• Claudio Giuliano, Silvia Cerri, Valentina Cesaroni, and Fabio Blandini.
• Unit of Cellular and Molecular Neurobiology, IRCCS Mondino Foundation, 27100 Pavia, Italy.
• Neuroscience. 2023 Feb 10; 511: 100109100-109.

AbstractParkinson's disease (PD) is a multifactorial neurodegenerative disorder characterised by the progressive loss of dopaminergic neurons in the nigrostriatal tract. The identification of disease-modifying therapies is the Holy Grail of PD research, but to date no drug has been approved as such a therapy. A possible reason is the remarkable phenotypic heterogeneity of PD patients, which can generate confusion in the interpretation of results or even mask the efficacy of a therapeutic intervention. This heterogeneity should be taken into account in clinical trials, stratifying patients by their expected response to drugs designed to engage selected molecular targets. In this setting, stratification methods (clinical and genetic) should be supported by biochemical phenotyping of PD patients, in line with the deep phenotyping concept. Collection, from single patients, of a range of biological samples would streamline the generation of these profiles. Several studies have proposed biochemical characterisations of patient cohorts based on analysis of blood, cerebrospinal fluid, urine, stool, saliva and skin biopsy samples, with extracellular vesicles attracting increasing interest as a source of biomarkers. In this review we report and critically discuss major studies that used a biochemical approach to stratify their PD cohorts. The analyte most studied is α-synuclein, while other studies have focused on neurofilament light chain, lysosomal proteins, inflammasome-related proteins, LRRK2 and the urinary proteome. At present, stratification of PD patients, while promising, is still a nascent approach. Deep phenotyping of patients will allow clinical researchers to identify homogeneous subgroups for the investigation of tailored disease-modifying therapies, enhancing the chances of therapeutic success.Copyright © 2022. Published by Elsevier Ltd.

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