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

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.

Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson’s disease and dementia with Lewy bodies

“…Recent studies reported lower CSF protein levels of AP-2-complex subunit beta, cathepsin F, ganglioside GM2 activator, lysosomal-associated membrane glycoprotein 1 and 2, and ubiquitin in PD compared to patients with Alzheimer’s disease and controls, and decreased CSF levels of chromogranin-A and B, neurosecretory protein VGF, and secretogranin species in PD and DLB compared to controls [ 30 , 31 ]. Interestingly, lower CSF levels of VGF were associated with lower CSF levels of α-Syn while no association was found with Aβ 1–42 [ 32 , 33 ]. These data suggest that amplification assays such as RT-QuIC might provide new tools to study in-vivo the mechanistic link between proteins linked to α-Syn proteostasis and seeding, which was previously shown only in post-mortem studies and cell models [ 34 – 39 ].…”

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

“…This could be due to an impairment of the GABAergic transmission and a possible interneuron dysfunction in this region (Khundakar et al 2016 ), where NPTXs participate in synaptic refinement (Bjartmar et al 2006 ). NPTX2 CSF levels were lower in patients with DLB than in cognitive healthy controls (Boiten et al 2020 ). Additionally, these values correlated with cognitive function in the visual spatial domain (Boiten et al 2020 ).…”

“…NPTX2 CSF levels were lower in patients with DLB than in cognitive healthy controls (Boiten et al 2020 ). Additionally, these values correlated with cognitive function in the visual spatial domain (Boiten et al 2020 ). These results suggested an impairment of the principal neuron-interneuron microcircuit in the primary visual cortex in DLB patients, reflected by a decline in CSF NPTX2 levels (Boiten et al 2020 ).…”

“…Recent studies in cerebrospinal fluid (CSF) revealed altered NPTXs levels in several neurodegenerative disorders. Even though AD patients have been mostly investigated so far (Begcevic et al 2018 ; Brinkmalm et al 2018 ; Duits et al 2018 ; Galasko et al 2019 ; Hendrickson et al 2015 ; Lim et al 2019 ; Llano et al 2017 ; Nilsson et al 2021 ; Ringman et al 2012 ; Soldan et al 2019 ; Spellman et al 2015 ; Swanson et al 2016 ; Wildsmith et al 2014 ; Xiao et al 2017 ; Yin et al 2009 ), some data are also available for other neurodegenerative disorders such as frontotemporal lobar degeneration (FTLD) and synucleinopathies, as well as for psychiatric disorders (Barschke et al 2020 ; Boiten et al 2020 ; Charbonnier-Beaupel et al 2015 ; Eastwood and Harrison 2010 ; Moran et al 2008 ; Remnestål et al 2020 ; van der Ende et al 2020 , 2019 ). To date, measurements of NPTXs can only be performed in CSF samples, due to the insufficient assay sensitivity for a reliable quantification in blood.…”

Correction: Boiten et al. Pathologically Decreased CSF Levels of Synaptic Marker NPTX2 in DLB Are Correlated with Levels of Alpha-Synuclein and VGF. Cells 2021, 10, 38

“…The authors want to notify that they have made the following changes to the author list of the paper [ 1 ]. Barbara Noli, Cristina Cocco, Gian-Luca Ferri have been added as the co-authors.…”