Cerebrospinal Fluid Biomarkers of Synaptic Dysfunction are Altered in Parkinson's Disease and Related Disorders

Abstract

A BS TRACT: Background: Synaptic dysfunction and degeneration are central contributors to the pathogenesis and progression of parkinsonian disorders. Therefore, identification and validation of biomarkers reflecting pathological synaptic alterations are greatly needed and could be used in prognostic assessment and to monitor treatment effects. Objective: To explore candidate biomarkers of synaptic dysfunction in Parkinson's disease (PD) and related disorders. Methods: Mass spectrometry was used to quantify 15 synaptic proteins in two clinical cerebrospinal fluid (CSF) cohorts, including PD (n 1 = 51, n 2 = 101), corticobasal degeneration (CBD) (n 1 = 11, n 2 = 3), progressive supranuclear palsy (PSP) (n 1 = 22, n 2 = 21), multiple system atrophy (MSA) (n 1 = 31, n 2 = 26), and healthy control (HC) (n 1 = 48, n 2 = 30) participants, as well as Alzheimer's disease (AD) (n 2 = 23) patients in the second cohort.Results: Across both cohorts, lower levels of the neuronal pentraxins (NPTX; 1, 2, and receptor) were found in PD, MSA, and PSP, compared with HC. In MSA and PSP, lower neurogranin, AP2B1, and complexin-2 levels compared with HC were observed. In AD, levels of 14-3-3 zeta/delta, beta-and gamma-synuclein were higher compared with the parkinsonian disorders. Lower pentraxin

Alzheimer's Disease Biomarker Analysis Using Targeted Mass Spectrometry

“…Of special interest is that the levels seem to follow a constant linear decrease from controls to MCI and finally to AD ( 105 ). A similar pattern has also been found in PD ( 105 ), and the neuronal pentraxins seem to be potential monitoring biomarkers of the decline of cognitive and motor functions across neurodegenerative diseases; however, they seem to change later in the AD continuum than other synaptic biomarkers and possibly be more affected at later stages of AD ( 106 ).…”

“…Different members of the neuronal pentraxin family have been quantified in several SRM-based TMS assays and have commonly been found to have reduced CSF levels in AD in comparison with controls ( 106 ). Of special interest is that the levels seem to follow a constant linear decrease from controls to MCI and finally to AD ( 105 ).…”

“…Lately, four of the 14-3-3 proteins (ζ/δ, θ, η, and ε) were targeted in an SRM-based synaptic CSF panel assay ( 106 ). Across the studies, progressively higher concentrations of 14-3-3 ζ/δ were found in the AD continuum.…”

Proteomic analysis of the human hippocampus identifies neuronal pentraxin 1 (NPTX1) as synapto‐axonal target in late‐stage Parkinson's disease

“…Only few studies explored the relevance of neuronal pentraxins for PD pathology (Li et al, 2019; Moran et al, 2008). A couple of studies have recently reported decreased levels of NPTX1, NPTX2, and NPTXR in PD CSF (Lerche et al, 2021; Nilsson et al, 2023).…”

Lysosomal and synaptic dysfunction markers in longitudinal cerebrospinal fluid spanning from healthy subjects to prodromal and manifest Parkinson’s disease

“…We sought to ll this gap by investigating an established panel of lysosomal and synaptic markers (Table 2) validated in different cohorts [26][27][28] . Over a 10-year follow-up, we used this approach to longitudinally assess differently expressed proteins in CSF between subjects with iRBD, de novo PD, and healthy controls from our ongoing, prospective, single-center de novo Parkinson's disease (DeNoPa) cohort 29 .…”