Cerebrospinal fluid biomarker and brain biopsy findings in idiopathic normal pressure hydrocephalus

Abstract

Background: The significance of amyloid precursor protein (APP) and neuroinflammation in idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD) is unknown.

Objective: To investigate the role of soluble APP (sAPP) and amyloid beta (Aβ) isoforms, proinflammatory cytokines, and biomarkers of neuronal damage in the cerebrospinal fluid (CSF) in relation to brain biopsy Aβ and hyperphosphorylated tau (HPτ) findings.

Methods: The study population comprised 102 patients with possible NPH with cortical brain biopsies, ventricular and lumbar CSF samples, and DNA available. The final clinical diagnoses were: 53 iNPH (91% shunt-responders), 26 AD (10 mixed iNPH+AD), and 23 others. Biopsy samples were immunostained against Aβ and HPτ. CSF levels of AD-related biomarkers (Aβ42, p-tau, total tau), non-AD-related Aβ isoforms (Aβ38, Aβ40), sAPP isoforms (sAPPα, sAPPβ), proinflammatory cytokines (several interleukins (IL), interferon-gamma, monocyte chemoattractant protein-1, tumor necrosis factor-alpha) and biomarkers of neuronal damage (neurofilament light and myelin basic protein) were measured. All patients were genotyped for APOE.

Results: Lumbar CSF levels of sAPPα were lower (p<0.05) in patients with shunt-responsive iNPH compared to non-iNPH patients. sAPPβ showed a similar trend (p = 0.06). CSF sAPP isoform levels showed no association to Aβ or HPτ in the brain biopsy. Quantified Aβ load in the brain biopsy showed a negative correlation with CSF levels of Aβ42 in ventricular (r = -0.295, p = 0.003) and lumbar (r = -0.356, p = 0.01) samples, while the levels of Aβ38 and Aβ40 showed no correlation. CSF levels of proinflammatory cytokines and biomarkers of neuronal damage did not associate to the brain biopsy findings, diagnosis, or shunt response. Higher lumbar/ventricular CSF IL-8 ratios (p<0.001) were seen in lumbar samples collected after ventriculostomy compared to the samples collected before the procedure.

Conclusions: The role of sAPP isoforms in iNPH seems to be independent from the amyloid cascade. No neuroinflammatory background was observed in iNPH or AD.

Figure 1. CSF sAPP isoforms in true iNPH patients and patients with no diagnosis of iNPH.

Scatterplots of soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ) concentrations in ventricular (A and C) and lumbar (B and D) cerebrospinal fluid (CSF) in patients with no diagnosis of idiopathic normal pressure hydrocephalus (iNPH) and patients with true (shunt-responsive) iNPH are presented. Cases are color-labeled according to their APOE-ε4 status. P-values were determined using a Mann–Whitney U test.

Figure 2. CSF Aβ and sAPP isoforms in different brain biopsy groups.

Scatterplots of amyloid beta 1–38 (Aβ38) (A), Aβ40 (B), Aβ42 (C), soluble amyloid precursor protein alpha (sAPPα) (D), and beta (sAPPβ) (E) in groups of positive/negative Aβ and hyperphosphorylated tau (HPτ) immunoreactivity in brain biopsy are presented. Cases are color-labeled according to their APOE-ε4 status. P-values were determined using a Kruskal–Wallis H test and post-hoc Mann–Whitney U test with Bonferroni correction. Only statistically significant p-values are shown.

Figure 3. CSF Aβ42 in relation to amyloid-β deposits in cortical brain biopsies.

Scatterplots of ventricular (A) and lumbar (B) cerebrospinal fluid (CSF) amyloid beta 1–42 (Aβ42) levels in relation to the percentage of Aβ area in frontal cortical brain biopsies are presented. Cases are color-labeled according to their APOE-ε4 status. Correlation coefficients and P-values were determined using Pearson correlation.

Figure 4. Lumbar/ventricular CSF IL-8 ratio in relation to time between the CSF samples.

Scatterplot of lumbar/ventricular cerebrospinal fluid (CSF) interleukin 8 (IL-8) ratio in individual cases in relation to the time difference between lumbar and ventricular samples is presented. Cases are color-labeled according to whether lumbar CSF sample was collected before or after the ventricular sample.