Pathologically Decreased CSF Levels of Synaptic Marker NPTX2 in DLB Are Correlated with Levels of Alpha-Synuclein and VGF.

Walter Boiten,Cristina Cocco,Barbara Noli,Gian-Luca Ferri,Paul Worley,Afina Lemstra,Mei-Fang Xiao,Charlotte Teunissen,Inger Van Steenoven

doi:10.3390/cells10010038

Abstract

Background: Dementia with Lewy bodies (DLB) is a neurodegenerative disease where synaptic loss and reduced synaptic integrity are important neuropathological substrates. Neuronal Pentraxin 2(NPTX2) is a synaptic protein that drives the GABAergic inhibitory circuit. Our aim was to examine if NPTX2 cerebral spinal fluid (CSF) levels in DLB patients were altered and how these levels related to other synaptic protein levels and to cognitive function and decline. Methods: NPTX2, VGF, and α-synuclein levels were determined in CSF of cognitive healthy (n = 27), DLB (n = 48), and AD (n = 20) subjects. Multiple cognitive domains were tested, and data were compared using linear models. Results: Decreased NPTX2 levels were observed in DLB (median = 474) and AD (median = 453) compared to cognitive healthy subjects (median = 773). Strong correlations between NPTX2, VGF, and α-synuclein were observed dependent on diagnosis. Combined, these markers had a high differentiating power between DLB and cognitive healthy subjects (AUC = 0.944). Clinically, NPTX2 levels related to global cognitive function and cognitive decline in the visual spatial domain. Conclusion: NPTX2 CSF levels were reduced in DLB and closely correlated to decreased VGF and α-synuclein CSF levels. CSF NPTX2 levels in DLB related to decreased functioning in the visual spatial domain.

Highlights

One is the abnormal accumulation of α-synuclein into Lewy bodies (LBs) that is observed in Parkinson disease (PD), multiple systems atrophy, and Parkinson’s disease dementia (PDD)
A similar decrease in Alzheimer’s disease (AD) and Dementia with Lewy bodies (DLB) compared to controls was observed for the AD biomarker data
Differences in cerebral spinal fluid (CSF) levels of NPTX2 compared to subjective cognitive decline (SCD) were observed for DLB and AD (Figure 1A depicts the levels of NTPX2)

Summary

Introduction

To better understand the disease trajectory and how the underlying biological mechanisms affect disease progression, it is essential to accurately measure these processes during a individuals lifetime. In dementia with Lewy bodies (DLB), multiple pathological processes converge. One is the abnormal accumulation of α-synuclein into Lewy bodies (LBs) that is observed in Parkinson disease (PD), multiple systems atrophy, and Parkinson’s disease dementia (PDD). In a substantial portion of DLB patients (40–60%), pathological changes of Alzheimer’s disease (AD) are observed (Aβ1–42 aggregation into amyloid plaques and the phosphorylation and aggregation of tau protein) [3]. Last, reduced synaptic integrity and synaptic loss are integral pathological processes occurring in both DLB and AD [4,5]. Specific synaptic loss has been observed in primary visual cortex of DLB patient [6]

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