Parkinson’s disease (PD), the second most common progressive neurodegenerative disease,
develops and progresses for 10-15 years before the clinical diagnostic symptoms of the
disease are manifested. Furthermore, several aspects of PD pathology overlap with other
neurodegenerative diseases (NDDs) linked to alpha-synuclein aggregation, also called
synucleinopathies. Therefore, there is an urgent need to discover and validate early
diagnostic and prognostic markersthat reflect disease pathophysiology, progression, severity,
and potential differences in disease mechanisms between PD and other NDDs. The close
association between alpha-synuclein (aSyn) and the development of pathology in
synucleinopathies, along with the identification of aSyn species in biological fluids, has led to
increasing interest in aSyn species as potential biomarkers to detect PD and differentiate it
from other synucleinopathies. In this review, we 1) provide an overview of the progress
toward mapping the distribution of aSyn species in the brain, peripheral tissues, and biological
fluids; 2) present comparative and critical analysis of previous studies to measure total aSyn
as well as specific forms of monomeric, modified and aggregated forms of aSyn in different
biological fluids; and 3) highlight conceptual and technical gaps and challenges that could
hinder the development and validation of reliable aSyn biomarkers and outline a series of
recommendations to address these challenges. Finally, we propose a combined biomarker
approach based on integrating total aSyn levels with specific biomarkers based on the
biochemical features (posttranslational modifications), aggregation and structure of aSyn, in
addition to other biomarkers of neurodegeneration. We believe that capturing the diversity
of aSyn species is essential to developing robust assays and diagnostics for early detection,
patient stratification, monitoring of disease progression, and differentiation between
synucleinopathy subtypes. This could transform clinical trial design and implementation,
accelerate the development of new therapies, and improve clinical decisions and treatment
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