SEATTLE—Neuroprotective mechanisms are difficult to document, said Ira Shoulson, MD, especially in the setting of the symptomatic amelioration of Parkinson's disease. However, the development of biomarkers may help improve the power of clinical trials to discern neuroprotective effects of therapies.

NOT THE BEST MEASURES

Clinical end points may not be the best measures of neuroprotective efficacy for two reasons, said Dr. Shoulson. First, they do not measure preclinical progression of Parkinson's disease, he pointed out, noting that preclinical intervention may be the most effective means of preventing neurodegeneration. Second, clinical scales may not accurately measure a therapy's underlying effects on the disease process of Parkinson's disease, added Dr. Shoulson, who is Professor of Neurology, Pharmacology, and Physiology at the University of Rochester.

Speaking at the 124th Annual Meeting of the American Neurological Association, Dr. Shoulson contended that Parkinson's disease therapies can be evaluated much more accurately with two advanced neuroimaging techniques. Single photon emission computed tomography (SPECT) can be used to produce an image of the presynaptic dopamine transporter (using a cocaine analog, beta-CIT, as a ligand). And positron emission tomography can produce an image of presynaptic dopamine synthesis (using fluorodopa). Neuroimaging might also help differentiate neuroprotective and neurorestorative effects of therapeutic interventions.

Recent studies have confirmed the relevance of SPECT imaging for tracking clinical progression of Parkinson's disease, Dr. Shoulson continued. A correlation has been demonstrated between the loss of beta-CIT uptake and an increased severity score on the Unified Parkinson's Disease Rating Scale. Imaging via SPECT is also useful for detecting preclinical disease in cases of hemiparkinsonism, since diminution is apparent both contralateral and ipsilateral to the affected side, Dr. Shoulson reported. Neuroimaging can also be used to track restorative therapies, such as the transplantation of dopaminergic tissue. In a number of clinical trials, SPECT with beta-CIT is currently being used; one is the ELLDOPA trial, comparing the effect of early and late commencement of levodopa on the progression of Parkinson's disease.

"THE PATIENTS WE CAN'T YET INDENTIFY"

Nevertheless, improved uptake of a biomarker such as fluorodopa or beta-CIT does not necessarily indicate that a patient has improved, Dr. Shoulson cautioned. "We've seen much more impressive changes with our biomarkers than in the primary clinical end points," he said. In fact, the greatest potential for biomarkers may be in detecting preclinical disease in patients at risk and, thus, allowing much earlier intervention, he said. "These are the patients we can't yet identify; neuroimaging may allow us to identify them," said Dr. Shoulson.

Neuroimaging is expected to facilitate clinical trials of therapies for Parkinson's disease. Controlled trials of potentially neuroprotective agents began in 1986 with the DATATOP (Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism) trial. The evaluation of putative neuroprotective strategies continues with ongoing trials of coenzyme Q10, neuroimmunophilins, monoamine oxidase inhibitors, glutamate antagonists, and other agents.

Previous and ongoing clinical trials have suggested that glutamate antagonists—agents that block excitotoxic glutamate release—are some of the most interesting agents to examine, said Dr. Shoulson. One such agent, remacemide, is now in clinical trials. Dopamine agonists are also being considered for their neuroprotective potential, with several trials of the newer agonists currently under way.

Interest persists in selegiline, once considered a promising neuroprotective agent for Parkinson's disease after the DATATOP trial showed that it could delay the need for levodopa in de novo patients. However, the symptomatic effect of selegiline and its very long washout period made the interpretation of the DATATOP trial results less than conclusive, Dr. Shoulson believes. For those reasons, and some of selegiline's unexplained long-term effects, "I don't think anybody would view it as neuroprotective therapy with reasonably clear confidence," said Dr. Shoulson.

A HIGH STANDARD

The standard for neuroprotection is the therapy for Wilson's disease, Dr. Shoulson said. As intervention can slow or halt clinical progression or prevent the development of clinical manifestations entirely—if administered presymptomatically—it is no longer considered a neurodegenerative disease. "This is a high standard, but it is what we're looking for with Parkinson's disease," he emphasized.

However, he noted, the dramatic improvement in the treatment of Wilson's disease depended on an understanding of its pathogenesis, while the causes and processes that account for Parkinson's disease are still unknown. Although identification of some implicated genes has helped direct subsequent research, much has yet to be learned.

Clues to the causes of Parkinson's disease may come from parallel developments in the understanding of other neurodegenerative diseases, including Huntington's disease and Alzheimer's disease, said Dr. Shoulson. So far, he pointed out, most research has been focused on excitotoxic hypotheses of neurodegeneration in which oxidative stress triggers excitotoxicity and neuronal death. However, he concluded, the actual cause of Parkinson's disease may be distant from these propagating factors, accounting for the limited results seen to date.

—Richard Robinson
Contributing Writer

Suggested Reading
Shoulson I. Experimental therapeutics of neurodegenerative disorders: Unmet needs. Science. 1998;282:1072-1074.
Shoulson I. Where do we stand on neuroprotection? Where do we go from here? Mov Disord. 1998;13(suppl 1):46-48.

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