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Biomarker Promise for Parkinson’s Disease

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Reliable biomarkers that can be used for early diagnosis and tracking disease progression are the cornerstone of research into disease-modifying treatments for neurodegenerative diseases. Although important strides have been made in biomarker research, for Parkinson’s disease (PD) as for other diseases, no validated, inexpensive, and simple markers are available. The launch of the Parkinson’s Progression Markers Initiative (PPMI), a public-private partnership spearheaded by the Michael J. Fox Foundation that aims to identify clinical, imaging, and biological markers of disease progression is therefore welcome news. But what do patients and the research community stand to gain from this initiative and can it fullfil its promise?

Modelled on the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the PPMI is the first large-scale international prospective observational study—involving 20 centres in the USA and Europe—designed to identify and validate markers of disease progression in patients with PD. The initiative, expected to cost US$40 million and last for 5 years, will enrol 400 newly diagnosed patients who are not yet on medication and who have evidence of dopamine transporter loss on DAT imaging with SPECT and 200 healthy age-matched controls. The most promising biomarker candidates will be tested using advanced brain imaging techniques, blood, urine, CSF, and DNA sampling, and motor, neuropsychiatric, and cognitive assessments; the emphasis will initially be on fluid markers including alpha synuclein, DJ-1, amyloid beta, and tau in CSF and urate in blood. As with ADNI, a crucial aspect of the PPMI is that all data and biological specimens, stored in a central repository, will be available for the research community. The PPMI will thus provide a valuable resource to fuel further academic and industry-initiated investigations and innovations, and promising biomarker candidates identified through such efforts could be validated against the large, prospective PPMI dataset.

It is hoped that the PPMI will lead to the identification and development of objective and validated markers that could provide indicators of risk for developing PD before symptom onset and for conversion to clinical disease. In-depth studies of correlations between different markers might help to generate a useful screening algorithm. Biomarker studies might also enable identification of different pathophysiological subgroups of patients who respond differently to certain drugs, thus providing hope that treatment could be tailored to individuals. Use of objective biomarkers in trials of disease-modifying therapies to assist in patient stratification or more accurately track disease progression and drug response could substantially reduce the numbers of patients needed and study duration, and hence costs. Furthermore, pharmacodynamic biomarkers could help to determine whether a drug is reaching its intended target of action, which could be particularly useful for understanding reasons for failed trials.

A major hurdle for the PPMI investigators is that data or specimen collection, processing, and storage methods currently differ across centres. A central aim of the PPMI is to standardise processes across participating centres, and quality-control mechanisms will be in place to ensure data are acceptable before they are made publicly available. Standardisation seems feasible for CSF and blood biomarker data, but combining imaging data that are collected with different devices is likely to be much more complicated and technological improvements might mean that earlier imaging data could quickly become outdated. Moreover, for biomarkers to be useful, they would need to be cheap and easy to apply on a large scale, so fluid-based biomarkers, for example, might be more broadly applicable than those based on sophisticated imaging methods.

The answers are unlikely to be simple and even if biomarkers are successfully validated, those that work for diagnosis might not work for tracking disease progression, for example. Moreover, PD is not likely to be a single entity and there is much variability between patients. Much larger sample sizes might therefore be required to identify sensitive biomarkers for different subforms of the disease. And while this initiative might give rise to biomarkers that would be useful at a group level, the substantial variability in disease manifestations means that their applicability to individual patients—and the hope for personalised medicine—might be wishful thinking.

Despite the many challenges, this collaborative effort will provide a comprehensive, longitudinal, prospective dataset, with open access ensuring that this valuable resource will complement and stimulate traditional investigator-initiated biomarker research in PD. Only time will tell whether the PPMI will fulfil its promise of delivering objective biomarkers to improve research and treatment prospects for patients with PD, but we have reason to be optimistic.

Source: The Lancet Neurology