Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus

Heikki Lukkarinen, Ina Tesseur, Darrel Pemberton, Peter Van Der Ark, Maarten Timmers, Randy Slemmon, Luc Janssens, Johannes Streffer, Luc Van Nueten, Astrid Bottelbergs, Tuomas Rauramaa, Anne M Koivisto, Sanna-Kaisa Herukka, Ville E Korhonen, Antti Junkkari, Mikko Hiltunen, Sebastiaan Engelborghs, Kaj Blennow, Henrik Zetterberg, Hartmuth C Kolb, Ville Leinonen, Heikki Lukkarinen, Ina Tesseur, Darrel Pemberton, Peter Van Der Ark, Maarten Timmers, Randy Slemmon, Luc Janssens, Johannes Streffer, Luc Van Nueten, Astrid Bottelbergs, Tuomas Rauramaa, Anne M Koivisto, Sanna-Kaisa Herukka, Ville E Korhonen, Antti Junkkari, Mikko Hiltunen, Sebastiaan Engelborghs, Kaj Blennow, Henrik Zetterberg, Hartmuth C Kolb, Ville Leinonen

Abstract

Background: Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant.

Objective: To examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared.

Methods: L-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aβ plaques in frontal cortical brain biopsy and 13 iNPH patients without Aβ pathology. CSF Amyloid-β42 (Aβ42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs.

Results: All biomarkers but Aβ42 increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. Aβ42 instead showed divergent longitudinal decrease between Aβ-positive and -negative patients in L-CSF, and thereafter increase in Aβ-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aβ42 R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p < 0.0001) but were systematically lower in V-CSF (Aβ42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aβ42 showed higher concentration in non-carriers of allele ɛ4.

Conclusion: Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aβ pathology, while NFL normalized toward its pre-shunt levels. Aβ42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations.

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

Conflict of interest statement

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/20-1361r2).

Figures

Fig. 1
Fig. 1
Selection of shunted iNPH patients presented as a flow-chart. Eligible patients were sorted to groups based on the histopathological examination of Aβ in frontal cortical brain biopsy. Based on participating Aβ-positive patients, controls were requested with the ratio of 2 : 1, leading eventually to the group sizes of 28 Aβ-positive individuals and 13 Aβ-negative individuals. iNPH, idiopathic normal pressure hydrocephalus; Aβ, amyloid- β; MMSE, Mini-Mental State Examination.
Fig. 2
Fig. 2
Sample collection over time with the number of samples collected for V- and L-CSF in the Aβ-positive and -negative groups. Pre-shunt L-CSF was collected prior to the surgery. The B0 sample collection point was at least 3 but up to 73 months (mean 24 months; median, 18 months) after the shunt placement, followed by 3 M, 6 M, and 18 M sample collection points. L-CSF and V-CSF from the same patient were collected on the same day. Drop-outs and deaths between the time points presented as numbers from study population. Cognition was tested at B0, 6 M, and 18M. #7 revision before B1; ##2 revision before B0; *B0 partial samples: 6 in Aβ+ and 3 in Aβ-, 3 M partial samples: 5 in Aβ+ and 5 in Aβ-, 6 M partial samples: 4 in Aβ+ and 4 in Aβ-, 18 M partial samples: 3 in Aβ+ and 5 in Aβ-; **B0: bloody CSF in 2 Aβ+ samples, 3 M: bloody CSF in 1 Aβ+ and 1 Aβ- sample; B1, pre-surgery sample collection time point; B0, baseline visit of the follow-up; 3 M, three-month study visit; 6 M, six-month study visit; 18 M, 18-month study visit; L-CSF, cerebrospinal fluid collected with lumbar puncture; V-CSF, cerebrospinal fluid collected with shunt valve puncture.
Fig. 3
Fig. 3
Longitudinal analysis of biomarkers of neurodegeneration in lumbar (A, C, E, G, and I) and ventricular (B, D, F, H, and J) CSF for amyloid-β42 (Aβ42; A, B), total tau (T-tau; C, D), tau phosphorylated at threonine 181 (P-tau; E, F), neurofilament light (NFL; G, H), and neurogranin (NRGN; I, J). iNPH patients were grouped into to biopsy positive (dark gray) and biopsy negative (light gray) patients based on the presence or absence of Aβ pathology in their corresponding frontal biopsy. Values expressed as means±standard error. *p < 0.05; **p < 0.01 between biopsy-positive and -negative patients in specific time point. B1, pre-surgery sample collection time point; B0, baseline visit of the follow-up; 3 M, three-month study visit; 6 M, six-month study visit; 18 M, 18-month study visit; L-CSF, cerebrospinal fluid collected with lumbar puncture; V-CSF, cerebrospinal fluid collected with shunt valve puncture.
Fig. 4
Fig. 4
Longitudinal analysis of Aβ42 in lumbar (A) and ventricular (B) CSF in iNPH patients grouped according to APOEɛ4 genotype carriers (dark gray) and non-carriers (light gray). Values expressed as means±standard error. *p < 0.05*; **p < 0.01 iNPH, idiopathic normal pressure hydrocephalus; APOEɛ4, apolipoprotein E ɛ4 allele; B1, pre-surgery sample collection timepoint; B0, baseline visit of the follow-up; 3M, three-month study visit; 6 M, six-month study visit; 18 M, 18-month study visit; L-CSF, cerebrospinal fluid collected with lumbar puncture; V-CSF, cerebrospinal fluid collected with shunt valve puncture.
Fig. 5
Fig. 5
Ratios of Aβ42 (A), T-tau (B), P-tau (C), NFL (D), NRGN (E), and Aβ42/40 ratio (F) in V- and L-CSF. Ratios are presented as box and whiskers plot that portrays the median (center line), mean (cross), Q1 (lower edge of box), Q3 (upper edge of box), minimum and maximum (lines) values. Each boxplot presents all results of one sample collection point of the CSF and single dots demonstrate results of a single iNPH patient. The Aβ42/40 result is from 18M time point and presented as correlation matrix. The Aβ42/40 ratios presented showed strong correlation between lumbar and ventricular CSF, expressed as Pearson R2. Linear trend-line adjusted for values to enhance the visibility of correlation. Aβ, amyloid- β; B1, pre-surgery sample collection timepoint; B0, baseline visit of the follow-up; 3M, three-month study visit; 6M, six-month study visit; 18M, 18-month study visit; Aβ42, Amyloid-β 42 protein; T-tau, total tau; P-tau, tau phosphorylated at threonine 181; NFL, neurofilament light; NRGN, neurogranin; L-CSF, cerebrospinal fluid collected with lumbar puncture; V-CSF, cerebrospinal fluid collected with shunt valve puncture; Q1, quartile 1 holding values up to 25 percentile; Q3, quartile 3 holding values up to 75 percentile.
Fig. 6
Fig. 6
Correlation analysis of T-tau levels versus levels of P-tau (A), T-tau versus NRGN (B), P-tau versus NRGN (C) in lumbar (L-CSF, black triangle) and ventricular (V-CSF, light gray circle) samples. Pearson R2 values and significance level were calculated, and linear graphs adjusted according to the values. All time points of B1, B0, 3 M, 6 M, and 18 M are included in correlation analysis. T-tau, total tau; P-tau, tau phosphorylated at threonine 181; NRGN, neurogranin; B1, pre-surgery sample collection timepoint; B0, baseline visit of the follow-up; 3 M, three-month study visit; 6 M, six-month study visit; 18 M, 18-month study visit; L-CSF, cerebrospinal fluid collected with lumbar puncture; V-CSF, cerebrospinal fluid collected with shunt valve puncture.
Fig. 7
Fig. 7
The schematic presentation of the temporal dynamics in biomarkers of neurodegeneration plotted with the time in years (y) from shunt surgery and percentual change from the pre-surgery values (100%). The plots are formed with local polynomial regression and based on the data shown in Supplementary Figure 1A-E. Multipliers added to figure, are highlighting the longitudinal elevation found for biomarkers. Aβ42, Amyloid-β 42; T-tau, total tau; P-tau, tau phosphorylated at threonine 181; NFL, neurofilament light; NRGN, neurogranin.

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