title: Quantitative assessments of traumatic axonal injury in human brain: concordance of microdialysis and advanced MRI.
abstract: Axonal injury is a major contributor to adverse outcomes following brain trauma. However, the extent of axonal injury cannot currently be assessed reliably in living humans. Here, we used two experimental methods with distinct noise sources and limitations in the same cohort of 15 patients with severe traumatic brain injury to assess axonal injury. One hundred kilodalton cut-off microdialysis catheters were implanted at a median time of 17 h (13-29 h) after injury in normal appearing (on computed tomography scan) frontal white matter in all patients, and samples were collected for at least 72 h. Multiple analytes, such as the metabolic markers glucose, lactate, pyruvate, glutamate and tau and amyloid-β proteins, were measured every 1-2 h in the microdialysis samples. Diffusion tensor magnetic resonance imaging scans at 3 T were performed 2-9 weeks after injury in 11 patients. Stability of diffusion tensor imaging findings was verified by repeat scans 1-3 years later in seven patients. An additional four patients were scanned only at 1-3 years after injury. Imaging abnormalities were assessed based on comparisons with five healthy control subjects for each patient, matched by age and sex (32 controls in total). No safety concerns arose during either microdialysis or scanning. We found that acute microdialysis measurements of the axonal cytoskeletal protein tau in the brain extracellular space correlated well with diffusion tensor magnetic resonance imaging-based measurements of reduced brain white matter integrity in the 1-cm radius white matter-masked region near the microdialysis catheter insertion sites. Specifically, we found a significant inverse correlation between microdialysis measured levels of tau 13-36 h after injury and anisotropy reductions in comparison with healthy controls (Spearman's r = -0.64, P = 0.006). Anisotropy reductions near microdialysis catheter insertion sites were highly correlated with reductions in multiple additional white matter regions. We interpret this result to mean that both microdialysis and diffusion tensor magnetic resonance imaging accurately reflect the same pathophysiological process: traumatic axonal injury. This cross-validation increases confidence in both methods for the clinical assessment of axonal injury. However, neither microdialysis nor diffusion tensor magnetic resonance imaging have been validated versus post-mortem histology in humans. Furthermore, future work will be required to determine the prognostic significance of these assessments of traumatic axonal injury when combined with other clinical and radiological measures.
authors.affiliation: 1 Department of Anaesthesiology and Intensive Care, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Magnoni
authors.affiliation: 2 Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Mac Donald
authors.affiliation: 3 Department of Neurology, Washington University, St Louis, MO, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Esparza
authors.affiliation: 1 Department of Anaesthesiology and Intensive Care, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Conte
authors.affiliation: 3 Department of Neurology, Washington University, St Louis, MO, USA.
authors.forename: James
authors.initials: J
authors.lastname: Sorrell
authors.affiliation: 4 Milan University, Milano, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Macrì
authors.affiliation: 5 Department of Neurosurgery, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Bertani
authors.affiliation: 6 Department of Neuroradiology, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Biffi
authors.affiliation: 6 Department of Neuroradiology, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Costa
authors.affiliation: 3 Department of Neurology, Washington University, St Louis, MO, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Sammons
authors.affiliation: 7 Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, USA.
authors.forename: Abraham Z
authors.initials: AZ
authors.lastname: Snyder
authors.affiliation: 7 Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, USA.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Shimony
authors.affiliation: 6 Department of Neuroradiology, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Triulzi
authors.affiliation: 1 Department of Anaesthesiology and Intensive Care, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milano, Italy 4 Milan University, Milano, Italy.
authors.forename: Nino
authors.initials: N
authors.lastname: Stocchetti
authors.affiliation: 3 Department of Neurology, Washington University, St Louis, MO, USA 8 Hope Centre for Neurological Disorders, Washington University, St Louis, MO, USA brodyd@neuro.wustl.edu.
authors.forename: David L
authors.initials: DL
authors.lastname: Brody
mesh_terms: D000293:Adolescent; D000328:Adult; D001369:Axons / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D001930:Brain Injuries / Q000473:pathology*; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods; D056324:Diffusion Tensor Imaging / Q000379:methods; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008297:Male; D017551:Microdialysis; D008875:Middle Aged; D055815:Young Adult
keywords: diffusion tensor imaging; microdialysis; tau; traumatic axonal injury; traumatic brain injury