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The preclinical detection of Parkinson's disease: Ready for prime time?

In the past decade, molecular neuroscience has drastically expanded our understanding of neurodegeneration. There are numerous compounds that show promise in the laboratory for interrupting the underlying disease process, but our progress is slowed because of the challenges inherent in showing clinical effects in diseases that generally begin later in life, progress slowly over many years, and lack sufficient biological markers to be useful in a clinical trial. In this “new age” of neurological therapeutics, we have developed terminology to describe what we hope to accomplish but, as yet, has eluded us. “Neuroprotection” and “disease modification” have become the buzzwords of today’s clinical trialists and the ideal goal of therapy for neurodegenerative diseases, in which restoring function or curing disease may be more unrealistic. Clinical trials in Parkinson’s disease (PD) have addressed the concept of slowing disease progression since the study of deprenyl and tocopherol antioxidative therapy of parkinsonism (DATATOP) in the late 1980s. In this early attempt to demonstrate an effect on disease progression, deprenyl’s symptomatic effects confounded the primary outcome measure, the need for dopaminergic therapy. Although several unsuccessful “neuroprotective” trials followed DATATOP, more recent studies have been promising. A pilot study with coenzyme Q10 in early PD showed slower decline in function in the highest dose group of otherwise untreated patients. A placebo-controlled, randomized, delayed-start trial with the novel monoamine oxidase type B inhibitor, rasagiline, found patients treated for 1 year less impaired than those treated for only 6 months. Although neither study can claim with certainty that the underlying PD process has been altered, the experimental therapeutics of PD indeed has evolved, and the quest to prove that an intervention affects disease progression is well at hand and supported by initiatives in both industry and the National Institutes of Health. Choosing the “right” clinical end point, the most appropriate patient population, study design, and possible surrogate end points have challenged modern PD experimental therapeutics. There is a lengthy preclinical phase of disease in which the degenerative process proceeds long before clinically recognizable symptoms emerge. Although this presents a formidable challenge in early diagnosis, it also presents a unique opportunity to approach PD and other neurodegenerative disorders from the perspective of disease prevention. The ultimate proof of neuroprotection lies in disease prevention or, at the very least, delay in PD onset. Rather than choosing certain milestones of PD as end points, the onset of PD may be the most relevant and appropriate end point for clinical trials of “neuroprotection.” Delaying onset of disease would almost assuredly translate into delaying disability with the obvious public health benefits of prolonged neurological health, employability, reduced health care burden, and long-term quality of life. To consider novel strategies that might slow the development of PD, we must be able to detect the evolving pathological process early in its course, before the emergence of PD symptoms. In this issue of the Annals, Ponsen and colleagues report results from their studies of hyposmia as a preclinical marker of PD. Studies by Doty and colleagues previously had laid the foundation for considering olfaction as a preclinical marker of PD. Using the University of Pennsylvania Smell Identification Test (UPSIT), significant loss of olfactory function was found in PD patients regardless of duration of disease, stage of disease, or medications. Interestingly, this deficit is present in the earliest stages of PD, but not observed in other causes of parkinsonism. Because olfactory loss occurs in many other settings including head trauma and Alzheimer’s disease, it cannot stand alone as a screening test for PD. Moreover, recent studies suggest that olfactory loss may be greater in sporadic PD than in PD secondary to the parkin mutation. However, Ponsen and colleagues utilized advances in metabolic imaging to increase their preclinical yield. Single-photon emission computed tomography (SPECT) imaging with [I] B-CIT, which binds to the dopamine transporter (DAT), provides a measure of dopamine terminal function, and studies have established its utility in reflecting nigrostriatal dopamine cell loss. B-CIT SPECT imaging already has been used in clinical trials evaluating progression of DAT loss in PD patients treated with either L-dopa or dopamine agonists. Furthermore, the degree of dopamine cell loss detected at disease onset, the loss of binding in the asymptomatic striatum of hemiparkinon patients, and the measurable rate of decline in binding with PD progression suggest that loss of dopamine terminals can be detected by DAT imaging well before clinical symptoms emerge. In addition, in familial PD, studies have shown loss of binding in clinically asymptomatic but genetically positive family members. Ponsen and colleagues found that 10% of asymptomatic, hyposmic relatives of PD patients had abnormal [I] B-CIT SPECT scans at baseline and developed PD at 2 years. An additional 12% of hyposmic relatives had an increased rate of decline in DAT binding suggestive of evolving PD. None of the normosmic inEDITORIALS