Concordance of Alzheimer's Disease-Related Biomarkers Between Intraventricular and Lumbar Cerebrospinal Fluid in Idiopathic Normal Pressure Hydrocephalus

Abstract

Background: Alzheimer's disease cerebrospinal fluid (CSF) biomarkers amyloid-β 1-42 (Aβ42), total tau (T-tau), and phosphorylated tau 181 (P-tau181) are widely used. However, concentration gradient of these biomarkers between intraventricular (V-CSF) and lumbar CSF (L-CSF) has been demonstrated in idiopathic normal pressure hydrocephalus (iNPH), potentially affecting clinical utility.

Objective: Here we aim to provide conversion factors for clinical and research use between V-CSF and L-CSF.

Methods: Altogether 138 iNPH patients participated. L-CSF samples were obtained prior to shunt surgery. Intraoperative V-CSF samples were obtained from 97 patients. Post-operative follow-up L- and V-CSF (shunt reservoir) samples of 41 patients were obtained 1-73 months after surgery and then after 3, 6, and 18 months. CSF concentrations of Aβ42, T-tau, and P-tau181 were analyzed using commercial ELISA assays.

Results: Preoperative L-CSF Aβ42, T-tau, and P-tau181 correlated to intraoperative V-CSF (ρ= 0.34-0.55, p < 0.001). Strong correlations were seen between postoperative L- and V-CSF for all biomarkers in every follow-up sampling point (ρs Aβ42: 0.77-0.88, T-tau: 0.91-0.94, P-tau181: 0.94-0.96, p < 0.0001). Regression equations were determined for intraoperative V- and preoperative L-CSF (Aβ42: V-CSF = 185+0.34*L-CSF, T-tau: Ln(V-CSF) = 3.11+0.49*Ln(L-CSF), P-tau181: V-CSF = 8.2+0.51*L-CSF), and for postoperative V- and L-CSF (Aβ42: V-CSF = 86.7+0.75*L-CSF, T-tau: V-CSF = 86.9+0.62*L-CSF, P-tau181: V-CSF = 2.6+0.74*L-CSF).

Conclusion: Aβ42, T-tau, and P-tau181 correlate linearly in-between V- and L-CSF, even stronger after CSF shunt surgery. Equations presented here, provide a novel tool to use V-CSF for diagnostic and prognostic entities relying on the L-CSF concentrations and can be applicable to clinical use when L-CSF samples are not available or less invasively obtained shunt reservoir samples should be interpreted.

Keywords: Aβ42; P-tau; T-tau; biomarkers; idiopathic normal pressure hydrocephalus.

Fig. 1

Formation of the study cohorts. Flowchart is presenting the formation of the cohorts and cerebrospinal fluid sampling. * Kuopio iNPH protocol of diagnosis is published previously [22]. iNPH, idiopathic normal pressure hydrocephalus; CSF cerebrospinal fluid.

Fig. 2A-C

Boxplots of ventricular-/lumbar CSF ratios. Box and whiskers plots are presenting ventricular-/lumbar CSF ratios of the biomarkers of Aβ₄₂ (A), T-tau (B), and P-tau₁₈₁ (C). Light gray boxplots are illustrating the ratios of intraoperative V-CSF and preoperative L-CSF. White boxplots are presenting the ratios of postoperative V- and L-CSF. Repeated V- and L-CSF samples of the follow-up were pooled per patient before the calculation of the V-/L-CSF ratios. Aβ₄₂, amyloid-β 1-42; T-tau, total tau protein; P-tau₁₈₁, phosphorylated tau at threonine 181; V-CSF, ventricular cerebrospinal fluid; L-CSF, lumbar cerebrospinal fluid.

Fig. 3A-C

Scatterplots of pre- and intraoperative Aβ₄₂, T-tau, and P-tau₁₈₁ in L- and V-CSF. Scatterplots of V- and L-CSF values of the biomarkers Aβ₄₂ (A), T-tau (B), and P-tau₁₈₁ (C) and linear trendlines are illustrating the linear dependency of intraoperative V- and preoperative L-CSF. Mean confidence intervals (95%) are drawn for linear trendlines. Regression equations of the linear univariate regression models are presented at upper right corner of the figure. T-tau values are presented at natural logarithmic scale due the non-normally distributed values. Aβ₄₂, amyloid-β 1–42; T-tau, total tau protein; P-Tau₁₈₁, hyperphosphorylated tau at threonine 181; V-CSF, ventricular cerebrospinal fluid; L-CSF lumbar cerebrospinal fluid; Ln, natural logarithm transferred variable; R², Coefficient of determination.

Fig. 4A-C

Scatterplots of postoperative Aβ₄₂, T-tau, and P-tau₁₈₁ in V- and L-CSF. Scatterplots of V- and L-CSF values of the biomarkers Aβ₄₂ (A), T-tau (B), and P-tau₁₈₁ (C) and linear trendlines are illustrating the linear dependency of postoperative V- and L-CSF. Mean confidence intervals (95%) are drawn for linear trendlines. Regression equations of the linear mixed effects models are presented at upper right corner of the figure. Aβ₄₂, amyloid-β 1-42; T-tau, total tau protein; P-Tau₁₈₁, hyperphosphorylated tau at threonine 181; V-CSF, ventricular cerebrospinal fluid; L-CSF, lumbar cerebrospinal fluid.