CSF Biomarkers Predict Gait Outcomes in Idiopathic Normal Pressure Hydrocephalus

Abstract

Objective:The assessment of biomarkers in selecting idiopathic normal pressure hydrocephalus (iNPH) patients for shunt surgery has been limited to small cohort studies and those with limited follow-up. We assessed the potential for cerebrospinal fluid (CSF) biomarkers in predicting immediate response to CSF tap test (TT) and long-term response after shunt surgery.Methods:CSF was obtained from iNPH patients referred for CSF TT after baseline assessment of cognition and gait. CSF neurofilament-light (NFL), β-amyloid-42 (Aβ1-42), β-amyloid-40 (Aβ1-40), total tau (t-Tau), and phosphorylated-tau-181(pTau181) and leucine-rich-alpha-2-glycoprotein1 (LRG1) were measured by ELISA. The ability of these measures to predict immediate improvement following CSF TT and long-term improvement following shunt surgery was compared by univariate and adjusted multivariate regression.Results:Lower NFL, pTau181, tTau and Aβ1-40 were individually predictive of long-term improvement in gait outcomes after shunt surgery. A multivariate model of these biomarkers and MRI Evan's index, adjusted for age, improved prediction (AUC-ROC: 0.76, (95% CI [0.66, 0.86]). tTau, pTau181 and Aβ1-40 levels were statistically different in those whose gait improved after CSF TT compared to those who did not. Using a multivariate model, combining these markers with Evan's index and transependymal flow did not significantly improve prediction of an immediate response to CSF TT.Conclusion:A combination of CSF biomarkers can predict improvement following shunt surgery for iNPH. However, these measures only modestly discriminate responders from non-responders following CSF TT. The findings further suggest that abnormal CSF biomarkers in non-responders may represent comorbid neurodegenerative pathology or a pre-degenerative phase that presents with an iNPH phenotype.

Cerebrospinal Fluid Biomarkers in iNPH: A Narrative Review

“…Nevertheless, a most recent metanalysis made by Thavarajasingam et al (2022), did not support the aforementioned conclusion, suggesting that CSF concentrations of t-tau and p-tau are significantly higher among iNPH patients that did not respond to shunt surgery compared to those who responded [ 85 ]. Finally, in 2022, Darrow et al concluded that lower CSF concentrations of p-tau, t-tau and Aβ40 are associated with long-term improvement of kinetic symptoms [ 86 ].…”

“…As regards NFL, higher concentrations were correlated with more extensive periventricular pathological density, worse gait, balance, wakefulness and neuropsychological performance, while lower concentrations were correlated to long-term kinetic improvement. Postoperatively, a greater improvement in gait and balance performance correlated with a greater reduction in NFL [ 55 , 56 , 86 ]. Despite the above, Jeppsson et al (2013) concluded that NFL concentrations were increased after shunt surgery [ 39 ].…”

“…Greater increase of Aβ42 after shunt surgery seems to correlate positively with shunt responsiveness [ 39 , 82 ], even though Kang et al in 2014 suggested that lower concentrations of Aβ42 were associated with worse cognitive performance [ 89 ]. Lower concentrations of t-tau, reflecting less neuronal damage, are correlated with less severe symptoms and greater possibility of kinetic improvement [ 34 , 86 ]. NFL concentration seems to positively correlate both with the severity of iNPH symptoms and the periventricular load of pathological densities, whereas the extent of reduction of its concentration after shunt surgery correlates positively with patients’ functional improvement [ 55 , 56 ].…”

Neuronal pentraxin 2 correlates with neurodegeneration but not cognition in idiopathic normal pressure hydrocephalus (iNPH)

“…There have been many studies that have examined CSF biomarkers in iNPH, most notably the established AD CSF biomarkers including Aβ1-42, Aβ1-40, pTau-181 and NFL www.journals.viamedica.pl/neurologia_neurochirurgia_polska Megha Patel et al, Neuronal pentraxin 2 correlates with neurodegeneration but not cognition [20,21]. Studies have focused on the measurement of CSF pTau-181 concentration primarily as a potential biomarker for differentiating NPH from other neurodegenerative diseases, including AD [22].…”

Molecular Signatures of Normal Pressure Hydrocephalus: A Large-scale Proteomic Analysis of Cerebrospinal Fluid

“…Previous studies have mainly focused on the potential of classical AD cerebrospinal fluid (CSF) biomarkers in differential diagnosis of iNPH from similar clinical entities and long-term response after shunt surgery 11,12 . Lower levels of neurofilament light (NfL), amyloidβ 1-42 (Aβ 1-42 ), amyloidβ 1-40 (Aβ 1-40 ), total tau (t-tau), and phosphorylated tau 181 (p-Tau181) have been associated with long-term improvement in gait outcomes after shunt surgery [11][12][13] .…”