The search for reliable and easily accessible
biomarkers in
Parkinson's disease is receiving a growing emphasis, to detect neurodegeneration from the prodromal phase and to enforce disease-modifying
therapies. Despite the need for non-invasively accessible
biomarkers, the majority of the studies have pointed to cerebrospinal fluid or peripheral biopsies
biomarkers, which require invasive collection procedures. Saliva represents an easily accessible biofluid and an incredibly wide source of molecular
biomarkers. In the present study, after presenting the morphological and biological bases for looking at saliva in the search of
biomarkers for
Parkinson's disease, we systematically reviewed the results achieved so far in the saliva of different cohorts of
Parkinson's disease patients. A comprehensive literature search on PubMed and SCOPUS led to the discovery of 289 articles. After screening and exclusion, 34 relevant articles were derived for systematic review.
Alpha-synuclein, the histopathological hallmark of
Parkinson's disease, has been the most investigated
Parkinson's disease biomarker in saliva, with oligomeric
alpha-synuclein consistently found increased in
Parkinson's disease patients in comparison to healthy controls, while conflicting results have been reported regarding the levels of total
alpha-synuclein and phosphorylated
alpha-synuclein, and few studies described an increased oligomeric
alpha-synuclein/total
alpha-synuclein ratio in
Parkinson's disease. Beyond
alpha-synuclein, other
biomarkers targeting different molecular pathways have been explored in the saliva of
Parkinson's disease patients: total tau, phosphorylated tau, amyloid-β1-42 (
pathological protein aggregation biomarkers); DJ-1, heme-oxygenase-1, metabolites (altered energy homeostasis
biomarkers); MAPLC-3beta (aberrant proteostasis
biomarker);
cortisol,
tumor necrosis factor-alpha (
inflammation biomarkers); DNA methylation,
miRNA (
DNA/
RNA defects
biomarkers);
acetylcholinesterase activity (synaptic and neuronal network dysfunction
biomarkers); Raman spectra,
proteome, and
caffeine. Despite a few studies investigating
biomarkers targeting molecular pathways different from
alpha-synuclein in
Parkinson's disease, these results should be replicated and observed in studies on larger cohorts, considering the potential role of these
biomarkers in determining the molecular variance among
Parkinson's disease subtypes. Although the need for standardization in sample collection and processing, salivary-based
biomarkers studies have reported encouraging results, calling for large-scale longitudinal studies and multicentric assessments, given the great molecular potentials and the non-invasive accessibility of saliva.