain from both the gut and the olfactory bulb. The publication’s abstract outlines the concept.

Accumulating evidence suggests that sporadic Parkinson's disease has a long prodromal period during which several non-motor features develop, in particular, impairment of olfaction, vagal dysfunction and sleep disorder. Early sites of Lewy pathology are the olfactory bulb and enteric plexus of the stomach. We propose that a neurotropic pathogen, probably viral, enters the brain via two routes: (i) nasal, with anterograde progression into the temporal lobe; and (ii) gastric, secondary to swallowing of nasal secretions in saliva. These secretions might contain a neurotropic pathogen that, after penetration of the epithelial lining, could enter axons of the Meissner's plexus and, via transsynaptic transmission, reach the preganglionic parasympathetic motor neurones of the vagus nerve. This would allow retrograde transport into the medulla and, from here, into the pons and midbrain until the substantia nigra is reached and typical aspects of disease commence. Evidence for this theory from the perspective of olfactory and autonomic dysfunction is reviewed, and the possible routes of pathogenic invasion are considered. It is concluded that the most parsimonious explanation for the initial events of sporadic Parkinson's disease is pathogenic access to the brain through the stomach and nose — hence the term 'dual-hit.'


Braak H, Rüb U, Gai WP, Del Tredici K. 2003. Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 110(5):517-536.

Hawkes CH, Del Tredici K, Braak H. 2007. Parkinson's disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol 33(6):599-614.

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