Serotonin, β-amyloid, and cognition in Parkinson disease

Ann Neurol. 2018 May;83(5):994-1002. doi: 10.1002/ana.25236. Epub 2018 May 11.

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 [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.

MeSH terms

  • Aged
  • Amyloid beta-Peptides / metabolism*
  • Brain / metabolism
  • Cognition / physiology
  • Cognitive Dysfunction / metabolism*
  • Cognitive Dysfunction / physiopathology
  • Female
  • Humans
  • Male
  • Middle Aged
  • Parkinson Disease / metabolism*
  • Parkinson Disease / physiopathology
  • Serotonin / metabolism*
  • tau Proteins / metabolism

Substances

  • Amyloid beta-Peptides
  • tau Proteins
  • Serotonin