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 utilizing data from a prospective cohort study including N = 59 patients with bipolar disorder (BD) and N = 37 healthy control individuals (HC). Biomarkers of synaptic dysfunction were analyzed by targeted mass spectrometry. They 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 primary cognition measure was a global cognitive composite score based on neuropsychological tests probing verbal learning and memory, executive function, psychomotor speed, and sustained attention, respectively. Our primary hypothesis was that levels of NPTX1 and NPTX2 were associated with global cognition and verbal memory after adjustment for age, sex, and follow-up time as potential confounders. The study revealed consistent positive associations between CSF protein 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 testing. In contrast, no consistent trends and no significant relationships were found between NPTX1 and NPTX2 and the verbal learning and memory domain. In exploratory analyses, NPTXs showed positive associations with sustained attention, and the NPTX receptor showed a positive association with global cognition scores. Similar trends were found in BD patients and HC individuals, although results remain statistically uncertain, and a spurious finding cannot be ruled out due to multiple testing. In summary, 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.