Relevance of Biochemical Deep Phenotyping for a Personalised Approach to Parkinson?s Disease

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 a-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.(c) 2022 Published by Elsevier Ltd on behalf of IBRO.

Automated summary

Parkinson's disease (PD) is a degenerative disorder characterized by the loss of dopaminergic neurons in the brain. The search for disease-modifying therapies for PD has been challenging due to the heterogeneity of patients and the lack of approved drugs. Stratification of PD patients based on their expected response to targeted drugs and biochemical phenotyping is a promising approach for clinical trials. Various studies have proposed biochemical characterizations of PD cohorts using different biological samples, with a focus on biomarkers such as α-synuclein and neurofilament light chain. Although still in its early stages, deep phenotyping of PD patients has the potential to identify homogeneous subgroups for tailored therapies and improve therapeutic outcomes.