Is the Time Right to Start Testing if Late-Onset Depression is Associated With the Development of an α-Synucleinopathy Like Parkinson's Disease? A Double Systematic Review and Meta-Analysis

Parkinson's disease (PD) is characterized by two neurobiological markers: pathological α-synuclein and/or a dopaminergic deficit. Depression is common in PD, and may precede motor signs, particularly in late-onset depression (LOD). We conducted two systematic reviews and a meta-analysis to examine the relationship between depression and PD development. First, we evaluated whether depression is associated with an increased risk of developing PD, and whether pathological α-synuclein or dopaminergic deficits were observed in depressed patients prior to PD diagnosis. Second, we evaluated whether studies examined neurobiological markers in LOD patients, regardless of subsequent PD development. Our first review identified 39 studies showing a positive association between depression and subsequent PD. This was supported by an exploratory meta-analysis, stratified by index condition: 1) retrospective studies of patients with PD reporting prior depression (odds ratio [OR] = 2.17, 95% CI: 1.92-2.46) and 2) prospective studies of depressed patients who developed PD (OR = 2.01, 95% CI: 1.20-3.38). Importantly, none of these studies examined neurobiological data. Our second review identified three cross-sectional studies reporting that 24%-79% of the LOD patients had a dopaminergic deficit as detected by dopamine transporter (DAT) imaging. We found no studies in LOD in which α-synuclein was determined. Given the observed moderately elevated risk for developing PD in depressed patients, the high incidence of abnormal DAT scans in LOD, and ageing as a major risk factor for developing PD, longitudinal studies in LOD patients are essential to establish neurobiological evidence that depression can be an early manifestation of an α-synucleinopathy like PD.