title: Cerebral tau is elevated after aneurysmal subarachnoid haemorrhage and associated with brain metabolic distress and poor functional and cognitive long-term outcome.
abstract: BACKGROUND
  Recent evidence suggests axonal injury after aneurysmal subarachnoid haemorrhage (aSAH). The microtubule-associated protein, tau, has been shown to be elevated in the cerebrospinal fluid after aSAH, however, brain extracellular tau levels and their relation to long-term neurological and cognitive outcomes have not been investigated.
  
  
  METHODS
  Serial cerebral microdialysis (CMD) samples were collected from 22 consecutive aSAH patients with multimodal neuromonitoring to determine CMD-total-tau by ELISA. CMD-total-tau was analysed considering other brain metabolic parameters, brain tissue oxygen tension (PbtO2), and functional and neuropsychological outcome at 12 months. All outcome models were analysed using generalised estimating equations with an autoregressive working correlation matrix to account for multiple measurements of brain extracellular proteins per subject.
  
  
  RESULTS
  CMD-total-tau levels positively correlated with brain extracellular fluid levels of lactate (r=0.40, p<0.001), glutamate (r=0.45, p<0.001), pyruvate (r=0.26, p<0.001), and the lactate-pyruvate ratio (r=0.26, p<0.001), and were higher in episodes of hypoxic (PbtO2<20 mm Hg) brain extracellular lactate elevation (>4 mmol/L) (p<0.01). More importantly, high CMD-total-tau levels were associated with poor functional outcome (modified Rankin Scale ≥4) 12 months after aSAH even after adjusting for disease severity and age (p=0.001). A similar association was found with 3/5 neuropsychological tests indicative of impairments in cognition, psychomotor speed, visual conceptualisation and frontal executive functions at 1 year after aSAH (p<0.01).
  
  
  CONCLUSIONS
  These results suggest that CMD-total tau may be an important biomarker for predicting long-term outcome in patients with severe aSAH. The value of axonal injury needs further confirmation in a larger patient cohort, preferably combined with advanced imaging techniques.
authors.affiliation: Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Raimund
authors.initials: R
authors.lastname: Helbok
authors.affiliation: Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Alois
authors.initials: A
authors.lastname: Schiefecker
authors.affiliation: Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Margarete
authors.initials: M
authors.lastname: Delazer
authors.affiliation: Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Ronny
authors.initials: R
authors.lastname: Beer
authors.affiliation: Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bodner
authors.affiliation: Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Bettina
authors.initials: B
authors.lastname: Pfausler
authors.affiliation: Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Benke
authors.affiliation: Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Lackner
authors.affiliation: Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Marlene
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Department of Neurosurgery, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Sohm
authors.affiliation: UMIT-University for Health Sciences, Medical Informatics and Technology, Hall, Austria.
authors.forename: Werner
authors.initials: W
authors.lastname: Hackl
authors.affiliation: Fresenius Kabi, Bad Homburg, Germany.
authors.forename: John F
authors.initials: JF
authors.lastname: Stover
authors.affiliation: Department of Neurosurgery, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Claudius
authors.initials: C
authors.lastname: Thomé
authors.affiliation: Department of Psychiatry and Psychotherapy, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Humpel
authors.affiliation: Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Erich
authors.initials: E
authors.lastname: Schmutzhard
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003072:Cognition Disorders / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D018698:Glutamic Acid; D006801:Humans; D002532:Intracranial Aneurysm / Q000150:complications / Q000378:metabolism* / Q000523:psychology*; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D008875:Middle Aged; D009483:Neuropsychological Tests; D017063:Outcome Assessment, Health Care; D010100:Oxygen / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000378:metabolism* / Q000523:psychology*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D016875:tau Proteins; D019344:Lactic Acid; D018698:Glutamic Acid; D019289:Pyruvic Acid; D010100:Oxygen
keywords: Cerebrovascular Disease; Intensive Care; Subarachnoid Haemorrhage