Serotonin, β‐amyloid, and cognition in Parkinson disease

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Abstract
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 [11C]3‐amino‐4‐(2‐dimethylaminomethyl‐phenylsulfaryl)‐benzonitrile (DASB) and amyloid PET Pittsburgh compound B ([11C]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 [123I]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

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