Longitudinal Cerebrospinal Fluid Biomarker Changes Following Shunt Surgery in Idiopathic Normal Pressure Hydrocephalus - Insights from the Gothenburg POiNT study

Background The underlying pathophysiology of idiopathic normal pressure hydrocephalus (iNPH) is incompletely understood and reliable predictors of shunt response are lacking. Cerebrospinal fluid (CSF) biomarkers may provide insights into disease mechanisms and help identify patients most likely to benefit from surgery. The aim of this study was to explore CSF biomarker dynamics following shunt surgery and their relationship with clinical outcome. Methods The POiNT (Prediction of Outcome in iNPH) was a prospective longitudinal study. One hundred and thirty-five patients with iNPH underwent standardized clinical assessment and lumbar CSF sampling 3.6 (SD 2.1) months before and 5.7 months (SD 2.4) after shunt surgery. CSF was analyzed for biomarkers of astrogliosis, axonal injury, amyloid, and tau pathology, and synaptic dysfunction. Clinical outcomes were assessed using the iNPH scale. Associations between baseline biomarker levels, postoperative biomarker changes, and clinical outcomes were evaluated using adjusted correlation and regression analyses. Results In total, 69% (n=93) improved after shunt surgery. Substantial postoperative increases were observed for most CSF biomarkers: The largest relative increases were seen for growth-associated protein 43 (GAP43) (2.92-fold change), followed by Phosphorylated tau (2.65-fold change), Neurogranin and total-tau (both 2.29-fold change) as well as Aβ40 (1.93-fold change), and Aβ42 (1.76-fold change) (all p<0.001). In adjusted analyses, postoperative change in several biomarker levels were associated with degree of clinical improvement. However, baseline biomarker levels generally showed limited predictive value. Lower baseline monocyte chemoattractant protein-1 (MCP1) levels were associated with greater odds of overall clinical improvement but had a modest predictive performance (AUC 0.67). No baseline biomarker demonstrated strong discrimination of treatment response. Conclusion Shunt surgery was associated with substantial changes in CSF biomarker concentrations, several of which correlated with the degree of clinical improvement. Although baseline levels did not predict clinical outcome, the observed biomarker changes may reflect biological responses to treatment, altered CSF dynamics, or both .iNPH. Future studies examining these processes relating to disease reversibility might help elucidate pathophysiological mechanisms in iNPH.