Cerebrospinal fluid biomarker panel of synaptic dysfunction in Alzheimer's disease and other neurodegenerative disorders

Abstract

Introduction: Synaptic degeneration is a key part of the pathophysiology of neurodegenerative diseases, and biomarkers reflecting the pathological alterations are greatly needed.

Method: Seventeen synaptic proteins were quantified in a pathology-confirmed cerebrospinal fluid cohort of patients with Alzheimer's disease (AD; n = 63), frontotemporal lobar degeneration (FTLD; n = 53), and Lewy body spectrum of disorders (LBD; n = 21), as well as healthy controls (HC; n = 48).

Results: Comparisons revealed four distinct patterns: markers decreased across all neurodegenerative conditions compared to HC (the neuronal pentraxins), markers increased across all neurodegenerative conditions (14-3-3 zeta/delta), markers selectively increased in AD compared to other neurodegenerative conditions (neurogranin and beta-synuclein), and markers selectively decreased in LBD and FTLD compared to HC and AD (AP2B1 and syntaxin-1B).

Discussion: Several of the synaptic proteins may serve as biomarkers for synaptic dysfunction in AD, LBD, and FTLD. Additionally, differential patterns of synaptic protein alterations seem to be present across neurodegenerative diseases.

Highlights: A panel of synaptic proteins were quantified in the cerebrospinal fluid using mass spectrometry. We compared Alzheimer's disease, frontotemporal degeneration, and Lewy body spectrum of disorders. Pathology was confirmed by autopsy or familial mutations. We discovered synaptic biomarkers for synaptic degeneration and cognitive decline. We found differential patterns of synaptic proteins across neurodegenerative diseases.

Keywords: Alzheimer's disease; Lewy body spectrum of disorders; biomarkers; frontotemporal lobar degeneration; mass spectrometry; synaptic pathology.

Figure 1.

(A) Hierarchical cluster analysis by using Spearman rank correlation coefficient as distance. From the cluster analysis it emerged that some of the measured proteins correlated strongly with each other. (B) MRM analysis of the synaptic panel proteins (one representative peptide for each protein) in the clinical sample consisting of healthy controls (HC, n=48), and pathology confirmed cases of Alzheimer’s disease (AD, n=63), Lewy body spectrum of disorders (LBD, n=21), and frontotemporal lobar degeneration (FTLD, n=53). Statistical comparison was performed with rank-based analyses of covariance, including age and sex as covariates, with p-value adjustment for multiple group comparisons. P-values: * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001 and **** p ≤ 0.0001.

Figure 2.

CSF concentrations of 14-3-3 zeta/delta, and beta-synuclein in the pathology confirmed cases of Alzheimer’s disease (AD, n=63), Lewy body spectrum of disorders (LBD, n=21), and frontotemporal lobar degeneration (FTLD, n=53). From left to right; the groups are based on primary pathology group, ADNC (Not, Low, Intermediate [Int], High), CERAD score, and Braak stage. Statistical comparison was performed with rank-based ANCOVA adjusted for interval from CSF to death and sex. P-values: * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001 and **** P ≤ 0.0001.

Figure 3.

(A) Receiver operating curves calculated for Alzheimer’s disease versus healthy controls, healthy controls vs non-Alzheimer’s disease, and Alzheimer’s disease versus non-Alzheimer’s disease for the five synaptic proteins with the highest area under the curve vales. (B) Association between neuronal pentraxin-2 and MMSE for Alzheimer’s disease and non-Alzheimer’s disease with Spearman rank correlation coefficient and p-value.