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From the National Institute of Neurological Disorders and Stroke (Drs. Ravina, Gwinn-Hardy, McFarland, Morin, Moy, Murphy, Oliver, and Sheehy), National Institutes of Health, Bethesda, MD; Center for Neurosciences (Drs. Carbon, Dhawan, Eidelberg, and Feigin), Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY; Department of Neurology (Dr. Ahlskog), Mayo Clinic, Rochester, MN; Department of Neurology, University of Michigan and Ann Arbor VAMC GRECC (Dr. Albin), Ann Arbor, MI; Faculty of Medicine (Dr. Brooks), Imperial College, London, UK; Department of Neurology (Dr. Fahn), Columbia University/College of Physicians and Surgeons, New York, NY; Human Neurochemical Pathology Laboratory (Drs. Guttman and Kish), Center for Addiction and Mental Health, Ontario, Canada; National Institute of Mental Health (Dr. Innis), National Institutes of Health, Bethesda, MD; US Food and Drug Administration (Dr. Katz), Rockville, MD; Department of Neurology (Drs. Kieburtz and Holloway), University of Rochester, NY; Departments of Psychiatry and Biostatistics (Dr. Lange), Harvard University Schools of Medicine and Public Health, Boston, MA; The Parkinson’s Institute (Dr. Langston), Sunnyvale, CA; Institute for Neurodegenerative Disorders (Drs. Marek and Seibyl), New Haven, CT; Department of Neurology (Dr. Oertel), Philipps University of Marburg, Marburg, Germany; Departments of Biometry and Epidemiology (Dr. Palesch), Medical University of South Carolina, Charleston, SC; Department of Neurology, Washington University School of Medicine (Dr. Powers), St. Louis, MO; Department of Neurology (Dr. Sethi), Medical College of Georgia, Augusta, GA; Department of Neuroscience (Dr. Shults), University of California, San Diego, CA; Pacific Parkinson’s Research Center, University of British Columbia (Dr. Stoessl), Vancouver, British Columbia, Canada.
Address correspondence and reprint requests to Dr. Bernard Ravina, Program Director, Clinical Trials, NINDS, Neuroscience Center, Room 2225, 6001 Executive Boulevard, Rockville, MD 20892-9257; e-mail: ravinab{at}ninds.nih.gov
Radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in Parkinson disease (PD). Here the authors review the concepts of biomarker development and the evidence to support the use of four radiotracers as biomarkers in PD: [18F]fluorodopa PET, (+)-[11C]dihydrotetrabenazine PET, [123I]ß-CIT SPECT, and [18F]fluorodeoxyglucose PET. Biomarkers used to study disease biology and facilitate drug discovery and early human trials rely on evidence that they are measuring relevant biologic processes. The four tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons. Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biologic relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials. Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.
This work was supported by the National Institute of Neurologic Disorders and Stroke and a National Institute of Neurologic Disorders and Stroke-sponsored workshop on imaging in PD.
Dr. Brooks has received consulting fees from GlaxoSmithKline and is an employee of Imanet, Amersham Health PLC. Dr. Innis received consulting fees in excess of $10,000 from Imanet, Amersham Health PLC. Dr. Kish received a research grant from Boehringer Ingelheim Canada. Drs. Marek and Seibyl have equity interests in Molecular NeuroImaging, LLC.
Received March 22, 2004. Accepted in final form September 15, 2004.
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