title: 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.
authors.affiliation: Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Okko T
authors.initials: OT
authors.lastname: Pyykkö
authors.affiliation: Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Miikka
authors.initials: M
authors.lastname: Lumela
authors.affiliation: Department of Pathology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Jaana
authors.initials: J
authors.lastname: Rummukainen
authors.affiliation: Neurology of NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Ossi
authors.initials: O
authors.lastname: Nerg
authors.affiliation: Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Toni T
authors.initials: TT
authors.lastname: Seppälä
authors.affiliation: Neurology of NeuroCenter, Kuopio University Hospital, Kuopio, Finland; Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Sanna-Kaisa
authors.initials: SK
authors.lastname: Herukka
authors.affiliation: Neurology of NeuroCenter, Kuopio University Hospital, Kuopio, Finland; Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Koivisto
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Irina
authors.initials: I
authors.lastname: Alafuzoff
authors.affiliation: Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Lakshman
authors.initials: L
authors.lastname: Puli
authors.affiliation: Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Sakari
authors.initials: S
authors.lastname: Savolainen
authors.affiliation: Neurology of NeuroCenter, Kuopio University Hospital, Kuopio, Finland; Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.affiliation: Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Juha E
authors.initials: JE
authors.lastname: Jääskeläinen
authors.affiliation: Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Hiltunen
authors.affiliation: Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Leinonen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000134:cerebrospinal fluid / Q000235:genetics; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001706:Biopsy; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D016207:Cytokines / Q000134:cerebrospinal fluid / Q000378:metabolism; D005260:Female; D005387:Finland; D006801:Humans; D006850:Hydrocephalus, Normal Pressure / Q000134:cerebrospinal fluid* / Q000175:diagnosis / Q000209:etiology / Q000473:pathology*; D018836:Inflammation Mediators / Q000134:cerebrospinal fluid / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012042:Registries
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053327:Apolipoprotein E4; D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators