Vijiaratnam, Nirosen; Foltynie, Thomas; (2023) How should we be using biomarkers in trials of disease modification in Parkinson’s disease? Brain 10.1093/brain/awad265. (In press).

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Abstract

The recent validation of the alpha synuclein seed amplification assay as a biomarker with high sensitivity and specificity for the diagnosis of Parkinson’s disease has formed the backbone for a proposed staging system for incorporation in Parkinson’s disease clinical studies and trials. The routine use of this biomarker should greatly aid in the accuracy of diagnosis during recruitment of Parkinson’s disease patients into trials (as distinct from patients with non- Parkinson’s disease parkinsonism or non- Parkinson’s disease tremors). There remain however further challenges in the pursuit of biomarkers for clinical trials of disease modifying agents in Parkinson’s disease, namely: optimising the distinction between different alpha synucleinopathies; the selection of subgroups most likely to benefit from a candidate disease modifying agent; as sensitive means of confirming target engagement; and in the early prediction of longer-term clinical benefit. For example; levels of cerebrospinal fluid proteins such as the lysosomal enzyme ß-glucocerebrosidase may assist in prognostication or allow enrichment of appropriate patients into disease modifying trials of agents with this enzyme as the target; the presence of coexisting Alzheimer disease like pathology (detectable through cerebrospinal fluid levels of Amyloid Beta-42 and tau) can predict subsequent cognitive decline; imaging techniques such as free-water or neuromelanin MRI may objectively track decline of Parkinson’s disease even in its later stages. The exploitation of additional biomarkers to the alpha synuclein seed amplification assay will therefore greatly add to our ability to plan trials and assess disease modifying properties of interventions. The choice of which biomarker(s) to use in the context of disease modifying clinical trials will depend on the intervention, the stage (at risk, premotor, motor, complex) of the population recruited and the aims of the trial. The progress already made lends hope that panels of fluid biomarkers in tandem with structural or functional imaging may provide sensitive and objective methods of confirming that an intervention is modifying a key pathophysiological process of Parkinson’s disease. However, correlation with clinical progression does not necessarily equate to causation and the ongoing validation of quantitative biomarkers will depend on insightful clinical-genetic-pathophysiological comparisons incorporating longitudinal biomarker changes from those at genetic risk with evidence of onset of the pathophysiology and those at each stage of manifest clinical Parkinson’s disease.

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