NPTX2 in Cerebrospinal Fluid Predicts the Progression From Normal Cognition to Mild Cognitive Impairment

Abstract

ObjectiveThis study examined whether cerebrospinal fluid (CSF) baseline levels of the synaptic protein NPTX2 predict time to onset of symptoms of mild cognitive impairment (MCI), both alone and when accounting for traditional CSF Alzheimer's disease (AD) biomarker levels. Longitudinal NPTX2 levels were also examined.MethodsCSF was collected longitudinally from 269 cognitively normal BIOCARD Study participants (mean baseline age = 57.7 years; mean follow‐up = 16.3 years; n = 77 progressed to MCI/dementia). NPTX2 levels were measured from 3 correlated peptides using quantitative parallel reaction monitoring mass spectrometry. Levels of Aβ42/Aβ40, p‐tau181, and t‐tau were measured from the same CSF specimens using Lumipulse automated electrochemiluminescence assays.ResultsIn Cox regression models, lower baseline NPTX2 levels were associated with an earlier time to MCI symptom onset (hazard ratio [HR] = 0.76, SE = 0.09, p = 0.023). This association was significant for progression within 7 years (p = 0.036) and after 7 years from baseline (p = 0.001). Baseline NPTX2 levels improved prediction of time to MCI symptom onset after accounting for baseline AD biomarker levels (p < 0.01), and NPTX2 did not interact with the CSF AD biomarkers or APOE‐ε4 genetic status. In linear mixed effects models, higher baseline p‐tau181 and t‐tau levels were associated with higher baseline levels of NPTX2 (both p < 0.001) and greater rates of NPTX2 declines over time.InterpretationNPTX2 may be a valuable prognostic biomarker during preclinical AD that provides additive and independent prediction of MCI onset among individuals who are cognitively normal. We hypothesize that NPTX2‐mediated circuit homeostasis confers resilience during the early phase of AD. ANN NEUROL 2023

Biomarker discovery in progressive supranuclear palsy from human cerebrospinal fluid using mass spectrometry-based proteomics

“…Other than the top differentially expressed proteins, we also observed downregulation of NPTX2 (0.31 of mean of bootstrap AUC and 0.005 of q-value in PSP vs. PD plus HC: 0.31), which is a synaptic protein that plays a crucial role in regulating cortical network dynamics, synaptic adaptability, memory, and is associated with cognitive decline and AD progression. 25–27 These results suggest that we successfully identified differentially expressed proteins in PSP.…”

“…In this study, NPTX2 was downregulated in PSP compared to PD and HC. The downregulation of NPTX2 is a predictive marker for the progression from normal cognition to mild cognitive impairment, 25 and cognitive decline is a typical symptom of PSP. 64 This suggests that dysregulated synaptic adaptability mediated by NPTX2 downregulation could be a potential mechanism of the cognitive decline of PSP patients.…”

Association of reduced cerebrospinal fluid NPTX2 levels with postoperative delirium in patients undergoing knee/hip replacement: a prospective cohort study

“…Studies have shown that NPTX2 can improve microglia-mediated synaptic loss by inhibiting complement activity in the brain, and the decrease of NPTX2 concentration may exacerbate complement-mediated neurodegeneration [ 9 ]. In recent years, NPTX2 has been suggested to provide additional and independent prediction of the onset of mild cognitive impairment (MCI) in cognitively normal individuals, and it might serve as an important prognostic biomarker during preclinical AD [ 26 ]. In addition to CSF NPTX2 levels, serum NPTX2 levels are also thought to be independently associated with cognitive function and can be used as a predictor of cognitive function [ 27 ].…”

Neutrophil-Mediated Progression of Mild Cognitive Impairment to Dementia

“…Many studies have identified novel targets for monitoring disease progression and improving prognosis. Research approaches for biomarkers have been studied to evaluate abnormal CSF levels of amyloid and tau among individuals with normal cognition and patients with MCI or dementia [16,19,20]. A recent study longitudinally collected samples from 269 cognitively healthy individuals and measured the synaptic protein neuronal pentraxin 2 (NPTX2) levels [16,19,20].…”

“…Research approaches for biomarkers have been studied to evaluate abnormal CSF levels of amyloid and tau among individuals with normal cognition and patients with MCI or dementia [16,19,20]. A recent study longitudinally collected samples from 269 cognitively healthy individuals and measured the synaptic protein neuronal pentraxin 2 (NPTX2) levels [16,19,20]. NPTX2 plays a role in homeostatic regulation in the CNS, including memory in the brain [21].…”