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Cerebral Microvascular Injury: A Potentially Treatable Endophenotype of Traumatic Brain Injury-Induced Neurodegeneration

2019; Cell Press; Volume: 103; Issue: 3 Linguagem: Inglês

10.1016/j.neuron.2019.06.002

1097-4199

Danielle K. Sandsmark, Asma Bashir, Cheryl L. Wellington, Ramon Diaz‐Arrastia,

Intracerebral and Subarachnoid Hemorrhage Research

Traumatic brain injury (TBI) is one the most common human afflictions, contributing to long-term disability in survivors. Emerging data indicate that functional improvement or deterioration can occur years after TBI. In this regard, TBI is recognized as risk factor for late-life neurodegenerative disorders. TBI encompasses a heterogeneous disease process in which diverse injury subtypes and multiple molecular mechanisms overlap. To develop precision medicine approaches where specific pathobiological processes are targeted by mechanistically appropriate therapies, techniques to identify and measure these subtypes are needed. Traumatic microvascular injury is a common but relatively understudied TBI endophenotype. In this review, we describe evidence of microvascular dysfunction in human and animal TBI, explore the role of vascular dysfunction in neurodegenerative disease, and discuss potential opportunities for vascular-directed therapies in ameliorating TBI-related neurodegeneration. We discuss the therapeutic potential of vascular-directed therapies in TBI and the use and limitations of preclinical models to explore these therapies. Traumatic brain injury (TBI) is one the most common human afflictions, contributing to long-term disability in survivors. Emerging data indicate that functional improvement or deterioration can occur years after TBI. In this regard, TBI is recognized as risk factor for late-life neurodegenerative disorders. TBI encompasses a heterogeneous disease process in which diverse injury subtypes and multiple molecular mechanisms overlap. To develop precision medicine approaches where specific pathobiological processes are targeted by mechanistically appropriate therapies, techniques to identify and measure these subtypes are needed. Traumatic microvascular injury is a common but relatively understudied TBI endophenotype. In this review, we describe evidence of microvascular dysfunction in human and animal TBI, explore the role of vascular dysfunction in neurodegenerative disease, and discuss potential opportunities for vascular-directed therapies in ameliorating TBI-related neurodegeneration. We discuss the therapeutic potential of vascular-directed therapies in TBI and the use and limitations of preclinical models to explore these therapies. Traumatic brain injury (TBI) is a prevalent condition affecting all ages, races, and socioeconomic classes throughout the world. In the United States alone, there are at least 2.8 million emergency department visits for TBIs annually, although many more TBIs likely go unreported (Taylor et al., 2017Taylor C.A. Bell J.M. Breiding M.J. Xu L. Traumatic Brain Injury-Related Emergency Department Visits, Hospitalizations, and Deaths - United States, 2007 and 2013.MMWR Surveill. Summ. 2017; 66: 1-16Crossref PubMed Scopus (297) Google Scholar). The incidence of TBI is disproportionately higher in low- and middle-income countries, where TBIs are the leading cause of death and disability in young adults (Maas et al., 2017Maas A.I.R. Menon D.K. Adelson P.D. Andelic N. Bell M.J. Belli A. Bragge P. Brazinova A. Büki A. Chesnut R.M. et al.InTBIR Participants and InvestigatorsTraumatic brain injury: integrated approaches to improve prevention, clinical care, and research.Lancet Neurol. 2017; 16: 987-1048Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). Because head injuries often affect young people in their most productive years, the cumulative loss of productivity is high compared with other injuries and illnesses (Max et al., 1991Max W. MacKenzie E.J. Rice D.P. Head injuries: costs and consequences.J. Head Trauma Rehab. 1991; 6: 76-91Crossref Google Scholar). Even mild TBI (mTBI), often termed concussion, which accounts for 80%–90% of all TBIs, results in a tremendous societal and economic burden and accounts for up to 44% of the total lifetime costs of TBI (Max et al., 1991Max W. MacKenzie E.J. Rice D.P. Head injuries: costs and consequences.J. Head Trauma Rehab. 1991; 6: 76-91Crossref Google Scholar). As the population ages, TBIs from falls in older persons are becoming increasingly prevalent and are associated with more morbidity and mortality because of coexisting medical illness, anticoagulant use, and slower recovery trajectories (Peters and Gardner, 2018Peters M.E. Gardner R.C. Traumatic brain injury in older adults: do we need a different approach?.Concussion. 2018; 3: CNC56Crossref Google Scholar). Public health initiatives focused on injury prevention through bike helmets, fall prevention, seat belt use, sport impact policy changes, and other public safety measures have been very effective in reducing the incidence of and the mortality associated with severe TBI (Taylor et al., 2017Taylor C.A. Bell J.M. Breiding M.J. Xu L. Traumatic Brain Injury-Related Emergency Department Visits, Hospitalizations, and Deaths - United States, 2007 and 2013.MMWR Surveill. Summ. 2017; 66: 1-16Crossref PubMed Scopus (297) Google Scholar). Clinical management has focused on controlling intracranial pressure and cerebral edema (Chesnut et al., 2012Chesnut R.M. Temkin N. Carney N. Dikmen S. Rondina C. Videtta W. Petroni G. Lujan S. Pridgeon J. Barber J. et al.Global Neurotrauma Research GroupA trial of intracranial-pressure monitoring in traumatic brain injury.N. Engl. J. Med. 2012; 367: 2471-2481Crossref PubMed Scopus (538) Google Scholar), oxygen deprivation (Okonkwo et al., 2017Okonkwo D.O. Shutter L.A. Moore C. Temkin N.R. Puccio A.M. Madden C.J. Andaluz N. Chesnut R.M. Bullock M.R. Grant G.A. et al.Brain oxygen optimization in severe traumatic brain injury phase-II: A Phase II Randomized Trial.Crit. Care Med. 2017; 45: 1907-1914Crossref PubMed Scopus (34) Google Scholar), or brain metabolic demand (Andrews et al., 2015Andrews P.J.D. Sinclair H.L. Rodriguez A. Harris B.A. Battison C.G. Rhodes J.K.J. Murray G.D. Eurotherm3235 Trial CollaboratorsHypothermia for intracranial hypertension after traumatic brain injury.N. Engl. J. Med. 2015; 373: 2403-2412Crossref PubMed Scopus (211) Google Scholar) in cases of severe injury, although the effects of these interventions on clinical outcomes have been disappointing (Maas et al., 2017Maas A.I.R. Menon D.K. Adelson P.D. Andelic N. Bell M.J. Belli A. Bragge P. Brazinova A. Büki A. Chesnut R.M. et al.InTBIR Participants and InvestigatorsTraumatic brain injury: integrated approaches to improve prevention, clinical care, and research.Lancet Neurol. 2017; 16: 987-1048Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). Furthermore, there are no therapies that diminish the burden of disability resulting from mild TBI, which has historically been ignored by the health care system (Levin and Diaz-Arrastia, 2015Levin H.S. Diaz-Arrastia R.R. Diagnosis, prognosis, and clinical management of mild traumatic brain injury.Lancet Neurol. 2015; 14: 506-517Abstract Full Text Full Text PDF PubMed Google Scholar). TBI has traditionally been conceptualized as a primary injury event caused by an initial mechanical impact, followed by secondary insults because of the molecular and cellular responses in reaction to the primary injury. Secondary injury can propagate a trauma-induced cascade in the surrounding brain tissue. This secondary injury, even in the most severe cases, has been thought to extend only for a few weeks or, at most, a month, followed by a trajectory of recovery that has generally been thought to be largely complete within months or, at most, 1 year. Evidence accumulated over the past decade has led to recognition that, for many patients, the consequences of TBI continue to evolve long after the acute period of initial recovery (Wilson et al., 2017Wilson L. Stewart W. Dams-O’Connor K. Diaz-Arrastia R. Horton L. Menon D.K. Polinder S. The chronic and evolving neurological consequences of traumatic brain injury.Lancet Neurol. 2017; 16: 813-825Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). Longitudinal studies have shown that outcomes following TBI are not fixed because there can be improvement and/or deterioration in neurological function many years after injury (Corrigan and Hammond, 2013Corrigan J.D. Hammond F.M. Traumatic brain injury as a chronic health condition.Arch. Phys. Med. Rehabil. 2013; 94: 1199-1201Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, Wilson et al., 2017Wilson L. Stewart W. Dams-O’Connor K. Diaz-Arrastia R. Horton L. Menon D.K. Polinder S. The chronic and evolving neurological consequences of traumatic brain injury.Lancet Neurol. 2017; 16: 813-825Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). TBI can therefore be best conceptualized as a chronic health condition triggered by the injury, which initiates long-lasting and still poorly understood downstream events that can affect brain function for decades (Corrigan and Hammond, 2013Corrigan J.D. Hammond F.M. Traumatic brain injury as a chronic health condition.Arch. Phys. Med. Rehabil. 2013; 94: 1199-1201Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar) and have life-long effects on multiple health outcomes (Masel and DeWitt, 2010Masel B.E. DeWitt D.S. Traumatic brain injury: a disease process, not an event.J. Neurotrauma. 2010; 27: 1529-1540Crossref PubMed Scopus (377) Google Scholar). Given this complexity, there is an urgent need to better understand the specific pathophysiological mechanisms contributing to TBI-related dysfunction in both the acute and chronic phases of disease. In animal models, interventions aimed at molecular targets involved in secondary injury have been successful in limiting the extent of injury and improving neurologic recovery (Marklund et al., 2006Marklund N. Bakshi A. Castelbuono D.J. Conte V. McIntosh T.K. Evaluation of pharmacological treatment strategies in traumatic brain injury.Curr. Pharm. Des. 2006; 12: 1645-1680Crossref PubMed Scopus (0) Google Scholar, McIntosh et al., 1998McIntosh T.K. Juhler M. Wieloch T. Novel pharmacologic strategies in the treatment of experimental traumatic brain injury: 1998.J. Neurotrauma. 1998; 15: 731-769Crossref PubMed Google Scholar). These results provide a convincing proof of principle that effective therapeutic intervention is possible, but therapeutic efficacy has yet to be achieved in the human condition. In this review, we specifically focus on TBI-related injury of the cerebral microvasculature, discuss the relationship of vascular injury to chronic neurodegenerative sequelae of TBI, and highlight opportunities for preclinical and clinical studies to improve our understanding of this disease process and promote the development of effective therapies. The brain is critically dependent on a steady blood supply that is acutely responsive to the constantly changing metabolic demands of the brain tissue. To accomplish this, the brain parenchyma is served by a vascular network of arteries, arterioles, capillaries, venules, and veins that runs approximately 400 miles in length (Sweeney et al., 2018Sweeney M.D. Kisler K. Montagne A. Toga A.W. Zlokovic B.V. The role of brain vasculature in neurodegenerative disorders.Nat. Neurosci. 2018; 21: 1318-1331Crossref PubMed Scopus (19) Google Scholar). Several cell types distributed along this network act in concert to regulate cerebral blood flow (CBF), vascular permeability, and micronutrient supply. Collectively, these cells are termed the neurovascular unit (NVU) (Shlosberg et al., 2010Shlosberg D. Benifla M. Kaufer D. Friedman A. Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury.Nat. Rev. Neurol. 2010; 6: 393-403Crossref PubMed Scopus (339) Google Scholar). The NVU consists of the endothelial lining of the blood vessels, smooth muscle cells (at the artery, arteriole, and venule levels), and pericytes (at the capillary level; Figure 1A), which help to regulate vascular tone, neurons, and perivascular astrocytes. The endothelial cells form a monolayer consisting of intercellular tight and adherens junctions to form the blood-brain barrier (BBB), 85% of which is provided by the capillary endothelium (Sweeney et al., 2018Sweeney M.D. Kisler K. Montagne A. Toga A.W. Zlokovic B.V. The role of brain vasculature in neurodegenerative disorders.Nat. Neurosci. 2018; 21: 1318-1331Crossref PubMed Scopus (19) Google Scholar). This BBB forms an exquisitely regulated barrier between the systemic vasculature and the brain parenchyma. All components of the NVU undergo continuous crosstalk under normal physiological conditions to form an integrated system keenly responsive to changing cerebral and systemic factors. This process, termed neurovascular coupling, ensures consistent CBF and micronutrient supply across the BBB as a function of neuronal activity. Following brain injury, these normal patterns of communication among the elements of the NVU can be severely altered (Figure 1B). Disturbed NVU function leads to inappropriate changes in CBF in response to the altered metabolic demands of the injured brain. Dysfunction of the BBB disrupts the extracellular environment because of protein and electrolyte leakage and can trigger other downstream processes, like microglia activation and recruitment (Shlosberg et al., 2010Shlosberg D. Benifla M. Kaufer D. Friedman A. Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury.Nat. Rev. Neurol. 2010; 6: 393-403Crossref PubMed Scopus (339) Google Scholar, Zlokovic, 2011Zlokovic B.V. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders.Nat. Rev. Neurosci. 2011; 12: 723-738Crossref PubMed Scopus (1034) Google Scholar). Emerging evidence, as we discuss below, indicates that these disruptions last far longer than previously assumed and may contribute to ongoing neuropathology long after the primary injury. Clinical evidence indicates that microvascular dysfunction extends across the spectrum of TBI-related injury. Histologically detected ischemic damage is seen in nearly 60% of fatal TBI without evidence of large-vessel occlusions (Graham and Adams, 1971Graham D.I. Adams J.H. Ischaemic brain damage in fatal head injuries.Lancet. 1971; 1: 265-266Abstract PubMed Scopus (129) Google Scholar). In moderate to severe TBI, vasospasm of larger cerebral arteries can precipitate cerebral ischemia (Martin et al., 1995Martin N.A. Doberstein C. Alexander M. Khanna R. Benalcazar H. Alsina G. Zane C. McBride D. Kelly D. Hovda D. et al.Posttraumatic cerebral arterial spasm.J. Neurotrauma. 1995; 12: 897-901Crossref PubMed Google Scholar), but more universally trauma-induced vascular injury occurs at the arteriole and capillary level (Bouma and Muizelaar, 1992Bouma G.J. Muizelaar J.P. Cerebral blood flow, cerebral blood volume, and cerebrovascular reactivity after severe head injury.J. Neurotrauma. 1992; 9: S333-S348PubMed Google Scholar). Rodríguez-Baeza et al., 2003Rodríguez-Baeza A. Reina-de la Torre F. Poca A. Martí M. Garnacho A. Morphological features in human cortical brain microvessels after head injury: a three-dimensional and immunocytochemical study.Anat. Rec. A Discov. Mol. Cell. Evol. Biol. 2003; 273: 583-593Crossref PubMed Google Scholar created vascular corrosion casts to examine the cerebral microcirculation in patients who died following severe head trauma. They found that arterioles and capillaries in the middle and deep cortical vascular zones showed extensive injury characterized by sunken endothelial surfaces, longitudinal folds in the vessel wall, decreased lumen diameter, and corrugations, indicating a separation between the endothelium and smooth muscle cells and a disrupted BBB. Notably, larger pial and subpial vessels were histologically normal. In nonfatal head injury, cerebral intravascular microthromboses seem to be a nearly universal feature; Stein et al., 2002Stein S.C. Chen X.-H. Sinson G.P. Smith D.H. Intravascular coagulation: a major secondary insult in nonfatal traumatic brain injury.J. Neurosurg. 2002; 97: 1373-1377Crossref PubMed Google Scholar observed intravascular thromboses in arterioles and venules in rodent, pig, and human TBI specimens. Multifocal BBB disruption has been observed in American football players who have sustained subconcussive injuries (without clinical signs of concussion) using the same dynamic contrast-enhanced MRI technique utilized in studies of BBB disruption in Alzheimer’s disease (AD) (Weissberg et al., 2014Weissberg I. Veksler R. Kamintsky L. Saar-Ashkenazy R. Milikovsky D.Z. Shelef I. Friedman A. Imaging blood-brain barrier dysfunction in football players.JAMA Neurol. 2014; 71: 1453-1455Crossref PubMed Scopus (0) Google Scholar). At the endothelial level, endothelin-1, a peptide that acts as a vasoconstrictor, is upregulated following TBI (Chatfield et al., 2011Chatfield D.A. Brahmbhatt D.H. Sharp T. Perkes I.E. Outrim J.G. Menon D.K. Juguloarterial endothelin-1 gradients after severe traumatic brain injury.Neurocrit. Care. 2011; 14: 55-60Crossref Scopus (6) Google Scholar, Maier et al., 2007Maier B. Lehnert M. Laurer H.L. Marzi I. Biphasic elevation in cerebrospinal fluid and plasma concentrations of endothelin 1 after traumatic brain injury in human patients.Shock. 2007; 27: 610-614Crossref Scopus (17) Google Scholar, Salonia et al., 2010Salonia R. Empey P.E. Poloyac S.M. Wisniewski S.R. Klamerus M. Ozawa H. Wagner A.K. Ruppel R. Bell M.J. Feldman K. et al.Endothelin-1 is increased in cerebrospinal fluid and associated with unfavorable outcomes in children after severe traumatic brain injury.J. Neurotrauma. 2010; 27: 1819-1825Crossref PubMed Scopus (37) Google Scholar) and activates vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), and other inflammatory pathways (Koyama et al., 2007Koyama Y. Baba A. Matsuda T. Intracerebroventricular administration of an endothelin ETB receptor agonist increases expression of tissue inhibitor of matrix metalloproteinase-1 and -3 in rat brain.Neuroscience. 2007; 147: 620-630Crossref Scopus (13) Google Scholar, Koyama et al., 2012Koyama Y. Maebara Y. Hayashi M. Nagae R. Tokuyama S. Michinaga S. Endothelins reciprocally regulate VEGF-A and angiopoietin-1 production in cultured rat astrocytes: implications on astrocytic proliferation.Glia. 2012; 60: 1954-1963Crossref Scopus (30) Google Scholar). These molecules, in turn, contribute to further BBB disruption. Microvascular injury sequelae are not limited to the acute period following the primary injury. Hay et al., 2015Hay J.R. Johnson V.E. Young A.M.H. Smith D.H. Stewart W. Blood-brain barrier disruption Is an early event that may persist for many years after traumatic brain injury in humans.J. Neuropathol. Exp. Neurol. 2015; 74: 1147-1157PubMed Google Scholar showed that 47% of brains examined from long-term TBI survivors (1–47 years post-injury) exhibited histological evidence of multifocal BBB breakdown, as demonstrated by fibrinogen and immunoglobulin G immunostaining, in perivascular and parenchymal gray matter. Tomkins et al., 2011Tomkins O. Feintuch A. Benifla M. Cohen A. Friedman A. Shelef I. Blood-brain barrier breakdown following traumatic brain injury: a possible role in posttraumatic epilepsy.Cardiovasc. Psychiatry Neurol. 2011; 2011: 765923Crossref PubMed Scopus (87) Google Scholar used contrast-enhanced MRI to evaluate subjects with relatively mild head injuries (Glasgow coma score, GCS > 13) assessed in the subacute (1 week) to chronic (3 months) period after injury. They found that subjects who developed post-traumatic epilepsy were more likely to have BBB disturbance than those who had a history of TBI but did not have epilepsy (82% versus 25%). In 4 subjects, BBB disruption was evident using this MRI technique 1.5–11 years after injury. Doherty et al., 2016Doherty C.P. O’Keefe E. Wallace E. Loftus T. Keaney J. Kealy J. Humphries M.M. Molloy M.G. Meaney J.F. Farrell M. Campbell M. Blood-brain barrier dysfunction as a hallmark pathology in chronic traumatic encephalopathy.J. Neuropathol. Exp. Neurol. 2016; 75: 656-662Crossref PubMed Scopus (20) Google Scholar examined a case of chronic traumatic encephalopathy (CTE) using immunohistochemical techniques to examine expression of the BBB tight junction proteins claudin-1 and zona occludens-1. Perivascular p-tau was present at sites with evidence of decreased tight junction protein expression. Fibrinogen and immunoglobulin G extravasation, indicative of BBB dysfunction, were also evident at these sites. Similarly, Tagge et al., 2018Tagge C.A. Fisher A.M. Minaeva O.V. Gaudreau-Balderrama A. Moncaster J.A. Zhang X.-L. Wojnarowicz M.W. Casey N. Lu H. Kokiko-Cochran O.N. et al.Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model.Brain. 2018; 141: 422-458Crossref PubMed Scopus (58) Google Scholar found focal cortical lesions with perivascular accumulation of immunoglobulin G in 4 cases of mild concussive injury examined in the subacute to chronic period after injury. These findings are consistent with extravasation and accumulation of serum proteins at sites of focal microvascular injury. BBB disruption in the acute period after severe brain injury, determined by a cerebrospinal fluid (CSF)/plasma protein ratio of more than 0.007, may correlate with worse long-term outcome (Ho et al., 2014Ho K.M. Honeybul S. Yip C.B. Silbert B.I. Prognostic significance of blood-brain barrier disruption in patients with severe nonpenetrating traumatic brain injury requiring decompressive craniectomy.J. Neurosurg. 2014; 121: 674-679Crossref PubMed Scopus (13) Google Scholar), although the prognostic significance across the TBI spectrum needs to be explored further. In addition to these changes at the BBB, CBF has been studied extensively after TBI in humans, mostly in the acute period within a few days of injury (Furuya et al., 2003Furuya Y. Hlatky R. Valadka A.B. Diaz P. Robertson C.S. Comparison of cerebral blood flow in computed tomographic hypodense areas of the brain in head-injured patients.Neurosurgery. 2003; 52: 340-345, discussion 345–346Crossref Scopus (29) Google Scholar, Menon, 2006Menon D.K. Brain ischaemia after traumatic brain injury: lessons from 15O2 positron emission tomography.Curr. Opin. Crit. Care. 2006; 12: 85-89Crossref PubMed Scopus (24) Google Scholar) although several studies have examined CBF weeks to years after TBI (Kim et al., 2010Kim J. Whyte J. Patel S. Avants B. Europa E. Wang J. Slattery J. Gee J.C. Coslett H.B. Detre J.A. Resting cerebral blood flow alterations in chronic traumatic brain injury: an arterial spin labeling perfusion FMRI study.J. Neurotrauma. 2010; 27: 1399-1411Crossref PubMed Scopus (0) Google Scholar). There is a consistent body of literature regarding humans, indicating that deficits in CBF are common after TBI, including repetitive mild TBI (Bonne et al., 2003Bonne O. Gilboa A. Louzoun Y. Kempf-Sherf O. Katz M. Fishman Y. Ben-Nahum Z. Krausz Y. Bocher M. Lester H. et al.Cerebral blood flow in chronic symptomatic mild traumatic brain injury.Psychiatry Res. 2003; 124: 141-152Crossref PubMed Scopus (0) Google Scholar). Studies using single-photon emission computed tomography (SPECT) to measure regional CBF in patients with chronic TBI (Barkai et al., 2004Barkai G. Goshen E. Tzila Zwas S. Dolberg O.T. Pick C.G. Bonne O. Schreiber S. Acetazolamide-enhanced neuroSPECT scan reveals functional impairment after minimal traumatic brain injury not otherwise discernible.Psychiatry Res. 2004; 132: 279-283Crossref PubMed Scopus (0) Google Scholar, Bonne et al., 2003Bonne O. Gilboa A. Louzoun Y. Kempf-Sherf O. Katz M. Fishman Y. Ben-Nahum Z. Krausz Y. Bocher M. Lester H. et al.Cerebral blood flow in chronic symptomatic mild traumatic brain injury.Psychiatry Res. 2003; 124: 141-152Crossref PubMed Scopus (0) Google Scholar, Lewine et al., 2007Lewine J.D. Davis J.T. Bigler E.D. Thoma R. Hill D. Funke M. Sloan J.H. Hall S. Orrison W.W. Objective documentation of traumatic brain injury subsequent to mild head trauma: multimodal brain imaging with MEG, SPECT, and MRI.J. Head Trauma Rehabil. 2007; 22: 141-155Crossref PubMed Scopus (140) Google Scholar) have consistently found regions of hypoperfusion in a subset of symptomatic TBI subjects (Raji et al., 2014Raji C.A. Tarzwell R. Pavel D. Schneider H. Uszler M. Thornton J. van Lierop M. Cohen P. Amen D.G. Henderson T. Clinical utility of SPECT neuroimaging in the diagnosis and treatment of traumatic brain injury: a systematic review.PLoS ONE. 2014; 9: e91088Crossref PubMed Scopus (0) Google Scholar). SPECT perfusion changes significantly correlated with neuropsychological or neurological deficits. Studies using xenon-computed tomography (CT) report similar findings (Lewine et al., 2007Lewine J.D. Davis J.T. Bigler E.D. Thoma R. Hill D. Funke M. Sloan J.H. Hall S. Orrison W.W. Objective documentation of traumatic brain injury subsequent to mild head trauma: multimodal brain imaging with MEG, SPECT, and MRI.J. Head Trauma Rehabil. 2007; 22: 141-155Crossref PubMed Scopus (140) Google Scholar). In addition to nuclear medicine studies, advanced MRI techniques have also been helpful in evaluating traumatic microvascular injury. Arterial spin labeling (ASL) reveals alterations in global and regional resting CBF in TBI patients of all severities. Kim et al., 2010Kim J. Whyte J. Patel S. Avants B. Europa E. Wang J. Slattery J. Gee J.C. Coslett H.B. Detre J.A. Resting cerebral blood flow alterations in chronic traumatic brain injury: an arterial spin labeling perfusion FMRI study.J. Neurotrauma. 2010; 27: 1399-1411Crossref PubMed Scopus (0) Google Scholar showed that patients with chronic moderate to severe TBI have reduced global CBF as well as decreased regional perfusion in the thalamus, posterior cingulate cortex, and frontal cortex. Regions with decreased resting CBF also had altered task-related activation during an ASL fMRI working memory paradigm in chronically injured subjects. Regional relative CBF can also be measured with perfusion-weighted imaging (Bartnik-Olson et al., 2014Bartnik-Olson B.L. Holshouser B. Wang H. Grube M. Tong K. Wong V. Ashwal S. Impaired neurovascular unit function contributes to persistent symptoms after concussion: a pilot study.J. Neurotrauma. 2014; 31: 1497-1506Crossref PubMed Scopus (53) Google Scholar). The exact causes of these alterations in CBF following TBI are unclear. Decreased CBF may result from a lower metabolic demand from injured tissue, resulting in an appropriately matched reduction in blood flow. However, studies using fluorodeoxyglucose positron emission tomography (FDG-PET) have suggested that glucose metabolism is disrupted following TBI but can be increased, decreased, or unchanged in ways that do not clearly correlate with structural abnormalities (Ito et al., 2016Ito K. Asano Y. Ikegame Y. Shinoda J. Differences in brain metabolic impairment between chronic mild/moderate TBI patients with and without visible brain lesions based on MRI.BioMed Res. Int. 2016; 2016: 3794029Crossref Scopus (5) Google Scholar, Yamaki et al., 2018Yamaki T. Uchino Y. Henmi H. Kamezawa M. Hayakawa M. Uchida T. Ozaki Y. Onodera S. Oka N. Odaki M. et al.Increased brain glucose metabolism in chronic severe traumatic brain injury as determined by longitudinal 18F-FDG PET/CT.J. Clin. Neurosci. 2018; 57: 20-25Abstract Full Text Full Text PDF Scopus (1) Google Scholar). The studies above describe alterations in resting CBF following TBI. In addition, cerebrovascular reserve, or the ability of the cerebral vasculature to react to vasodilatory or vasoconstrictive stimuli, termed cerebrovascular reactivity (CVR), can be altered after TBI. Breath holding (resulting in induced hypercapnia), hyperventilation, CO2 inhalation, or acetazolamide administration can be used in conjunction with non-invasive imaging techniques to assess CVR (Kassner and Roberts, 2004Kassner A. Roberts T.P.L. Beyond perfusion: cerebral vascular reactivity and assessment of microvascular permeability.Top. Magn. Reson. Imaging. 2004; 15: 58-65Crossref PubMed Scopus (0) Google Scholar). Transcranial Doppler (TCD) ultrasound, near infrared spectroscopy (NIRS), and MRI have been the most popular methods to examine post-TBI CVR in recent studies. TCD offers the advantage of very high temporal resolution but suffers from poor spatial resolution. A large prospective study of 299 acute TBI patients assessed the incidence of cerebral vasospasm via TCD (Oertel et al., 2005Oertel M. Boscardin W.J. Obrist W.D. Glenn T.C. McArthur D.L. Gravori T. Lee J.H. Martin N.A. Posttraumatic vasospasm: the epidemiology, severity, and time course of an underestimated phenomenon: a prospective study performed in 299 patients.J. Neurosurg. 2005; 103: 812-824Crossref PubMed Scopus (127) Google Scholar). Nearly half of the patients met at least one TCD criterion for vasospasm. After the acute stage, studies of professional boxers exposed to repetitive mild TBI showed that CVR was reduced in the subacute period when measured with both TCD and NIRS, particularly in boxers who had experienced the highest mild TBI exposure (Bailey et al., 2013Bailey D.M. Jones D.W. Sinnott A. Brugniaux J.V. New K.J. Hodson D. Marley C.J. Smirl J.D. Ogoh S. Ainslie P.N. Impaired cerebral haemodynamic function associated with chronic traumatic brain injury in professional boxers.Clin. Sci. (Lond.). 2013; 124: 177-189Crossref PubMed Scopus (0) Google Scholar). In the boxers, lower CVR measurements correlate with worse neurocognitive dysfunction and were inversely correlated with head injury exposure. A recent meta-analysis identified three studies examining sports-related concussion and CVR via TCD in 42 athletes (primarily boxers and hockey players) and 33 healthy controls (Gardner et al., 2015Gardner A.J. Tan C.O. Ainslie P.N. van Donkelaar P. Stanwell P. Levi C.R. Iverson G.L. Cerebrovascular reactivity assessed by transcranial Doppler ultrasoun