CSF Levels of NPTX2 Are Associated With Less Brain Atrophy Over Time in Cognitively Unimpaired Individuals.

Introduction: Neuronal pentraxin 2 (NPTX2) is a synaptic 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 mild cognitive impairment (MCI), a pre-dementia syndrome, even after CSF Alzheimer's Disease (AD) biomarkers (amyloid beta (Aβ_42/40), and phosphorylated tau (p-tau₁₈₁)) were considered. To date, however, it is not known whether CSF NPTX2 levels among cognitively unimpaired individuals are associated with longitudinal brain atrophy.

Objective(s): Evaluate the association between baseline CSF NPTX2 levels and measures of long-term brain atrophy in participants who were cognitively unimpaired at baseline.

Methods: Analyses included 213 participants (M baseline age = 57.2 years, 62% female) from the prospective longitudinal BIOCARD study with 13.9 years (max = 22.6 years) of magnetic resonance imaging (MRI) follow-up, on average. CSF NPTX2 was measured as a composite of three correlated peptides obtained by quantitative parallel reaction monitoring mass spectrometry. MRI brain atrophy was measured longitudinally with three composites. This included two spatial patterns of atrophy: (1) a composite of AD-signature regions (SPARE-AD) and (2) a composite of regions sensitive to brain aging (SPARE-BA), with higher values indicating more atrophy. Additionally, (3) a medial temporal lobe (MTL) composite included volumes of the amygdala, hippocampus, and entorhinal cortex. Linear mixed effect models assessed the association of baseline NPTX2 levels with the rate of change in the brain atrophy measures.

Results: When covarying biomarkers of AD pathology (i.e., the ratio of CSF p-tau₁₈₁/(Aβ_1-42/Aβ_1-40), age, sex, APOE4 genetic status, and years of education), lower baseline NPTX2 levels were associated with greater atrophy over time in both AD-vulnerable regions (SPARE-AD, standardized estimate = -0.008, p = 0.034) as well as regions sensitive to brain aging (SPARE-BA, standardized estimate = -0.011, p = 0.014). These associations were independent of participants having follow-up diagnoses of MCI or dementia.

Conclusion: Our findings suggest that after accounting for biomarkers of AD pathology, CSF NPTX2 is associated with slower longitudinal atrophy in AD-signature and aging-related regions. These findings are consistent with the view that NPTX2 may be a resilience factor in the presence of pathology and modifies rates of neurodegeneration.