Neuronal pentraxin 2: a synapse-derived CSF biomarker in genetic frontotemporal dementia

Ende, Emma L. van der; Xiao, Mei-Fang; Xu, Desheng; Poos, Jackie M.; Panman, Jessica L.; Jiskoot, Lize C.; Meeter, Lieke H.H.; Dopper, Elise G.P.; Papma, Janne M.; Heller, Carolin; Convery, Rhian S.; Moore, Katrina; Bocchetta, Martina; Neason, Mollie; Peakman, Georgia; Cash, David M.; Teunissen, Charlotte E.; Graff, Caroline; Synofzik, Matthis; Moreno, Fermín; Finger, Elizabeth; Sánchez‐Valle, Raquel; Vandenberghe, Rik; Laforce, Robert; Masellis, Mario; Tartaglia, Maria Carmela; Rowe, James B.; Butler, Chris; Ducharme, Simon; Gerhard, Alex; Danek, Adrian; Xiong, Chengjie; Pijnenburg, Yolande A.L.; Otto, Markus; Borroni, Barbara; Tagliavini, Fabrizio; Mendonça, Alexandre de; Santana, Isabel; Galimberti, Daniela; Seelaar, Harro; Rohrer, Jonathan D.; Worley, Paul F.; Swieten, John C. van

doi:10.1136/jnnp-2019-322493

Cited by 65 publications

(86 citation statements)

References 39 publications

(79 reference statements)

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“…In previous studies in sporadic AD, CSF NPTX2 levels correlated better with cognitive performance than the core AD biomarkers [12]. Furthermore, in genetic frontotemporal dementia, low CSF NPTX2 levels predicted subsequent decline in phonemic verbal fluency and Clinical Dementia Rating scale [41]. In contrast, here we report that reduced CSF NPTX2 levels were not associated with any measure of cognitive performance in adults with DS.…”

Section: Discussioncontrasting

confidence: 63%

Cerebrospinal fluid profile of NPTX2 supports role of Alzheimer’s disease-related inhibitory circuit dysfunction in adults with Down syndrome

Xiao

Carmona-Iragui

et al. 2020

Mol Neurodegeneration

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Background: Alzheimer's disease (AD) is the major cause of death in adults with Down syndrome (DS). There is an urgent need for objective markers of AD in the DS population to improve early diagnosis and monitor disease progression. NPTX2 has recently emerged as a promising cerebrospinal fluid (CSF) biomarker of Alzheimer-related inhibitory circuit dysfunction in sporadic AD patients. The objective of this study was to evaluate NPTX2 in the CSF of adults with DS and to explore the relationship of NPTX2 to CSF levels of the PV interneuron receptor, GluA4, and existing AD biomarkers (CSF and neuroimaging). Methods: This is a cross-sectional, retrospective study of adults with DS with asymptomatic AD (aDS, n = 49), prodromal AD (pDS, n = 18) and AD dementia (dDS, n = 27). Non-trisomic controls (n = 34) and patients with sporadic AD dementia (sAD, n = 40) were included for comparison. We compared group differences in CSF NPTX2 according to clinical diagnosis and degree of intellectual disability. We determined the relationship of CSF NPTX2 levels to age, cognitive performance (CAMCOG, free and cued selective reminding, semantic verbal fluency), CSF levels of a PV-interneuron marker (GluA4) and core AD biomarkers; CSF Aβ 1-42 , CSF t-tau, cortical atrophy (magnetic resonance imaging) and glucose metabolism ([ 18 F]-fluorodeoxyglucose positron emission tomography). Results: Compared to controls, mean CSF NPTX2 levels were lower in DS at all AD stages; aDS (0.6-fold, adj.p < 0.0001), pDS (0.5-fold, adj.p < 0.0001) and dDS (0.3-fold, adj.p < 0.0001). This reduction was similar to that observed in sporadic AD (0.5-fold, adj.p < 0.0001). CSF NPTX2 levels were not associated with age (p = 0.6), intellectual disability (p = 0.7) or cognitive performance (all p > 0.07). Low CSF NPTX2 levels were associated with low GluA4 in

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Section: Discussioncontrasting

confidence: 63%

Cerebrospinal fluid profile of NPTX2 supports role of Alzheimer’s disease-related inhibitory circuit dysfunction in adults with Down syndrome

Xiao

Carmona-Iragui

et al. 2020

Mol Neurodegeneration

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“…CHI3L2 and UCHL1 [20,21], which showed increases of ~6 fold and ~2 fold respectively and APOB [30], which was elevated by ~4 fold, were also identified in CSF from ALS patients. In addition, we identified several proteins that were downregulated in ALS, the most prominent of which included L1CAM1 and NPTX2, which was previously identified as downregulated in FTLD [31].…”

Section: Selection Of Candidate Biomarkers For Alsmentioning

confidence: 79%

Discovery of Biomarkers for Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration From Human Cerebrospinal Fluid Using Mass Spectrometry-Based Proteomics

Jang

VandeVrede

et al. 2021

Preprint

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BackgroundAmyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are progressive neurodegenerative diseases that share clinical and neuropathologic features. Critical to the mission of developing effective therapies for ALS and FTLD is the discovery of biomarkers that can illuminate shared mechanisms of neurodegeneration, which can then be evaluated for diagnostic, prognostic or pharmacodynamic value across the disease spectrums. MethodsHere, we merged unbiased discovery-based approaches and targeted quantitative comparative analyses between ALS and FTLD cerebrospinal fluid (CSF) to identify proteins that are altered in ALS and FTLD. ResultsDiscovery mass spectrometry (MS)-based proteomic approaches combined with tandem mass tags (TMT) quantification methods from 40 CSF samples comprising 20 patients with ALS and 20 healthy control (HC) individuals identified 19 differentially expressed candidate biomarker proteins after CSF fractionation. Notably, these candidate biomarkers included novel and previously identified proteins, thus validating our approach. Candidate biomarkers were subsequently examined using parallel reaction monitoring (PRM) MS methods on 80 unfractionated CSF samples comprising 30 patients with ALS, 19 patients with FTLD, and 31 HC individuals. Two candidate biomarkers (CNTNAP2 and CLSTN1) were downregulated in both ALS and FTLD compared to healthy controls, and 11 further candidate proteins were significantly downregulated in FTLD compared to HC. ConclusionsTaken together, this study identifies multiple novel proteins that are altered in ALS and FTLD, which provides the foundation for their evaluation and development as biomarkers for these diseases.

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“…Recent studies have investigated the neuronal pentraxin (NPTX) family of proteins as synaptic dysfunction markers 79,123 . NPs are multifunctional proteins implicated in synaptic plasticity.…”

Section: Other Synaptic Markersmentioning

confidence: 99%

“…Decreased CSF levels of neuronal pentraxin receptor (NPTXR) have been shown in symptomatic genetic FTD 123 whilst neuronal pentraxin 2 (NPTX2) is decreased in symptomatic GRN and C9orf72 mutation carriers but not in MAPT mutation carriers. Levels of NPTX2 in CSF correlate with disease progression and NfL levels, and can predict symptom onset 123 .…”

Section: Other Synaptic Markersmentioning

confidence: 99%

Fluid biomarkers in frontotemporal dementia: past, present and future

Swift

Sogorb‐Esteve

Heller

et al. 2020

J Neurol Neurosurg Psychiatry

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The frontotemporal dementia (FTD) spectrum of neurodegenerative disorders includes a heterogeneous group of conditions. However, following on from a series of important molecular studies in the early 2000s, major advances have now been made in the understanding of the pathological and genetic underpinnings of the disease. In turn, alongside the development of novel methodologies for measuring proteins and other molecules in biological fluids, the last 10 years have seen a huge increase in biomarker studies within FTD. This recent past has focused on attempting to develop markers that will help differentiate FTD from other dementias (particularly Alzheimer’s disease (AD)), as well as from non-neurodegenerative conditions such as primary psychiatric disorders. While cerebrospinal fluid, and more recently blood, markers of AD have been successfully developed, specific markers identifying primary tauopathies or TDP-43 proteinopathies are still lacking. More focus at the moment has been on non-specific markers of neurodegeneration, and in particular, multiple studies of neurofilament light chain have highlighted its importance as a diagnostic, prognostic and staging marker of FTD. As clinical trials get under way in specific genetic forms of FTD, measures of progranulin and dipeptide repeat proteins in biofluids have become important potential measures of therapeutic response. However, understanding of whether drugs restore cellular function will also be important, and studies of key pathophysiological processes, including neuroinflammation, lysosomal function and synaptic health, are also now becoming more common. There is much still to learn in the fluid biomarker field in FTD, but the creation of large multinational cohorts is facilitating better powered studies and will pave the way for larger omics studies, including proteomics, metabolomics and lipidomics, as well as investigations of multimodal biomarker combinations across fluids, brain imaging and other domains. Here we provide an overview of the past, present and future of fluid biomarkers within the FTD field.

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Neuronal pentraxin 2: a synapse-derived CSF biomarker in genetic frontotemporal dementia

Cited by 65 publications

References 39 publications

Cerebrospinal fluid profile of NPTX2 supports role of Alzheimer’s disease-related inhibitory circuit dysfunction in adults with Down syndrome

Cerebrospinal fluid profile of NPTX2 supports role of Alzheimer’s disease-related inhibitory circuit dysfunction in adults with Down syndrome

Discovery of Biomarkers for Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration From Human Cerebrospinal Fluid Using Mass Spectrometry-Based Proteomics

Fluid biomarkers in frontotemporal dementia: past, present and future

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