WASHINGTON, DC—Epidemiologists concerned with the causes and prevention of Parkinson’s disease are delving into large population studies to create a list of risk factors that can be used as a screening and interventional tool, similar to that developed by experts on cancer, stroke, and other diseases. In a presentation at the inaugural World Parkinson Congress, Caroline M. Tanner, MD, PhD, said that patterns emerging from genetic, behavioral, and environmental studies point to midlife factors that can predict Parkinson’s disease. Such factors include excessive daytime sleepiness, difficulty with odor recognition, severe constipation, obesity, skinfold thickness, and certain cardiac changes.

Dr. Tanner, Director of Clinical Research at the Parkinson’s Institute in Sunnyvale, California, noted that epidemiologists are also reviewing a growing body of studies in recent years that have suggested a strong inverse (neuroprotective) association between behavior and Parkinson’s disease. Research has shown that cigarette smoking, coffee consumption, and the use of nonsteroidal anti-inflammatory drugs appear to lower the risk of Parkinson’s disease. For example, in a study of identical male twins, Dr. Tanner and colleagues found that the twin without Parkinson’s disease had a greater exposure to cigarettes, measured in pack-years. "It’s just remarkable to me that you can see that difference," said Dr. Tanner.

GENETICS AND ENVIRONMENT

Researchers are also examining the interaction of genetics and environment and the impact of these factors on Parkinson’s disease. So far they have identified only one toxicant—1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)—that has shown a causal relationship with Parkinson’s disease.

In several reported cases, drug-addicted individuals have injected an impure synthetic drug tainted with MPTP that damaged their extrapyramidal nervous system, resulting in secondary Parkinson’s disease. These toxin-induced cases of parkinsonism provide support for the argument that lesions of the substantia nigra can produce motor symptoms and signs of Parkinson’s disease. This has led researchers to explore other environmental causes, including herbicides and pesticides, that might have the same effects on the brain as does MPTP.

Dr. Tanner believes that epidemiologic research efforts would benefit from the development of state registries of Parkinson’s disease cases. California recently mandated its Department of Health Services to create a database of people with Parkinson’s disease for research purposes. Dr. Tanner noted that a pilot study on how to implement the reporting is under way.

TRANSLATIONAL RESEARCH

Howard J. Federoff, MD, PhD, Director of the Center for Aging and Developmental Biology and Senior Associate Dean for Basic Research at the University of Rochester School of Medicine and Dentistry, New York, is studying biologic systems to try to find the common pathway by which cell death is initiated and carried out in patients with Parkinson’s disease.

"We want to identify one or more biochemical molecules that contribute to this pathway, both in the central nervous system and peripherally, so that we can then identify targets for therapeutic development," Dr. Federoff related at the World Parkinson Congress. Using a systems biology approach to identifying biochemical molecules in human brains and animal models, and a purely genetic form engineered in the lab, Dr. Federoff has been able to track sources down to "a tiny number of genes" that constitute a common pathway for dopamine-bearing neurons.

Based on the premise that cells have the capability to respond to stimuli, researchers are now exploring how different triggers influence the initiation of Parkinson’s disease. By observing peripheral white blood cells in patients with Parkinson’s disease and controls, investigators have identified molecular signatures or genes that are unique in patients with the disease. Further findings are that leukocytes traffic in and out of the brain and "report back," or mirror, what is going on in the brain, noted Dr. Federoff. Through future study of the blood-brain connection of molecular signatures, researchers may be able to establish that some biochemical dysfunction observed in white blood cells may also occur in the brain.

Dr. Federoff believes that there may be a common anatomic pathway at the cell level that defines the brain’s response to the injury. One question to be answered is whether genes identified in the lab are central to expression of the common pathway. The answer may soon become clear, he said, as researchers are studying individual molecules at an earlier preclinical, or presymptomatic stage, to see if they will hold up as signatures. If they do, investigators hope to use those findings to develop interventions that will alter or block the natural disease progression.

Alzheimer’s disease studies have found that some signatures have responded to drugs that act like nerve protectors. Ongoing research with valproic acid by the Alzheimer’s Disease Cooperative Group has shown that the agent targets enzymes and appears to prevent cell death. These trials have found "a discrete and very robust response" among individuals taking valproic acid for six to 10 weeks, said Dr. Federoff. He anticipates that valproic acid as a therapeutic will extend beyond Alzheimer’s to Parkinson’s and other diseases.

NR

—Kathy Stone

Suggested Reading
Miller RM, Federoff HJ. Altered gene expression profiles reveal similarities and differences between Parkinson disease and model systems. Neuroscientist. 2005;11:539-549.
Tanner CM, Goldman SM, Aston DA, et al. Smoking and Parkinson’s disease in twins. Neurology. 2002;58:581-588.
Vijitruth R, Liu M, Choi DY, et al. Cyclooxygenase-2 mediates microglial activation and secondary dopaminergic cell death in the mouse MPTP model of Parkinson’s disease. J Neuroinflammation. 2006 Mar 27; [Epub ahead of print].
Wirdefeldt K, Gatz M, Pawitan Y, Pedersen NL. Risk and protective factors for Parkinson’s disease: a study in Swedish twins. Ann Neurol. 2005;57:27-33.

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