Two-Point Dynamic Observation of Alzheimer's Disease Cerebrospinal Fluid Biomarkers in Idiopathic Normal Pressure Hydrocephalus

Abstract

Background: Extensive research into cerebrospinal fluid (CSF) biomarkers was performed in patients with idiopathic normal pressure hydrocephalus (iNPH). Most prior research into CSF biomarkers has been one-point observation.

Objective: To investigate dynamic changes in CSF biomarkers during routine tap test in iNPH patients.

Methods: We analyzed CSF concentrations of tau, amyloid-β (Aβ) 42 and 40, and leucine rich α-2-glycoprotein (LRG) in 88 consecutive potential iNPH patients who received a tap test. We collected two-point lumbar CSF separately at the first 1 ml (First Drip (FD)) and at the last 1 ml (Last Drip (LD)) during the tap test and 9 patients who went on to receive ventriculo-peritoneal shunt surgery each provided 1 ml of ventricular CSF (VCSF).

Results: Tau concentrations were significantly elevated in LD and VCSF compared to FD (LD/FD = 1.22, p = 0.003, VCSF/FD = 2.76, p = 0.02). Conversely, Aβ42 (LD/FD = 0.80, p < 0.001, VCSF/FD = 0.38, p = 0.03) and LRG (LD/FD = 0.74, p < 0.001, VCSF/FD = 0.09, p = 0.002) concentrations were significantly reduced in LD and VCSF compared to FD. Gait responses to the tap test and changes in cognitive function in response to shunt were closely associated with LD concentrations of tau (p = 0.02) and LRG (p = 0.04), respectively.

Conclusions: Dynamic changes were different among the measured CSF biomarkers, suggesting that LD of CSF as sampled during the tap test reflects an aspect of VCSF contributing to the pathophysiology of iNPH and could be used to predict shunt effectiveness.

Keywords: Alzheimer’s disease; amyloid-β; cerebrospinal fluid biomarker; idiopathic normal pressure hydrocephalus; leucine rich α-2-glycoprotein; tap test; tau.

Conflict of interest statement

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/19-0775r1).

Figures

Fig.1

Overview of study sample. iNPH, idiopathic normal pressure hydrocephalus; iNPHGS, iNPH Grading Scale; FD, First Drip; LD, Last Drip; LP, lumbo-peritoneal; VP, ventriculo-peritoneal; VCSF, ventricular CSF.

Fig.2

CSF biomarker concentrations of tau, Aβ42, Aβ40, and LRG. CSF biomarkers compared between FD and LD in studied samples (A), CSF biomarkers compared among FD, LD, and VCSF in patients received VP shunt (B). Horizontal lines within boxes show median values, boxes show upper and lower interquartile (IQ) ranges, whiskers indicate the 1.5 times IQ, a cross (x) in the figure indicate outlier values (1.5 times IQ). tau, total tau; Aβ, amyloid-β; LRG, leucine rich α-2-glycoprotein; FD, First Drip; LD, Last Drip; V, ventricular CSF.

Fig.3

Relationship of CSF tau concentrations (FD and LD) to iNPHGS (pre- and post-shunt surgery). Association between CSF tau concentrations in FD and iNPHGS (A) and association between CSF tau concentrations in LD and iNPHGS (B). tau, total tau; iNPHGS, iNPH Grading Scale; FD, First Drip; LD, Last Drip; r, Pearson correlation; rs, Spearman correlation

Fig.4

Schematic depiction of presumed CSF flow and tau passage during the tap test. Spinal tap releases a flow of CSF from ventricles to spinal subarachnoid space. In consequence, high concentration of tau in VCSF is reflected in the Last Drip.