Structural and functional connectivity of the whole brain and subnetworks in individuals with mild traumatic brain injury:predictors of patient prognosis

Patients with mild traumatic brain injury have a diverse clinical presentation,and the underlying pathophysiology remains poorly understood.Magnetic resonance imaging is a non-invasive technique that has been widely utilized to investigate neuro biological markers after mild traumatic brain injury.This approach has emerged as a promising tool for investigating the pathogenesis of mild traumatic brain injury.G raph theory is a quantitative method of analyzing complex networks that has been widely used to study changes in brain structure and function.However,most previous mild traumatic brain injury studies using graph theory have focused on specific populations,with limited exploration of simultaneous abnormalities in structural and functional connectivity.Given that mild traumatic brain injury is the most common type of traumatic brain injury encounte red in clinical practice,further investigation of the patient characteristics and evolution of structural and functional connectivity is critical.In the present study,we explored whether abnormal structural and functional connectivity in the acute phase could serve as indicators of longitudinal changes in imaging data and cognitive function in patients with mild traumatic brain injury.In this longitudinal study,we enrolled 46 patients with mild traumatic brain injury who were assessed within 2 wee ks of injury,as well as 36 healthy controls.Resting-state functional magnetic resonance imaging and diffusion-weighted imaging data were acquired for graph theoretical network analysis.In the acute phase,patients with mild traumatic brain injury demonstrated reduced structural connectivity in the dorsal attention network.More than 3 months of followup data revealed signs of recovery in structural and functional connectivity,as well as cognitive function,in 22 out of the 46 patients.Furthermore,better cognitive function was associated with more efficient networks.Finally,our data indicated that small-worldness in the acute stage could serve as a predictor of longitudinal changes in connectivity in patients with mild traumatic brain injury.These findings highlight the importance of integrating structural and functional connectivity in unde rstanding the occurrence and evolution of mild traumatic brain injury.Additionally,exploratory analysis based on subnetworks could serve a predictive function in the prognosis of patients with mild traumatic brain injury.

The Effects of Mindfulness-Based Interventions on Symptoms of Mild Traumatic Brain Injury:A Systematic Review

Mindfulness-based interventions(MBIs)are emerging non-pharmacological treatments for mild traumatic brain injury(mTBI).In this systematic review,the authors aimed to evaluate the potential efficacy of MBIs to provide recommendations for treating patients with mTBI.We searched of the English literature on MBIs for patients with mTBI as of 01 September,2023,using the PubMed,Web of Science,PsycINFO,and Scopus databases.One author performed data extraction and quality scoring of the included literature according to the proposed protocol,and another conducted the review.The review was not registered.A total of 11 studies met the final inclusion criteria,5 of which involved military personnel(veterans).MBIs covered in this review include goal-oriented attention self-regulation(GOALS),mindfulness-based stress reduction(MBSR),acceptance and commitment therapy(ACT),and so on.Research shows that MBSR mainly reduces mental fatigue symptoms in mTBI patients,and GOALS tend to improve their cognitive function.The effect of MBIs on psychological symptoms needs further exploration.Other studies,such as mindfulness-based group therapy and intervention studies targeting mTBI military personnel,are relatively sparse.MBIs have specific effects on mental fatigue and cognitive dysfunction in patients with mTBI.However,the effect on psychological distress and the sustained effectiveness across all symptoms still need further exploration.Considering the particularity of military personnel suffering from mTBI,researchers need to do more intervention studies targeting mTBI military personnel.Therefore,the design of future MBIs trials for mTBI patients’needs to take into account all the factors,such as different populations and severity of traumatic brain injury,to verify the effectiveness of MBIs in alleviating mTBI symptoms and explore the mechanism of intervention.

Exploring cerebral structural and functional abnormalities in a mouse model of post-traumatic headache induced by mild traumatic brain injury

Mild traumatic brain injury(mTBI)-induced post-traumatic headache(PTH)is a pressing public health concern and leading cause of disability worldwide.Although PTH is often accompanied by neurological disorders,the exact underlying mechanism remains largely unknown.Identifying potential biomarkers may prompt the diagnosis and development of effective treatments for mTBI-induced PTH.In this study,a mouse model of mTBI-induced PTH was established to investigate its effects on cerebral structure and function during short-term recovery.Results indicated that mice with mTBI-induced PTH exhibited balance deficits during the early post-injury stage.Metabolic kinetics revealed that variations in neurotransmitters were most prominent in the cerebellum,temporal lobe/cortex,and hippocampal regions during the early stages of PTH.Additionally,variations in brain functional activities and connectivity were further detected in the early stage of PTH,particularly in the cerebellum and temporal cortex,suggesting that these regions play central roles in the mechanism underlying PTH.Moreover,our results suggested that GABA and glutamate may serve as potential diagnostic or prognostic biomarkers for PTH.Future studies should explore the specific neural circuits involved in the regulation of PTH by the cerebellum and temporal cortex,with these two regions potentially utilized as targets for non-invasive stimulation in future clinical treatment.

Exosomes derived from microglia overexpressing miR-124-3p alleviate neuronal endoplasmic reticulum stress damage after repetitive mild traumatic brain injury

We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain injury.However,its impact on neuronal endoplasmic reticulum stress following repetitive mild traumatic brain injury remains unclear.In this study,we first used an HT22 scratch injury model to mimic traumatic brain injury,then co-cultured the HT22 cells with BV2 microglia expressing high levels of miR-124-3p.We found that exosomes containing high levels of miR-124-3p attenuated apoptosis and endoplasmic reticulum stress.Furthermore,luciferase reporter assay analysis confirmed that miR-124-3p bound specifically to the endoplasmic reticulum stress-related protein IRE1α,while an IRE1αfunctional salvage experiment confirmed that miR-124-3p targeted IRE1αand reduced its expression,thereby inhibiting endoplasmic reticulum stress in injured neurons.Finally,we delivered microglia-derived exosomes containing miR-124-3p intranasally to a mouse model of repetitive mild traumatic brain injury and found that endoplasmic reticulum stress and apoptosis levels in hippocampal neurons were significantly reduced.These findings suggest that,after repetitive mild traumatic brain injury,miR-124-3 can be transferred from microglia-derived exosomes to injured neurons,where it exerts a neuroprotective effect by inhibiting endoplasmic reticulum stress.Therefore,microglia-derived exosomes containing miR-124-3p may represent a novel therapeutic strategy for repetitive mild traumatic brain injury.

Traumatic axonal injury of the cingulum in patients with mild traumatic brain injury: a diffusion tensor tractography study

The cingulum,connecting the orbitofrontal cortex to the medial temporal lobe,involves in diverse cognition functions including attention,memory,and motivation.To investigate the relationship between the cingulum injury and cognitive impairment in patients with chronic mild traumatic brain injury,we evaluated the integrity between the anterior cingulum and the basal forebrain using diffusion tensor tractography in 73 patients with chronic mild traumatic brain injury(39 males,34 females,age 43.29±11.42 years)and 40 healthy controls(22 males,18 females,age 40.11±16.81 years).The patients were divided into three subgroups based on the integrity between the anterior cingulum and the basal forebrain on diffusion tensor tractography:subgroup A(n=19 patients)– both sides of the anterior cingulum were intact;subgroup B(n=36 patients)– either side of the anterior cingulum was intact;and subgroup C(18 patients)– both sides of the anterior cingulum were discontinued.There were significant differences in total Memory Assessment Scale score between subgroups A and B and between subgroups A and C.There were no significant differences in diffusion tensor tractography parameters(fractional anisotropy,apparent diffusion coefficient,and fiber volume)between patients and controls.These findings suggest that the integrity between the anterior cingulum and the basal forebrain,but not diffusion tensor tractography parameter,can be used to predict the cognitive function of patients with chronic mild traumatic brain injury.This study was approved by Yeungnam University Hospital Institutional Review Board(approval No.YUMC-2014-01-425-010)on August 16,2017.

Diffusion tensor tractography characteristics of axonal injury in concussion/mild traumatic brain injury

The main advantage of diffusion tensor tractography is that it allows the entire neural tract to be evaluated.In addition,configurational analysis of reconstructed neural tracts can indicate abnormalities such as tearing,narrowing,or discontinuations,which have been used to identify axonal injury of neural tracts in concussion patients.This review focuses on the characteristic features of axonal injury in concussion or mild traumatic brain injury(m TBI)patients through the use of diffusion tensor tractography.Axonal injury in concussion(m TBI)patients is characterized by their occurrence in long neural tracts and multiple injuries,and these characteristics are common in patients with diffuse axonal injury and in concussion(m TBI)patients with axonal injury.However,the discontinuation of the corticospinal tract is mostly observed in diffuse axonal injury,and partial tearing and narrowing in the subcortical white matter are frequently observed in concussion(m TBI)patients with axonal injury.This difference appears to be attributed to the observation that axonal injury in concussion(m TBI)patients is the result of weaker forces than those producing diffuse axonal injuries.In addition,regarding the fornix,in diffuse axonal injury,discontinuation of the fornical crus has been frequently reported,but in concussion(m TBI)patients,many collateral branches form in the fornix in addition to these findings in many case studies.It is presumed that the impact on the brain in TBI is relatively weaker than that in diffuse axonal injury,and that the formation of collateral branches occurs during the fornix recovery process.Although the occurrence of axonal injury in multiple areas of the brain is an important feature of diffuse axonal injury,case studies in concussion(m TBI)have shown that axonal injury occurs in multiple neural tracts.Because axonal injury lesions in m TBI patients may persist for approximately 10 years after injury onset,the characteristics of axonal injury in concussion(m TBI)patients,which are reviewed and categorized in this review,are expected to serve as useful supplementary information in the diagnosis of axonal injury in concussion(m TBI)patients.

Positron emission tomography imaging for the assessment of mild traumatic brain injury and chronic traumatic encephalopathy:recent advances in radiotracers

A chronic phase following repetitive mild traumatic brain injury can present as chronic traumatic encephalopathy in some cases,which requires a neuropathological examination to make a definitive diagnosis.Positron emission tomography(PET)is a molecular imaging modality that has high sensitivity for detecting even very small molecular changes,and can be used to quantitatively measure a range of molecular biological processes in the brain using different radioactive tracers.Functional changes have also been reported in patients with different forms of traumatic brain injury,especially mild traumatic brain injury and subsequent chronic traumatic encephalopathy.Thus,PET provides a novel approach for the further evaluation of mild traumatic brain injury at molecular levels.In this review,we discuss the recent advances in PET imaging with different radiotracers,including radioligands for PET imaging of glucose metabolism,tau,amyloid-beta,γ-aminobutyric acid type A receptors,and neuroinflammation,in the identification of altered neurological function.These novel radiolabeled ligands are likely to have widespread clinical application,and may be helpful for the treatment of mild traumatic brain injury.Moreover,PET functional imaging with different ligands can be used in the future to perform largescale and sequential studies exploring the time-dependent changes that occur in mild traumatic brain injury.

Injury of the dentatorubrothalamic tract in patients with post-traumatic tremor following mild traumatic brain injury: a case-control study

Post-traumatic movement disorder is one of the sequelae of traumatic brain injury. The dentatorubrothalamic tract(DRTT) is reported to be involved in the control of movement. Therefore, injury of the DRTT can be accompanied by abnormal movements, including ataxia, tremor, or dystonia. We investigated DRTT injuries in 27 patients who showed post-traumatic tremor in at least one of four extremities following mild traumatic brain injury. We classified DRTT injuries based on diffusion tensor tractography parameters and configuration: type A: the DRTT showed narrowing, type B: the DRTT showed partial tearing, and type C: the DRTT showed discontinuation. Fractional anisotropy and fiber number of the DRTT were significantly decreased in patients compared with the healthy controls. Based on our DRTT injury classification, among the 54 hemispheres of the 27 patients, type A injury occurred in 22 hemispheres(40.7%) of 17 patients, type B injury was present in 15 hemispheres(27.7%) of 10 patients, and type C injury was observed in 8 hemispheres(14.8%) of 6 patients. Our results suggest that diffusion tensor tractography-based evaluation of the DRTT would be useful when determining cause of post-traumatic tremor in patients with mild traumatic brain injury. The study protocol was approved by the Institutional Review Board of Yeungnam University Hospital(YUMC-2018-09-007) on September 5, 2018.

Quetiapine augmentation of prolonged exposure therapy in veterans with PTSD and a history of mild traumatic brain injury: design and methodology of a pilot study

Background: Selective serotonergic reuptake inhibitors(SSRIs) are first-line pharmacologic treatments for patients with posttraumatic stress disorder(PTSD), but must be given over extended period of time before the onset of action. The use of SSRIs in PTSD patients with mild traumatic brain injury(m TBI) is problematic since SSRIs could exacerbate post-concussion syndrome(PCS) symptoms. VA/DOD guidelines identify trauma-focused psychotherapy as the best evidence-based treatment for PTSD, but overall effectiveness is limited by reduced levels of patient engagement and retention. A previous study from this research group suggested that quetiapine monotherapy, but not risperidone or valproate, could increase engagement in trauma-focused psychotherapy.Methods: We report the study protocol of a pilot study funded under the South-Central Mental Illness Research, Education, and Clinical Center pilot study program from the U.S. Department of Veterans Affairs. This randomized, open-label study was designed to evaluate the feasibility of completing a randomized trial of quetiapine vs. treatment as usual to promote patient engagement in PTSD patients with a history of m TBI.Discussion: We expect that the success of this ongoing study should provide us with the preliminary data necessary to design a full-scale randomized trial. Positive efficacy results in a full-scale trial should inform new VA guidelines for clinical practice by showing that quetiapine-related improvements in patient engagement and retention may be the most effective approach to assure that VA resources achieve the best possible outcome for veterans.Trial registration: NCT04280965.

Weak phonation due to unknown injury of the corticobulbar tract in a patient with mild traumatic brain injury: a diffusion tensor tractography study

In this study,we report on a patient who showed weak phonation following mild traumatic brain injury（TBI）,which was demonstrated by diffusion tensor tractography（DTT）.

Application of diffusion kurtosis imaging technology in evaluating early mild traumatic brain injury

Objective To explore the value of magnetic resonance diffusion kurtosis imaging in diagnosing early tiny changes of brain tissue after mild traumatic brain injury.Methods A total of 22 patients with mild traumatic brain injury(study group)and 20 healthy subjects(control group)were enrolled in this study,and diffusion kurtosis imaging magnetic resonance scanning was employed in all subjects.fractional anisotropy,fractional anisotropy of kurtosis,mean kurtosis,axial kurtosis and radial kurtosis of diffusion kurtosis imaging parameters in the genu of corpus callosum,splenium corporis callosi,internal capsule,thalamus,putamen,cortex of frontal lobe,temporal lobe and parietal lobe at control group,the injured side and the mirror regions were measured,and the results were compared between the two groups.The receiver operating characteristic curve was used to evaluate the ability of different parameters in diagnosing mild traumatic brain injury.Results Compared with the control group,in the study group fractional anisotropy values of bilateral genu of corpus callosum,splenium corporis callosi,internal capsule and thalamus were significantly reduced,and fractional anisotropy of kurtosis values of bilateral thalamus and putamen were significantly reduced,and the differences were statistically significant(P<0.05).Compared with the control group,in the study group mean kurtosis and axial kurtosis values of bilateral genu of corpus callosum,posterior limb of Internal capsule,thalamus,putamen and cortex of temporal lobe were significantly reduced,while radial kurtosis values in the genu of corpus callosum,thalamus,cortex of frontal lobe,temporal lobe at the injured side were increased,and the differences were statistically significant(P<0.05).Conclusion DKI techniques can sensitively detect the early tiny pathologic changes of cerebral tissue in mild traumatic brain injury patients,which provide more imaging evidence for the clinical early diagnosis treatment and prognosis.

Neuroprotective effects of cold-inducible RNA-binding protein during mild hypothermia on traumatic brain injury

Cold-inducible RNA-binding protein（CIRP）, a key regulatory protein, could be facilitated by mild hypothermia in the brain, heart and liver. This study observed the effects of mild hypothermia at 31 ± 0.5℃ on traumatic brain injury in rats. Results demonstrated that mild hypothermia suppressed apoptosis in the cortex, hippocampus and hypothalamus, facilitated CIRP m RNA and protein expression in these regions, especially in the hypothalamus. The anti-apoptotic effect of mild hypothermia disappeared after CIRP silencing. There was no correlation between mitogen-activated extracellular signal-regulated kinase activation and CIRP silencing. CIRP silencing inhibited extracellular signal-regulated kinase-1/2 activation. These indicate that CIRP inhibits apoptosis by affecting extracellular signal-regulated kinase-1/2 activation, and exerts a neuroprotective effect during mild hypothermia for traumatic brain injury.

Pulsed arterial spin labeling effectively and dynamically observes changes in cerebral blood flow after mild traumatic brain injury

Cerebral blood flow is strongly associated with brain function, and is the main symptom and diagnostic basis for a variety of encephalopathies. However, changes in cerebral blood flow after mild traumatic brain injury remain poorly understood. This study sought to observe changes in cerebral blood flow in different regions after mild traumatic brain injury using pulsed arterial spin labeling. Our results demonstrate maximal cerebral blood flow in gray matter and minimal in the white matter of patients with mild traumatic brain injury. At the acute and subacute stages, cerebral blood flow was reduced in the occipital lobe, parietal lobe, central region, subcutaneous region, and frontal lobe. Cerebral blood flow was restored at the chronic stage. At the acute, subacute, and chronic stages, changes in cerebral blood flow were not apparent in the insula. Cerebral blood flow in the temporal lobe and limbic lobe diminished at the acute and subacute stages, but was restored at the chronic stage. These findings suggest that pulsed arterial spin labeling can precisely measure cerebral blood flow in various brain regions, and may play a reference role in evaluating a patient＇s condition and judging prognosis after traumatic brain injury.

Severe bilateral anterior cingulum injury in patients with mild traumatic brain injury

The cingulum,the neural tract connecting the orbitofrontal cortex with the medial temporal lobe,plays an important role in cognition（Bush et al.,2000）.It is also important in memory because it provides cholinergic innervations to the cerebral cortex after obtaining innervation from the medial septal nucleus,the vertical nucleus of the diagonal band, and the nucleus basalis of Meynert via the medial cholinergic pathway （Nieuwenhuys et al., 2008; Naidich and Duvernoy, 2009; Hong and Jang, 2010a）.

Longitudinal follow-up of patients with mild traumatic brain injury by magnetic resonance spectroscopic technique

Objective:To explore the changes in the concentrations of neural markers immediately or several months after mild traumatic brain injury(mTBI).Methods:The metabolic markers of neurons in white matter tissues above the lateral ventricle were semi-quantitatively determined by employing 1H magnetic resonance spectroscopic technique(1-H-MRS) in 30 clinically diagnosed cases of mTBI.At the same time,the neurological functions of the subjects,including ability to pay attention,memory,working memory and operational capacity etc were also assessed. Results:The patients were followed up for,on average,13 days after mTB1 and the results showed that Cre,PCre and Glx in the white matter tissues were significantly elevated in mTBI patients.17 patients(57%) recovered from the injury during the follow-up(median was defined as the 40th post-trauma day).Comparison in terms of intelligence among groups revealed that the levels of neural markers of intelligence development was positively related with intelligence scores).Conclusions:Change in Clx concentrations is most sensitive during trauma or in ensuing repairing processes,and might be different from normal status in the following months and Clx level tends to be accompanied with change in Cre,another energy-related marker.

Quantitative proteomic and phosphoproteomic analyses of the hippocampus reveal the involvement of NMDAR1 signaling in repetitive mild traumatic brain injury

The cumulative damage caused by repetitive mild traumatic brain injury can cause long-term neurodegeneration leading to cognitive impairment.This cognitive impairment is thought to result specifically from damage to the hippocampus.In this study,we detected cognitive impairment in mice 6 weeks after repetitive mild traumatic brain injury using the novel object recognition test and the Morris water maze test.Immunofluorescence staining showed that p-tau expression was increased in the hippocampus after repetitive mild traumatic brain injury.Golgi staining showed a significant decrease in the total density of neuronal dendritic spines in the hippocampus,as well as in the density of mature dendritic spines.To investigate the specific molecular mechanisms underlying cognitive impairment due to hippocampal damage,we performed proteomic and phosphoproteomic analyses of the hippocampus with and without repetitive mild traumatic brain injury.The differentially expressed proteins were mainly enriched in inflammation,immunity,and coagulation,suggesting that non-neuronal cells are involved in the pathological changes that occur in the hippocampus in the chronic stage after repetitive mild traumatic brain injury.In contrast,differentially expressed phosphorylated proteins were mainly enriched in pathways related to neuronal function and structure,which is more consistent with neurodegeneration.We identified N-methyl-D-aspartate receptor 1 as a hub molecule involved in the response to repetitive mild traumatic brain injury,and western blotting showed that,while N-methyl-D-aspartate receptor 1 expression was not altered in the hippocampus after repetitive mild traumatic brain injury,its phosphorylation level was significantly increased,which is consistent with the omics results.Administration of GRP78608,an N-methyl-D-aspartate receptor 1 antagonist,to the hippocampus markedly improved repetitive mild traumatic brain injury-induced cognitive impairment.In conclusion,our findings suggest that N-methyl-D-aspartate receptor 1 signaling in the hippocampus is involved in cognitive impairment in the chronic stage after repetitive mild traumatic brain injury and may be a potential target for intervention and treatment.

Experimental repetitive mild traumatic brain injury induces deficits in trabecular bone microarchitecture and strength in mice

To evaluate the long-term consequence of repetitive mild traumatic brain injury （mTBI） on bone, mTBI was induced in 10-week-old female C57BL/6J mice using a weight drop model, once per day for 4 consecutive days at different drop heights （0.5, 1 and 1.5 m） and the skeletal phenotype was evaluated at different time points after the impact. In vivo micro-CT （μ-CT） analysis of the tibial metaphysis at 2, 8 and 12 weeks after the impact revealed a 5%-32% reduction in trabecular bone mass. Histomorphometric analyses showed a reduced bone formation rate in the secondary spongiosa ofl.5 m impacted mice at 12 weeks post impact. Apparent modulus （bone strength）, was reduced by 30% （P 〈 0.05） at the proximal tibial metaphysis in the 1.5 m drop height group at 2 and 8 weeks post impact. Ex vivo μ-CT analysis of the fifth lumbar vertebra revealed a significant reduction in trabecular bone mass at 12 weeks of age in all three drop height groups. Serum levels of osteocalcin were decreased by 22%, 15%, and 19% in the 0.5, 1.0 and 1.5 m drop height groups, respectively, at 2 weeks post impact. Serum IGF-I levels were reduced by 18%-32% in mTBI mice compared to control mice at 2 weeks post impact. Serum osteocalcin and IGF-I levels correlated with trabecular BV/TV （r2 = 0.14 and 0.16, P 〈 0.05）. In conclusion, repetitive mTBI exerts significant negative effects on the trabecular bone microarchitecture and bone mechanical properties by influencing osteoblast function via reduced endocrine IGF-I actions.

The value of neurocognitive testing for acute outcomes after mild traumatic brain injury

Background: Traditionally, neurocognitive testing is performed weeks to months after head injury and is mostly performed on patients who continue to have symptoms or difficulties. In this study, we sought to determine whether these tests, when administered acutely, could assist in predicting short-term outcomes after acute traumatic brain injury(TBI).Methods: This is an IRB-approved prospective study of adult patients who came to the emergency department of our Level-1 trauma center with TBI. Patients were enrolled prospectively after providing written informed consent and underwent three separate neurocognitive tests: the Galveston Orientation Amnesia Test(GOAT), the Rivermead PostConcussion Survey Questionnaire(RPCSQ), and the Mini Mental Status Examination(MMSE).Results: A lower GOAT score was significantly associated with hospitalization(P=0.0212) and the development of post-concussion syndrome(PCS) at late follow-up(P=0.0081). A higher RPCSQ score was significantly associated with hospital admission(P=0.0098), re-admission within 30 days of discharge(P=0.0431) and evidence of PCS at early follow-up(P=0.0004). A higher MMSE score was significantly associated with not being admitted to the hospital(P=0.0002) and not returning to the emergency department(ED) within 72 hours of discharge(P=0.0078). Lower MMSE was also significantly associated with bleeding or a fracture on the brain CT(P=0.0431).Conclusions: While neurocognitive testing is not commonly performed in the ED in the setting of acute head injury, it is both feasible and appears to have value in predicting hospital admission and PCS. These data are especially important in terms of helping patients understand what to expect, thus, aiding in their recovery.

Animal model of repetitive mild traumatic brain injury for human traumatic axonal injury and chronic traumatic encephalopathy

Chronic traumatic encephalopathy（CTE）is a chronic neurodegenerative disease featured with tauopathy.CTE is tightly related with repetitive mild traumatic brain injury（m TBI）,which is interchangeably known as concussion（Mc Kee et al.,2009,2013）.This disease is differentiated by neuropathological features from other neurological diseases that involve tau protein aggregation and tangle formation abnormalities like Alzheimer＇s disease （AD）, frontotemporal dementia, and Parkinson- ism linked to chromosome 17 （FTDP-17）.