Synaptic biomarkers in CSF aid in diagnosis, correlate with cognition and predict progression in MCI and Alzheimer's disease

Jeroen Vanbrabant,Paul Worley,Hugo Vanderstichele,Eugeen Vanmechelen,Desheng Xu,Meifang Xiao,David P Salmon,Denis Smirnov,Nele Dewit,Dirk Jacobs,Douglas Galasko

doi:10.1016/j.trci.2019.11.002

Abstract

IntroductionAmyloid, Tau, and neurodegeneration biomarkers can stage Alzheimer's Disease (AD). Synaptic biomarkers may help track cognition. MethodsIn cognitively normal controls, Mild Cognitive Impairment (MCI) and AD, we investigated CSF biomarkers in relation to cognitive measures and as predictors of cognitive and global decline. ResultsThere were 90 normal controls (mean age 73.0, 58% women), 57 MCI (mean age 74.3, 35% women), and 46 AD (mean age 70.7, 41% women). CSF Aβ1-42 and Neuronal Pentraxin 2 (NPTX2) were decreased, and CSF Tau, neurogranin, and SNAP25 increased in AD versus controls. Aβ1-42/Tau or NPTX2/Tau discriminated AD and controls best. NPTX2/Tau correlated strongly with cognition in AD and MCI and predicted a 2–3-year decline. We replicated findings in the ADNI cohort. DiscussionCSF synaptic biomarkers, particularly NPTX2, which regulates synaptic homeostasis, relate to cognition and predict progression in AD beyond Aβ1-42 and Tau. This is relevant for prognosis and clinical trials.

Highlights

A recently proposed research framework emphasizes biomarkers for amyloid, tau, and neurodegeneration (A,T,N) for diagnosis and staging of Alzheimer’s Disease (AD) [1,2]
We reported that Neuronal Pentraxin 2 (NPTX2), a secreted synaptic protein that mediates homeostatic adaptation to increased excitability by enhancing inhibitory synaptic circuits [17,18], is markedly decreased in postmortem brain lysates and in CSF in Mild Cognitive Impairment (MCI) and AD [19]
This study extends previous efforts to link CSF biomarkers and cognition by focusing on markers of synaptic dysfunction across normal cognition, MCI, and mild AD-dementia

Summary

Introduction

A recently proposed research framework emphasizes biomarkers for amyloid, tau, and neurodegeneration (A,T,N) for diagnosis and staging of Alzheimer’s Disease (AD) [1,2]. Neurodegeneration biomarkers investigated in AD include brain atrophy measured by MRI [3], decreased regional. Synaptic damage or dysfunction is a key pathological feature of AD that correlates with cognitive function in clinical-pathological studies and may link Tau and amyloid pathogenetic mechanisms [8].

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Conclusion