Cerebrospinal Fluid Biomarker and Brain Biopsy Findings in Idiopathic Normal Pressure Hydrocephalus

Okko T Pyykkö,Hilkka Soininen,Mikko Hiltunen,Miikka Lumela,Anne M Koivisto,Henrik Zetterberg,Ossi Nerg,Sanna-Kaisa Herukka,Jaana Rummukainen,Sakari Savolainen,Irina Alafuzoff,Toni T Seppälä,Juha E Jääskeläinen,Ville Leinonen,Lakshman Puli,Massimo S Fiandaca

doi:10.1371/journal.pone.0091974

Okko T Pyykkö, Hilkka Soininen + Show 14 more

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https://doi.org/10.1371/journal.pone.0091974

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Abstract

BackgroundThe significance of amyloid precursor protein (APP) and neuroinflammation in idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD) is unknown.ObjectiveTo 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.MethodsThe 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.ResultsLumbar 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.ConclusionsThe role of sAPP isoforms in iNPH seems to be independent from the amyloid cascade. No neuroinflammatory background was observed in iNPH or AD.

Highlights

Idiopathic normal pressure hydrocephalus is a progressive neurodegenerative disorder of unknown etiology in the elderly presenting with gait disorder, cognitive impairment, and urinary incontinence, with enlarged ventricles of the brain but normal or slightly elevated cerebrospinal fluid (CSF) pressure [1,2]
The role of soluble APP (sAPP) isoforms in idiopathic normal pressure hydrocephalus (iNPH) seems to be independent from the amyloid cascade
No neuroinflammatory background was observed in iNPH or Alzheimer’s disease (AD)

Summary

Introduction

Idiopathic normal pressure hydrocephalus (iNPH) is a progressive neurodegenerative disorder of unknown etiology in the elderly presenting with gait disorder, cognitive impairment, and urinary incontinence, with enlarged ventricles of the brain but normal or slightly elevated cerebrospinal fluid (CSF) pressure [1,2]. Various procedures to evaluate CSF dynamics in patients with possible iNPH are used to identify those who could benefit from CSF shunting. These include the CSF tap test, external lumbar drainage test, infusion tests, and intraventricular or intracranial pressure (ICP) monitoring [6,7,8,9]. The significance of amyloid precursor protein (APP) and neuroinflammation in idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer’s disease (AD) is unknown

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