Associations between cerebrospinal fluid synaptic protein biomarkers and cognitive function in bipolar disorder

Abstract

This study is the first to investigate the association between a comprehensive panel of cerebrospinal fluid (CSF) synaptic protein biomarkers and cognitive function using data from a prospective cohort study including N = 59 patients with bipolar disorder (BD) in remission and N = 37 healthy control individuals (HC). The CSF synaptic protein biomarkers included neuronal pentraxin (NPTX)1, NPTX2, 14-3-3 proteins, AP-2 complex subunit-beta, beta-synuclein, complexin-2, gamma-synuclein, NPTX-receptor, phosphatidylethanolamine-binding proteins, rab GDP dissociation inhibitor-alpha, syntaxins-1B and 7. The biomarkers of synaptic dysfunction were analyzed by targeted mass spectrometry. The primary cognition measure was a global cognitive composite score based on neuropsychological tests of verbal learning and memory, executive function, psychomotor speed, and sustained attention. Our primary hypothesis was that levels of NPTX1 and NPTX2 were associated with global cognition and verbal memory. The study revealed consistent positive associations between CSF concentrations of NPTX1 and NPTX2 and global cognitive function. However, only the association with a tryptic peptide from NPTX2 (VAELEDEK) remained statistically significant after adjustment for multiple tests. No consistent trends or significant relationships were found between NPTX1 and NPTX2 and verbal memory. NPTXs showed positive associations with sustained attention, and the NPTX receptor was positively associated with global cognition scores. Similar trends were found in BD patients and HC individuals. The study provides novel evidence for a potentially pivotal role of CSF synaptic proteins, particularly NPTX1, NPTX2, and NPTX-receptor, in shaping global cognitive function across BD and HC populations and increases our understanding of the neurobiological foundations for cognitive functions across diagnostic boundaries.