title: Amyloid-β and Tau Dynamics in Human Brain Interstitial Fluid in Patients with Suspected Normal Pressure Hydrocephalus.
abstract: BACKGROUND
  Amyloid-β (Aβ1 - 42), total tau (T-tau), and phosphorylated tau (P-tau181) in the cerebrospinal fluid (CSF) are the most promising biomarkers of Alzheimer's disease (AD). Still, little is known about the dynamics of these molecules in the living brain. In a transgenic mouse brain, soluble Aβ decreases with increasing age and advanced Aβ pathology as seen similarly in CSF.
  
  
  OBJECTIVE
  To assess the relationship between AD-related pathological changes in human brain tissue, ventricular and lumbar CSF, and brain interstitial fluid (ISF).
  
  
  METHODS
  Altogether 11 patients with suspected idiopathic normal pressure hydrocephalus underwent frontal cortical brain biopsy, 24-h intraventricular pressure monitoring, and a microdialysis procedure. AD-related biomarkers were analyzed from brain tissue, CSF, and ISF.
  
  
  RESULTS
  ISF T-tau levels decreased strongly within the first 12 h, then plateauing until the end of the experiment. Aβ1 - 42 and P-tau181 remained stable during the experiment (n = 3). T-tau and P-tau were higher in the ISF than in ventricular or lumbar CSF, while Aβ1 - 42 levels were within similar range in both CSF and ISF samples. ISF P-tau correlated with the ventricular CSF T-tau (r = 0.70, p = 0.017) and P-tau181 (r = 0.64, p = 0.034). Five patients with amyloid pathology in the brain biopsy tended to reveal lower ISF Aβ1 - 42 levels than those six without amyloid pathology.
  
  
  CONCLUSIONS
  This is the first study to report ISF Aβ and tau levels in the human brain without significant brain injury. The set-up used enables sampling from the brain ISF for at least 24 h without causing adverse effects due to the microdialysis procedure to follow the dynamics of the key molecules in AD pathogenesis in the living brain at various stages of the disease.
authors.affiliation: Unit of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.|Neurology of NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Sanna-Kaisa
authors.initials: SK
authors.lastname: Herukka
authors.affiliation: Department of Pathology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Jaana
authors.initials: J
authors.lastname: Rummukainen
authors.affiliation: Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Jouni
authors.initials: J
authors.lastname: Ihalainen
authors.affiliation: Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland and Neurosurgery, Institute of Clinical Medicine, University of Eastern Finland Kuopio, Finland.
authors.forename: Mikael
authors.initials: M
authors.lastname: von Und Zu Fraunberg
authors.affiliation: Unit of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.|Neurology of NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Koivisto
authors.affiliation: Neurology of NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Ossi
authors.initials: O
authors.lastname: Nerg
authors.affiliation: Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Lakshman K
authors.initials: LK
authors.lastname: Puli
authors.affiliation: Unit of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Toni T
authors.initials: TT
authors.lastname: Seppälä
authors.affiliation: Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.|UCL Institute of Neurology, Queen Square, London, United Kingdom.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland and Neurosurgery, Institute of Clinical Medicine, University of Eastern Finland Kuopio, Finland.
authors.forename: Okko T
authors.initials: OT
authors.lastname: Pyykkö
authors.affiliation: Unit of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Seppo
authors.initials: S
authors.lastname: Helisalmi
authors.affiliation: Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Tanila
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University and Department of Pathology and Cytology, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Irina
authors.initials: I
authors.lastname: Alafuzoff
authors.affiliation: Unit of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.|Neurology of NeuroCenter, Kuopio University Hospital, Kuopio, Finland.|Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Hiltunen
authors.affiliation: Department of Neurosurgery, Turku University Hospital and University of Turku, Turku, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Rinne
authors.affiliation: Unit of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.|Neurology of NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.affiliation: Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland and Neurosurgery, Institute of Clinical Medicine, University of Eastern Finland Kuopio, Finland.
authors.forename: Juha E
authors.initials: JE
authors.lastname: Jääskeläinen
authors.affiliation: Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland and Neurosurgery, Institute of Clinical Medicine, University of Eastern Finland Kuopio, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Leinonen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D053327:Apolipoprotein E4 / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016009:Chi-Square Distribution; D003072:Cognition Disorders / Q000209:etiology; D045604:Extracellular Fluid / Q000378:metabolism*; D005260:Female; D006801:Humans; D006850:Hydrocephalus, Normal Pressure / Q000134:cerebrospinal fluid* / Q000150:complications / Q000235:genetics / Q000473:pathology*; D008297:Male; D017551:Microdialysis; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
keywords: Alzheimer’s disease; amyloid-β; biomarkers; normal pressure hydrocephalus; tau