Biomarkers of Parkinson's disease in perspective of early diagnosis and translation of neurotrophic therapies

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by progressive loss of dopamine neurons and aberrant deposits of alpha-synuclein (alpha-syn) in the brain. The symptomatic treatment is started after the onset of motor manifestations in a late stage of the disease. Preclinical studies with neurotrophic factors (NTFs) show promising results of disease-modifying neuroprotective or even neurorestorative effects. Four NTFs have entered phase I-II clinical trials with inconclusive outcomes. This is not surprising because the preclinical evidence is from acute early-stage disease models, but the clinical trials included advanced PD patients. To conclude the value of NTF therapies, clinical studies should be performed in early-stage patients with prodromal symptoms, that is, before motor manifestations. In this review, we summarize currently available diagnostic and prognostic biomarkers that could help identify at-risk patients benefiting from NTF therapies. Focus is on biochemical and imaging biomarkers, but also other modalities are discussed. Neuroimaging is the most important diagnostic tool today, but alpha-syn imaging is not yet viable. Modern techniques allow measuring various forms of alpha-syn in cerebrospinal fluid, blood, saliva, and skin. Digital biomarkers and artificial intelligence offer new means for early diagnosis and longitudinal follow-up of degenerative brain diseases.