Lower synaptic density in mood circuitry underlies depression in Parkinson's disease

Depression in Parkinson's disease is often reported as being more debilitating than the motor symptoms and has been shown to accelerate disease progression. Identifying its underlying neurobiology is crucial in the discovery of mechanism-informed treatments. We hypothesize that lower synaptic density in mood circuitry drives symptoms of depression in Parkinson's disease. To test this hypothesis, we used PET imaging and [¹¹C]UCB-J-a radiotracer that binds to synaptic vesicle protein 2A (SV2A) to image synaptic density across patients with Parkinson's disease and depressive symptoms (PDd; n = 10), Parkinson's disease patients without depressive symptoms (PDnd; n = 20) and healthy controls (HCs; n = 18). The primary outcome was binding potential (BP_ND) in mood circuitry. Participants with PDd exhibited significantly lower synaptic density compared to HC and PDnd in the dorsolateral prefrontal cortex (dlPFC) (-22.0%, P < 0.001; -19.9%, P = 0.002), anterior cingulate cortex (ACC) (-27.9%, P < 0.001; -24.0%, P = 0.002), amygdala (-25.1%, P < 0.001; -18.9%, P = 0.006) and hippocampus (-28.1%, P < 0.001; -20.3%, P = 0.003). Synaptic density was significantly and negatively correlated with the severity of depressive symptoms across all participants with Parkinson's disease (n = 30) in the dlPFC (r = -0.59, P = 0.002), ACC (r = -0.68, P < 0.001), amygdala (r = -0.53, P = 0.004) and hippocampus (r = -0.56, P = 0.003). These findings provide the first in vivo evidence that lower synaptic density in mood-related brain regions may contribute to depression in Parkinson's disease. If confirmed, they would support the evaluation of interventions that target synaptic loss/induce synaptic plasticity in individuals with Parkinson's disease and comorbid depression.