Preclinical clues may speed diagnosis of Parkinson's.

NEW YORK -- The recognition that Parkinson's disease is a systemic disease with identifiable prodromal features is providing hope for early detection and, ultimately, for possible early therapeutic intervention before the disabling clinical manifestations of the disease develop, Dr. Matthew Stern said at a meeting sponsored by the Parkinson's Disease Foundation.

"We know now that by the time the diagnosis [of Parkinson's disease] is made, the synuclein pathology is already fairly widespread, and much of the damage is done. We can't begin to think about preventing this damage until we've learned more about the preclinical phase," Dr. Stern said. This early phase of the disease is now referred to as Parkinson's disease-associated risk syndrome (PARS), which can be divided into specific stages:

* Prephysiologic. The first phase represents genetic predisposition. "There has been a tremendous amount of work in the last 10-15 years in identifying genes that are associated with familial Parkinson's disease, and by studying those we are finding some clues as to the mechanisms of nerve degeneration," said Dr. Stern, the Parker Family Professor of Neurology and director of the Parkinson's disease and movement disorder center, University of Pennsylvania, Philadelphia.

* Preclinical. In this next phase, changes in the brain can be detected with neuroimaging techniques, including single-photon emission computed tomography (SPECT) using [.sup.123I.[beta]]-CIT as a dopamine transporter ligand, and with transcranial ultrasound.

* Premotor. During this phase, nonmotor features such as olfactory dysfunction begin to emerge.

* Prediagnostic. The final stage before a diagnosis is typically made is characterized by subtle progressive motor features.

"It is an increased understanding of the premotor phase that is changing our view of Parkinson's disease from a brain disorder to its being a systemic illness," he said. Approximately 75% of patients with early Parkinson's disease do poorly on the UPSIT (University of Pennsylvania Smell Identification Test), which is a simple "scratch and sniff" test, and have significant olfactory loss (Lancet Neurol. 2006;5:235-45).

Dr. Stern and his colleagues at the University of Pennsylvania and elsewhere have begun investigating tools such as UPSIT for early screening. In a study in which 361 asymptomatic first-degree relatives of Parkinson's disease patients were screened with UPSIT, 40 had olfactory defects. Over the next 2 years, 4 of those 40 developed Parkinson's disease, and an additional 5 showed significant declines on SPECT imaging, he said.

No patients in a control cohort among the relatives who were normosmic at baseline went on the develop the disease, and the study concluded that idiopathic olfactory dysfunction in family members of Parkinson's disease patients is associated with at least a 10% increased risk of developing the disease (Ann. Neurol. 2004;56:173-81).

Moreover, the olfactory defect seems to be specific for Parkinson's disease, and is not a feature of other parkinsonian syndromes, Dr. Stern said. 'Also, importantly, if your olfaction is intact, it significantly lowers the risk of developing Parkinson's disease," he said.

Constipation is another common finding during the premotor phase of Parkinson's disease, as was shown by data from the longitudinal Honolulu-Asia Aging Study. Late-life bowel movement frequency was assessed in 245 men aged 71-93 years, and although none of the subjects had clinical Parkinson's disease, those with fewer bowel movements per day were more likely to have incidental Lewy bodies present on postmortem examinations of the substantia nigra and locus ceruleus (Mov. Disord. 2007;22:1581-6). The presence of incidental Lewy bodies is common in the disease prodrome, suggesting that GI tract involvement may be a very early feature of Parkinson's disease, he said.

Another possible early marker is rapid eye movement (REM) sleep behavior disorder (RBD), an unusual condition in which patients become very active--thrashing and calling out--during REM sleep. In a study of 54 polysomnographically confirmed cases of RBD and 54 age- and sex-matched controls, marked olfactory impairment was observed in 33 of the RBD group, compared with 9 of the controls (Brain Res. Bull. 2006;70:386-90).

Subtle visual and cardiac abnormalities also have been identified in patients in the prodromal phase of Parkinson's disease, "which brings us to where we are today: in the process of designing the first large-scale screening study of PARS," at the University of Pennsylvania and the Institute for Neurodegenerative Disorders in New Haven, Conn., Dr. Stern said.

The study will recruit thousands of patients and first-degree relatives who will undergo olfactory function testing and SPECT neuroimaging. "We will also look at some of these other preclinical markers and follow the patients over time.... Ultimately, we hope this will enable us to think about Parkinson's disease in the way we think about heart disease, as a condition that can be diagnosed before it becomes clinically manifest and disabling," he said.

Dr. Stern disclosed that he is a consultant for Novartis, Boehringer Ingelheim Pharmaceuticals Inc., Valeant Pharmaceuticals International, and Vernalis Pharmaceuticals Inc.

BY NANCY WALSH

New York Bureau