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

Olivia Belbin, Mei Fang Xiao, Desheng Xu, Maria Carmona-Iragui, Jordi Pegueroles, Bessy Benejam, Laura Videla, Susana Fernández, Isabel Barroeta, Raúl Nuñez-Llaves, Victor Montal, Eduard Vilaplana, Miren Altuna, Jordi Clarimón, Daniel Alcolea, Rafael Blesa, Alberto Lleó, Paul F. Worley, Juan Fortea

Research output: Contribution to journalArticlepeer-review

Abstract

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 Aβ1-42, CSF t-tau, cortical atrophy (magnetic resonance imaging) and glucose metabolism ([18F]-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 all clinical groups; controls (r 2 = 0.2, p = 0.003), adults with DS (r 2 = 0.4, p < 0.0001) and sporadic AD (r 2 = 0.4, p < 0.0001). In adults with DS, low CSF NPTX2 levels were associated with low CSF Aβ1-42 (r 2 > 0.3, p < 0.006), low CSF t-tau (r 2 > 0.3, p < 0.001), increased cortical atrophy (p < 0.05) and reduced glucose metabolism (p < 0.05). Conclusions: Low levels of CSF NPTX2, a protein implicated in inhibitory circuit function, is common to sporadic and genetic forms of AD. CSF NPTX2 represents a promising CSF surrogate marker of early AD-related changes in adults with DS.

Original languageEnglish (US)
Article number46
Pages (from-to)1-10
Number of pages10
JournalMolecular neurodegeneration
Volume15
Issue number1
DOIs
StatePublished - Aug 17 2020

Keywords

  • Alzheimer's disease
  • Biomarker
  • Cerebrospinal fluid
  • Cortical atrophy
  • Down syndrome
  • GluA4
  • Glucose metabolism
  • Inhibitory circuits
  • Neuronal Pentraxin-2

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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