Serotonin, β‐amyloid, and cognition in Parkinson disease

Objective Serotoninergic neurotransmission may modulate β‐amyloid peptide (Aβ) metabolism through upregulation of α‐secretase. Early Parkinson disease (PD) shows variable serotoninergic denervation, which may impact Aβ deposition. Methods We conducted 3 analyses to explore associations between serotoninergic neurotransmission and cerebral Aβ burden in PD. The first was a cross‐sectional imaging study of PD subjects (n = 23) using the serotoninergic transporter positron emission tomography (PET) ligand [ 11 C]3‐amino‐4‐(2‐dimethylaminomethyl‐phenylsulfaryl)‐benzonitrile (DASB) and amyloid PET Pittsburgh compound B ([ 11 C]PiB). The second was a baseline study of Parkinson's Progression Markers Initiative (PPMI) subjects exploring the influence of serotoninergic medications on cerebrospinal fluid (CSF) Aβ‐42 levels (n = 389), controlling for age, sex, Geriatric Depression Scale, disease duration, and education. Third, we fit an interval censored proportional hazard model with longitudinal PPMI data (n = 367) to test whether serotoninergic medication use associates with reduced risk of PD cognitive decline, defined as time to reach a Montreal Cognitive Assessment score ≤ 20, adjusting for baseline caudate dopamine transporter [ 123 I]ioflupane single photon emission computed tomography and CSF Aβ‐42 levels. Results Serotoninergic DASB distribution volume ratio (DVR) inversely associated with PiB DVR in the cerebral cortex (Pearson r = −0.478, p = 0.021) but not the striatum ( r = −0.264, p = 0.224). In the baseline PPMI analysis, serotoninergic medication use for ≥6 months associated with a lower level of CSF Aβ‐42 ( t = −2.20, p = 0.029). In the longitudinal PPMI model, baseline serotoninergic medication use associated with a reduced risk of cognitive decline ( t = −2.03, p = 0.043) after controlling for covariates. Interpretation Cortical Aβ burden in PD associates inversely with serotoninergic innervation. Serotoninergic medications may alter Aβ metabolism and reduce the risk of PD cognitive decline. Ann Neurol 2018;83:994–1002