Longitudinal associations between cerebrospinal fluid glial activation markers, depression, and dopamine transporter availability in patients with Parkinson’s disease

Depression and decreased dopamine transporter (DAT) availability are prevalent in Parkinson’s disease (PD), yet early predictive biomarkers are lacking. This study investigates the longitudinal associations between cerebrospinal fluid (CSF) neuroglial activation markers, sTREM2 and YKL-40, and depression, as well as DAT availability, in PD patients.

We analyzed data from 172 PD subjects and 80 matched healthy controls from a large longitudinal study. A generalized linear mixed-effects model assessed the longitudinal associations of CSF sTREM2 and YKL-40 with depression and DAT availability. Causal mediation analysis determined if DAT decline mediated the effects of sTREM2 and YKL-40 on depression.

Cross-sectional analysis revealed a negative correlation between CSF sTREM2 and baseline depression scores in PD patients. CSF YKL-40 negatively correlated with baseline left caudate nucleus, left anterior putamen, and right anterior putamen specific binding ratios (SBR). Longitudinally, higher baseline CSF sTREM2 predicted faster depression progression (β = 0.828, p < 0.001) and a rapid decline in right putamen SBR (β = 0.072, p = 0.016). Similarly, higher baseline CSF YKL-40 predicted faster depression progression (β = 0.586, p = 0.004) and a decline in left anterior putamen SBR (β = 0.058, p = 0.035). Causal mediation analysis indicated that baseline CSF sTREM2 accelerated depression progression via its effect on right putamen and right anterior putamen SBR (Indirect effect = 0.103, p = 0.020; Indirect effect = 0.129, p = 0.016).

CSF sTREM2 and YKL-40 are effective predictors for depression and DAT decline in PD, suggesting that neuroglial activation-induced dopaminergic neuron apoptosis significantly contributes to depression onset in PD.