Depression in the prodromal phase of Parkinson's disease: Clinical manifestations, biomarker evidence, and predictive implications.

Depression is one of the earliest and most frequent non-motor symptoms in the prodromal phase of Parkinson's disease (PD), often preceding motor signs by years to decades. This review synthesizes epidemiological, neuroimaging, biomarker, and genetic evidence to clarify whether depression is a risk factor, a direct prodromal manifestation, or both. Meta-analyses consistently show a two-fold increased risk of subsequent PD in individuals with depressive symptoms or major depressive disorder (MDD), with the highest risk occurring within 1-2 years of diagnosis but persisting for up to 25 years. Late-onset depressive syndrome (after age 50-60) is associated with dopaminergic deficits on dopamine transporter imaging in 24-79% of cases, supporting it as a prodromal symptom, whereas early-onset depression may act through shared genetic vulnerability or chronic inflammatory pathways. Neuroimaging in isolated REM sleep behavior disorder (iRBD) reveals that depression correlates with caudate atrophy, frontostriatal white matter disruption, and brainstem monoaminergic dysfunction, but not simply with nigrostriatal denervation. Depression frequently coexists with RBD, autonomic dysfunction, and olfactory impairment, likely reflecting shared brainstem pathology. Genetic forms of PD (GBA1, SNCA, LRRK2, PRKN) show variable depression prevalence, providing mechanistic insights into lysosomal, inflammatory, and proteostatic pathways. Emerging evidence implicates IL-17A, sIL-2R, and α-synuclein (α-syn) aggregation as convergent points linking depression and prodromal α-synucleinopathy, with gut-brain axis dysfunction potentially amplifying this process. Current Movement Disorder Society prodromal PD criteria include depression but have limited sensitivity in general populations. No disease-modifying trials have tested whether treating prodromal depression alters phenoconversion risk. We conclude that proximal, late-onset depressive syndrome is a robust prodromal marker, while distant or early-onset depression, including MDD, identifies a chronically elevated risk population. Future studies should integrate multimodal biomarkers and test therapeutic interventions in prodromal cohorts.