Objective:

Evaluate the association between baseline CSF NPTX2 levels and measures of brain atrophy in participants who were cognitively unimpaired at baseline. 

Background:

Neuronal pentraxin 2 (NPTX2) is a protein involved in synaptic plasticity and regulation of neuronal excitability. Lower baseline cerebrospinal fluid (CSF) NPTX2 levels have been shown to be associated with an earlier onset of symptoms of mild cognitive impairment (MCI), particularly when Alzheimer’s Disease (AD) biomarkers (e.g., cerebrospinal fluid (CSF) levels of amyloid beta (Aβ42/40) and phosphorylated tau (p-tau181) were considered. However, it is not known whether CSF NPTX2 levels among cognitively unimpaired individuals are associated with longitudinal brain atrophy. 

Design/Methods:

Analyses included 213 participants from the prospective longitudinal BIOCARD study, with 13.9 years of MRI follow-up on average. NPTX2 was measured in CSF as a composite of three correlated peptides obtained by quantitative parallel reaction monitoring mass spectrometry. Brain atrophy was measured longitudinally using MRI and quantified in two spatial patterns:  (1) a composite of AD-signature regions (SPARE-AD) and (2), a composite of regions sensitive to non-AD related brain aging (SPARE-BA), with higher values indicating more atrophy. Linear mixed effects models assessed the association of baseline NPTX2 levels with rate of change in the MRI atrophy patterns.

Results:

When covarying AD biomarkers (i.e., CSF p-tau181/(Aβ42/Aβ40 ratio), age, sex, APOE4, and years of education, higher NPTX2 levels were associated with less atrophy over time in both AD-vulnerable regions (SPARE-AD, β=-.008, p=.034) as well as regions sensitive to non-AD brain aging (SPARE-BA, β=-.011 p=.014). These associations did not differ by follow-up diagnosis.

Conclusions:

Findings suggest NPTX2 slows longitudinal brain atrophy in AD and aging-related regions, after accounting for biomarkers of AD pathology.  These findings are consistent with the view that NPTX2 may be a resilience factor in the presence of pathology and modify rates of neurodegeneration.