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

“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,” said Dr. Stern, the Parker Family Professor of Neurology and director of the Parkinson's disease and movement disorder center, University of Pennsylvania, Philadelphia. This early phase is called Parkinson's disease-associated risk syndrome (PARS). It is divided into stages:

P 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.

P Preclinical. In this next phase, brain changes can be detected with neuroimaging, including single-photon emission computed tomography (SPECT) using 123I?-CIT as a dopamine transporter ligand, as well as with transcranial ultrasound.

P Premotor. During this phase, nonmotor features like olfactory dysfunction emerge.

P Prediagnostic. This 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. About 75% of patients with early Parkinson's disease (PD) do poorly on the UPSIT (University of Pennsylvania Smell Identification Test), which is a simple “scratch and sniff” test. The olfactory loss is significant and begins with the degeneration of extranigral neurons in the olfactory bulb and anterior olfactory nucleus (Lancet Neurol. 2006;5:235-45).

Dr. Stern and colleagues are investigating tools like UPSIT for early screening. In a study in which 361 asymptomatic first-degree relatives of PD patients were screened with UPSIT, 40 had olfactory defects. Over the next 2 years, four of the 40 developed PD, and an additional five showed significant declines on SPECT imaging, he said. No patients in a control cohort among the relatives who were normosmic at baseline developed PD. The study concluded idiopathic olfactory dysfunction in family members of PD patients is associated with at least a 10% increased risk of the disease (Ann. Neurol. 2004;56:173-81).

Moreover, the olfactory defect seems to be specific for PD, and is not a feature of other parkinsonian syndromes. “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 premotor PD, as shown by the longitudinal Honolulu-Asia Aging Study. Late-life bowel movement frequency was assessed in 245 men aged 71–93 years. Though none had clinical PD, those with fewer bowel movements per day were more likely to have incidental Lewy bodies 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 GI tract involvement may be an early PD feature, he said.

A further possible early marker is rapid eye movement (REM) sleep behavior disorder (RBD), in which patients thrashing and call out during REM sleep. In a study of 54 polysomnographically confirmed cases of RBD and 54 age- and sex-matched controls, olfactory impairment was observed in 33 of the RBD group, versus 9 controls (Brain Res. Bull. 2006;70:386-90).

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

The study will recruit thousands of patients and first-degree relatives for olfactory function testing and SPECT neuroimaging. “We will also look at some of these other preclinical markers and follow the patients over time. If, in fact, we can identify several hundred individuals who go on to develop Parkinson's disease, the next phase of the study will be to actually test an intervention for slowing or perhaps even preventing the onset of disease. 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.”

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

70336_fx1.sml

Imaging can detect asymptomatic neurologic changes. A SPECT scan of a patient with early PD shows reduced dopamine transporter binding on the as-yet unaffected side. Danna Jennings/Ken Marek/The Institute for Neurodegeneration

Preclinical Clues May Speed Parkinson's Diagnosis