Cerebrospinal fluid biomarker panel for synaptic dysfunction in Alzheimer's disease

Abstract

Introduction Synaptic dysfunction and degeneration is one of the earliest events in Alzheimer's disease (AD) and the best correlate of cognitive decline. Thus, identification and validation of biomarkers reflecting synaptic degeneration to be used as prognostic biomarkers are greatly needed. Method Solid‐phase extraction and parallel reaction monitoring mass spectrometry were used to quantify 17 synaptic proteins in CSF, in two cross‐sectional studies including AD (n = 52) and controls (n = 37). Results Increased concentrations of beta‐synuclein, gamma‐synuclein, neurogranin, phosphatidylethanolamine‐binding protein 1, and 14‐3‐3 proteins were observed in AD patients compared to controls, while neuronal pentraxin‐2 and neuronal pentraxin receptor were decreased. Discussion We have established a method with a novel panel of synaptic proteins as biomarkers of synaptic dysfunction. The results indicate that several of the proteins included in the panel may serve as synaptic biomarkers for AD.

Neuronal pentraxins as biomarkers of synaptic activity: from physiological functions to pathological changes in neurodegeneration

“…Consequently, the reduction of NPTX2 could be linked to the disruption of pyramidal neuron-PV interneuron microcircuit, contributing to cognitive failure in AD (Xiao et al 2017). This was further sustained by studies that found NPTX2 correlating with medial temporal atrophy, hippocampal volume and cognitive impairment (Nilsson et al 2021;Swanson et al 2016;Xiao et al 2017). In addition, new evidence suggested NPTX2 as a strong prognostic biomarker candidate of cognitive decline (Libiger et al 2021).…”

“…NPTXs seemed to moderately correlate with many synaptic markers (e.g., β-synuclein, γ-synuclein, neurogranin, syntaxin, SNAP25) in the healthy control and the AD group. Intriguingly, they declined in AD patients, opposite to the other synaptic markers that primarily increased in CSF (Galasko et al 2019;Nilsson et al 2021). As for non-AD conditions, NPTX2 correlated with CSF levels of other synaptic proteins such as neurosecretory protein VGF and α-synuclein in DLB (Boiten et al 2020).…”

Cerebrospinal fluid concentration of complement component 4A is increased in first-episode schizophrenia

“…The copyright holder for this this version posted August 24, 2021. ; https://doi.org/10.1101/2021.08.17.21262131 doi: medRxiv preprint 8 disease 16,17 . Thus, we measured these three markers in CSF from the KaSP cohort (FEP patients n=43; HCs n=19).…”

“…Lastly, as C4A CNs predict synaptic complement deposition and synaptic pruning in experimental models 6 , we explored associations between CSF C4A protein concentrations and an in vivo proxy of synapse density. CSF levels of neuronal pentraxins (1, 2, and receptor) were recently shown to inversely correlate with prefrontal cortical thickness determined with MRI, as well as to predict synapse loss in dementia and Alzheimer's 8 disease 16,17 . Thus, we measured these three markers in CSF from the KaSP cohort (FEP patients n=43; HCs n=19).…”

“…Preparation of samples and LC-MS/MS analyses were performed as previously described 17 using micro-high-performance liquid chromatography-mass-spectrometry (6495 Triple Quadrupole LC/MS system, Agilent Technologies). Briefly, in a flow-rate of 0.3 mL/min, sample injection of 40 µL and a 30 min gradient was employed for separation on a Hypersil Gold reversed phase column (dim.…”