Rationale and design of the "NEurodegeneration: Traumatic brain injury as Origin of the Neuropathology (NEwTON)" study: a prospective cohort study of individuals at risk for chronic traumatic encephalopathy.

BACKGROUND: Repetitive head injury in contact sports is associated with cognitive, neurobehavioral, and motor impairments and linked to a unique neurodegenerative disorder: chronic traumatic encephalopathy (CTE). As the clinical presentation is variable, risk factors are heterogeneous, and diagnostic biomarkers are not yet established, the diagnostic process of CTE remains a challenge. The general objective of the NEwTON study is to establish a prospective cohort of individuals with high risk for CTE, to phenotype the study population, to identify potential fluid and neuroimaging biomarkers, and to measure clinical progression of the disease. The present paper explains the protocol and design of this case-finding study. METHODS: NEwTON is a prospective study that aims to recruit participants at risk for CTE, with features of the traumatic encephalopathy syndrome (exposed participants), and healthy unexposed control individuals. Subjects are invited to participate after diagnostic screening at our memory clinic or recruited by advertisement. Exposed participants receive a comprehensive baseline screening, including neurological examination, neuropsychological tests, questionnaires and brain MRI for anatomical imaging, diffusion tensor imaging (DTI), resting-state functional MRI (rsfMRI), and quantitative susceptibility mapping (QSM). Questionnaires include topics on life-time head injury, subjective cognitive change, and neuropsychiatric symptoms. Optionally, blood and cerebrospinal fluid are obtained for storage in the NEwTON biobank. Patients are informed about our brain donation program in collaboration with the Netherlands Brain Brank. Follow-up takes place annually and includes neuropsychological assessment, questionnaires, and optional blood draw. Testing of control subjects is limited to baseline neuropsychological tests, MRI scan, and also noncompulsory blood draw. RESULTS: To date, 27 exposed participants have finished their baseline assessments. First baseline results are expected in 2023. CONCLUSIONS: The NEwTON study will assemble a unique cohort with prospective observational data of male and female individuals with high risk for CTE. This study is expected to be a primary explorative base and designed to share data with international CTE-related cohorts. Sub-studies may be added in the future with this cohort as backbone.

Predicting long-term cognitive and neuropathological consequences of moderate to severe traumatic brain injury: Review and theoretical framework.

Prognostic modeling in moderate to severe traumatic brain injury (TBI) has historically focused primarily on the projection of crude outcomes such as the risk of mortality and disability. Initial work in this area has perpetuated the notion that prognosis after moderate to severe TBI can be measured as a single, static, and dichotomous outcome. However, more recent conceptualizations describe moderate to severe TBI as the initiation of a chronic disease state with high levels of inter-individual variability in terms of symptom manifestation and disease progression. Unfortunately, existing prognostic models provide limited insight into the extent of chronic cognitive and neurodegenerative changes experienced by moderate to severe TBI survivors. Though prior research has identified a variety of acute factors that appear to influence post-injury cognitive and neuropathological outcomes, an empirically supported framework for prognostic modeling of these injury-distal outcomes does not exist. The current review considers the literature on an expanded array of empirically supported predictors (both premorbid and injury-related) in association with long-term sequelae of moderate to severe TBI. We also provide a theoretical framework and statistical approach for prognostic modeling in moderate to severe TBI in order to unify efforts across research groups and facilitate important progress in this research area.

An examination of financial capacity and neuropsychological performance in chronic acquired brain injury (CABI).

PRIMARY OBJECTIVE: Financial Capacity (FC) is known to be impaired in the acute and subacute stages of brain injury. The current study sought to examine FC in the context of chronic, moderate to severe acquired brain injury (CABI). RESEARCH DESIGN: The Financial Competence Assessment Inventory (FCAI), developed in Australia, was adapted to examine the integrity of FC in an American sample. METHODS AND PROCEDURES: Healthy comparison (HC) participants were recruited from the community, whereas participants with CABI were recruited from a community-based rehabilitation center. Participants completed the FCAI and a neuropsychological battery. FCAI performance in the current study was compared against previously published Australian data. Multiple regression analyses examined group (CABI vs. HC) as a predictor of FC. Bivariate correlations examined the cognitive correlates of FCAI in the CABI group. MAIN OUTCOMES AND RESULTS: The HC group in the current study obtained similar mean scores as those in the Australian sample. CABI group membership predicted lower performance on each FCAI dimension. In the CABI group, attention, working memory, delayed verbal memory, abstract reasoning and impulsivity were uniquely associated with FCAI dimensions. CONCLUSIONS: Findings underscore the importance of continued monitoring of FC even after the subacute stage of injury, and identify cognitive impairments that may be particularly detrimental for specific dimensions of FC.

Balance in chronic traumatic brain injury: correlations between clinical measures and a self-report measure.

OBJECTIVE: To assess associations among commonly used self-report and clinical measures of balance in chronic TBI. DESIGN: Cross-sectional analysis of balance in a convenience sample of individuals at least one year post TBI. MAIN OUTCOME MEASURES: Activities-Specific Balance Confidence Scale (ABC) (self-reported balance impairment), Community Balance and Mobility Scale (CB&M) (clinical measure validated in TBI), and Balance Evaluation Systems Test (BESTest) (clinical measure not validated in TBI). METHODS: Fifty-nine individuals (64% male, mean age 48.2 years) ambulating independently within the home participated in testing. Pearson correlation coefficients were used to quantify the direction and magnitude of the relationships among the three balance impairment measures. RESULTS: A significant positive correlation was noted between the ABC and CB&M (r = 0.42, p = 0.0008), between the ABC and BESTest (r = 0.46, p = 0.0002), and between the CB&M and BESTest (r = 0.86, p < 0.0001). CONCLUSIONS: This is the first study we are aware of in the chronic moderate to severe TBI population directly comparing patient's self-reported balance impairment with clinical measures. Positive correlations were found between the self-report measure and both clinical measures. Overall, individuals with chronic TBI tend to self-report less impaired balance than clinical measures indicate. These results provide preliminary evidence to support the need for validation of the BESTest in this population. ABBREVIATIONS: ABC: Activities-specific balance confidence scale; BESTest: balance evaluation systems test; BOS: base of support; COM: center of mass; CB&M: community balance and mobility scale; CI: confidence interval; IQR: interquartile range; PTs: physical therapists; SD: standard deviation; SE: standard error; TBI: traumatic brain injury.

Usability of World Health Organization Disability Assessment Schedule in chronic traumatic brain injury.

OBJECTIVES: To investigate functioning measured with the 12-item World Health Organization Disability Assessment Schedule (WHODAS 2.0) in patients with mild, moderate and severe traumatic brain injury, and to compare patients' experiences with assessments made by their significant others and by consultant neurologists. METHODS: A total of 112 consecutive patients with traumatic brain injury (29 mild, 43 moderate, 40 severe) and their significant others completed a 12-item WHODAS 2.0 survey. A neurologist assessed functioning with the International Classification of Functioning, Disability and Health minimal generic set. RESULTS: The total patient and proxy WHODAS 2.0 sum score was rated as severe, and impairments in household tasks, learning, community life, emotional functions, concentrating, dealing with strangers, maintaining friendships, and working ability as around moderate in all 3 severity groups. In standing, walking, washing, and dressing oneself the reported impairments increased from mild in mild traumatic brain injury to moderate in severe traumatic brain injury. A neurologist rated the overall functioning, working ability, and motor activities most impaired in severe traumatic brain injury, while there were no between-group differences in energy and drive functions and emotional functions. CONCLUSION: Patients with chronic traumatic brain injury perceive a diversity of significant difficulties in activities and participation irrespective of the severity of the injury. We recommend assessing disability in traumatic brain injury with the short and understandable WHODAS 2.0 scale, when planning client-oriented services.

Photobiomodulation using low-level laser therapy (LLLT) for patients with chronic traumatic brain injury: a randomized controlled trial study protocol.

BACKGROUND: Photobiomodulation using low-level laser therapy (LLLT) has been tested as a new technique to optimize recovery of patients with traumatic brain injury (TBI). The aim of this study is to evaluate inhibitory attentional control after 18 sessions of active LLLT and compare with the placebo group (sham LLLT). Our exploratory analysis will evaluate the efficacy of the active LLLT on verbal and visuospatial episodic memory, executive functions (working memory, verbal and visuospatial fluency, attentional processes), and anxiety and depressive symptoms compared to the sham group. METHODS/DESIGN: A randomized double-blinded trial will be made in 36 patients with moderate and severe TBI. The active LLLT will use an optical device composed of LEDs emitting 632 nm of radiation at the site with full potency of 830 mW. The cranial region with an area of 400 cm2 will be irradiated for 30 min, giving a total dose per session of 3.74 J/cm2. The sham LLLT group contains only an LED device with power < 1 mW, only serving to simulate the irradiation. Each patient will be irradiated three times per week for six weeks, totaling 18 sessions. Neuropsychological assessments will be held one week before the beginning of the sessions, after one week, and three months after the end of LLLT sessions. Memory domain, attention, executive functioning, and visual construction will be evaluated, in addition to symptoms of depression, anxiety, and social demographics. DISCUSSION: LLLT has been demonstrated as a safe and effective technique in significantly improving the memory, attention, and mood performance in healthy and neurologic patients. We expect that our trial can complement previous finds, as an effective low-cost therapy to improve cognitive sequel after TBI. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02393079 . Registered on 20 February 2015.

Examining a Statewide Educational Consulting Program for Pediatric Brain Injury.

This study describes characteristics of students with acquired brain injury enrolled in a statewide educational consultation program and the program's support activities. Utilizing deidentified data from a statewide brain injury school consultation program, descriptive analyses of demographic and injury characteristics, including medical diagnosis (concussion/mild traumatic brain injury [TBI], moderate-severe TBI, and non-TBI), referral characteristics, educational placement, and the types of program activities were undertaken. 70% of students were referred for concussions/mild TBI and students were infrequently referred by medical professionals. Most students with concussion/mild TBI experienced recreational injuries (59%), while students with moderate/severe TBI commonly experienced road traffic injuries (48%). The greatest proportion of program team members' time was spent in consultation with school personnel (24%), communication with families (20%), and communication with school personnel (16%). Results suggest that the program addresses important communication and coordination needs among families, medical professionals, and educators and identifies opportunities to enhance program utilization.

Thermoregulate, autoregulate and ventilate: brain-directed critical care for pediatric cardiac arrest.

PURPOSE OF REVIEW: Cardiac arrest in childhood is associated with a high risk for mortality and poor long-term functional outcome. This review discusses the current evidence for neuroprotective therapies and goals for postarrest care in the context of the pathophysiology of hypoxic-ischemic injury, modalities for neurologic prognostication in these children and potential future monitoring paradigms for maximizing cerebral perfusion in the postarrest period. RECENT FINDINGS: The recent publication of the in-hospital and out-of-hospital Therapeutic Hypothermia After Cardiac Arrest trials demonstrated a lack of statistically significant benefit for the use of postarrest therapeutic hypothermia. As a result, targeted normothermic temperature management has become standard of care. Continuous electroencephalographic monitoring during the acute postarrest period provides useful additional data for neurologic prognostication, in addition to its value for detection of seizures. Ongoing research into noninvasive monitoring of cerebrovascular autoregulation has the potential to individualize blood pressure goals in the postarrest period, maximizing cerebral perfusion in these patients. SUMMARY: Therapeutic strategies after cardiac arrest seek to maximize cerebral perfusion while mitigating the effects of secondary brain injury and loss of autoregulation. Future research into new monitoring strategies and better long-term outcome measures may allow more precise targeting of therapies to these goals.

Hypoaminoacidemia Characterizes Chronic Traumatic Brain Injury.

Individuals with a history of traumatic brain injury (TBI) are at increased risk for a number of disorders, including Alzheimer's disease, Parkinson's disease, and chronic traumatic encephalopathy. However, mediators of the long-term morbidity are uncertain. We conducted a multi-site, prospective trial in chronic TBI patients (∼18 years post-TBI) living in long-term 24-h care environments and local controls without a history of head injury. Inability to give informed consent was exclusionary for participation. A total of 41 individuals (17 moderate-severe TBI, 24 controls) were studied before and after consumption of a standardized breakfast to determine if concentrations of amino acids, cytokines, C-reactive protein, and insulin are potential mediators of long-term TBI morbidity. Analyte concentrations were measured in serum drawn before (fasting) and 1 h after meal consumption. Mean ages were 44 ± 15 and 49 ± 11 years for controls and chronic TBI patients, respectively. Chronic TBI patients had significantly lower circulating concentrations of numerous individual amino acids, as well as essential amino acids (p = 0.03) and large neutral amino acids (p = 0.003) considered as groups, and displayed fundamentally altered cytokine-amino acid relationships. Many years after injury, TBI patients exhibit abnormal metabolic responses and altered relationships between circulating amino acids, cytokines, and hormones. This pattern is consistent with TBI, inducing a chronic disease state in patients. Understanding the mechanisms causing the chronic disease state could lead to new treatments for its prevention.

Critical illness acquired brain injury: Neuroimaging and implications for rehabilitation.

OBJECTIVE: The increasing likelihood of surviving critical illness has resulted in a large and growing number of individuals transitioning from medical and surgical intensive care units (ICUs) to their homes. Many ICU survivors develop pervasive morbidities in physical, psychological, and cognitive functioning that adversely impact day-to-day functioning, ability to return to work, and quality-of-life. These individuals have been extensively studied with neuropsychological test batteries, but relatively little research has been conducted using neuroimaging. This paper reviews neuroimaging findings in survivors of critical illness treated in medical or surgical ICUs. METHODS: We assessed the relationships between abnormalities on neuroimaging and cognitive outcomes and discussed the implications for rehabilitation. RESULTS: There are limited imaging studies in ICU survivors. These studies use a wide range of modalities including magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), fluid attenuated inversion recovery (FLAIR), and diffusion weighted imaging. Structural abnormalities in survivors of critical illness include cortical and subcortical lesions, white matter hyperintensities (WMHs), and generalized and focal atrophy. These abnormalities persist months to years after ICU discharge and are associated with cognitive impairments. (PsycINFO Database Record

The science and questions surrounding chronic traumatic encephalopathy.

Recently, the pathobiology, causes, associated factors, incidence and prevalence, and natural history of chronic traumatic encephalopathy (CTE) have been debated. Data from retrospective case series and high-profile media reports have fueled public fear and affected the medical community's understanding of the role of sports-related traumatic brain injury (TBI) in the development of CTE. There are a number of limitations posed by the current evidence that can lead to confusion within the public and scientific community. In this paper, the authors address common questions surrounding the science of CTE and propose future research directions.

Imaging in Chronic Traumatic Encephalopathy and Traumatic Brain Injury.

CONTEXT: The diagnosis of chronic traumatic encephalopathy (CTE) can only be made pathologically, and there is no concordance of defined clinical criteria for premorbid diagnosis. The absence of established criteria and the insufficient imaging findings to detect this disease in a living athlete are of growing concern. EVIDENCE ACQUISITION: The article is a review of the current literature on CTE. Databases searched include Medline, PubMed, JAMA evidence, and evidence-based medicine guidelines Cochrane Library, Hospital for Special Surgery, and Cornell Library databases. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: Chronic traumatic encephalopathy cannot be diagnosed on imaging. Examples of imaging findings in common types of head trauma are discussed. CONCLUSION: Further study is necessary to correlate the clinical and imaging findings of repetitive head injuries with the pathologic diagnosis of CTE.

Polypathology and dementia after brain trauma: Does brain injury trigger distinct neurodegenerative diseases, or should they be classified together as traumatic encephalopathy?

Neuropathological studies of human traumatic brain injury (TBI) cases have described amyloid plaques acutely after a single severe TBI, and tau pathology after repeat mild TBI (mTBI). This has helped drive the hypothesis that a single moderate to severe TBI increases the risk of developing late-onset Alzheimer's disease (AD), while repeat mTBI increases the risk of developing chronic traumatic encephalopathy (CTE). In this review we critically assess this position-examining epidemiological and case control human studies, neuropathological evidence, and preclinical data. Epidemiological studies emphasize that TBI is associated with the increased risk of developing multiple types of dementia, not just AD-type dementia, and that TBI can also trigger other neurodegenerative conditions such as Parkinson's disease. Further, human post-mortem studies on both single TBI and repeat mTBI can show combinations of amyloid, tau, TDP-43, and Lewy body pathology indicating that the neuropathology of TBI is best described as a 'polypathology'. Preclinical studies confirm that multiple proteins associated with the development of neurodegenerative disease accumulate in the brain after TBI. The chronic sequelae of both single TBI and repeat mTBI share common neuropathological features and clinical symptoms of classically defined neurodegenerative disorders. However, while the spectrum of chronic cognitive and neurobehavioral disorders that occur following repeat mTBI is viewed as the symptoms of CTE, the spectrum of chronic cognitive and neurobehavioral symptoms that occur after a single TBI is considered to represent distinct neurodegenerative diseases such as AD. These data support the suggestion that the multiple manifestations of TBI-induced neurodegenerative disorders be classified together as traumatic encephalopathy or trauma-induced neurodegeneration, regardless of the nature or frequency of the precipitating TBI.

Suicide and Chronic Traumatic Encephalopathy.

For nearly 80 years, suicidality was not considered to be a core clinical feature of chronic traumatic encephalopathy (CTE). In recent years, suicide has been widely cited as being associated with CTE, and now depression has been proposed to be one of three core diagnostic features alongside cognitive impairment and anger control problems. This evolution of the clinical features has been reinforced by thousands of media stories reporting a connection between mental health problems in former athletes and military veterans, repetitive neurotrauma, and CTE. At present, the science underlying the causal assumption between repetitive neurotrauma, depression, suicide, and the neuropathology believed to be unique to CTE is inconclusive. Epidemiological evidence indicates that former National Football League players, for example, are at lower, not greater, risk for suicide than men in the general population. This article aims to discuss the critical issues and literature relating to these possible relationships.

The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegeneration characterized by the abnormal accumulation of hyperphosphorylated tau protein within the brain. Like many other neurodegenerative conditions, at present, CTE can only be definitively diagnosed by post-mortem examination of brain tissue. As the first part of a series of consensus panels funded by the NINDS/NIBIB to define the neuropathological criteria for CTE, preliminary neuropathological criteria were used by 7 neuropathologists to blindly evaluate 25 cases of various tauopathies, including CTE, Alzheimer's disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, primary age-related tauopathy, and parkinsonism dementia complex of Guam. The results demonstrated that there was good agreement among the neuropathologists who reviewed the cases (Cohen's kappa, 0.67) and even better agreement between reviewers and the diagnosis of CTE (Cohen's kappa, 0.78). Based on these results, the panel defined the pathognomonic lesion of CTE as an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern. The group also defined supportive but non-specific p-tau-immunoreactive features of CTE as: pretangles and NFTs affecting superficial layers (layers II-III) of cerebral cortex; pretangles, NFTs or extracellular tangles in CA2 and pretangles and proximal dendritic swellings in CA4 of the hippocampus; neuronal and astrocytic aggregates in subcortical nuclei; thorn-shaped astrocytes at the glial limitans of the subpial and periventricular regions; and large grain-like and dot-like structures. Supportive non-p-tau pathologies include TDP-43 immunoreactive neuronal cytoplasmic inclusions and dot-like structures in the hippocampus, anteromedial temporal cortex and amygdala. The panel also recommended a minimum blocking and staining scheme for pathological evaluation and made recommendations for future study. This study provides the first step towards the development of validated neuropathological criteria for CTE and will pave the way towards future clinical and mechanistic studies.

Junior Seau: An Illustrative Case of Chronic Traumatic Encephalopathy and Update on Chronic Sports-Related Head Injury.

BACKGROUND: Few neurologic diseases have captured the nation's attention more completely than chronic traumatic encephalopathy (CTE), which has been discovered in the autopsies of professional athletes, most notably professional football players. The tragic case of Junior Seau, a Hall of Fame, National Football League linebacker, has been the most high-profile confirmed case of CTE. Here we describe Seau's case, which concludes an autopsy conducted at the National Institutes of Health that confirmed the diagnosis. CASE DESCRIPTION: Since 1990, Junior Seau had a highly distinguished 20-year career playing for the National Football League as a linebacker, from which he sustained multiple concussions. He committed suicide on May 2, 2012, at age 43, after which an autopsy confirmed a diagnosis of CTE. His clinical history was significant for a series of behavioral disturbances. Seau's history and neuropathologic findings were used to better understand the pathophysiology, diagnosis, and possible risk factors for CTE. CONCLUSIONS: This high-profile case reflects an increasing awareness of CTE as a long-term consequence of multiple traumatic brain injuries. The previously unforeseen neurologic risks of American football have begun to cast doubt on the safety of the sport.

Exploring caregivers' knowledge of and receptivity toward novel diagnostic tests and treatments for persons with post-traumatic disorders of consciousness.

BACKGROUND: A paucity of information is available regarding how caregivers of persons with post-traumatic disorders of consciousness (DOC) approach medical decision-making. Yet for evidence-based standards of care to be established, the onus is on caregivers' willingness to enroll their family members in clinical trials of novel tests and treatments (NTT). OBJECTIVE: To gather information regarding the beliefs and opinions of caregivers regarding NTT for DOC. METHODS: Exploratory qualitative data via focus groups from N = 17 caregivers of persons in post-traumatic DOC at both the acute (N = 7) and subacute (N = 10) phases of injury recovery. Supplemental survey data about knowledge of DOC. RESULTS: While attitudes toward NTT were generally favorable, two main themes emerged that influenced willingness to pursue NTT: patient and caregiver-specific factors, and the acquisition/use of information to guide decision-making. While survey data suggested a lack of knowledge about NTT, qualitative data revealed that this was better explained by different standards for knowledge, i.e., anecdotal versus empirical information. CONCLUSIONS: Current findings could support discussion between healthcare providers and caregivers regarding medical decision-making as well as suggestions for how to increase the likelihood of caregivers being willing to enroll their family members in clinical trials of NTT.

Assessment and Treatment of Cognition and Communication Skills in Adults With Acquired Brain Injury via Telepractice: A Systematic Review.

PURPOSE: This is a systematic review of assessment and treatment of cognitive and communicative abilities of individuals with acquired brain injury via telepractice versus in person. The a priori clinical questions were informed by previous research that highlights the importance of considering any functional implications of outcomes, determining disorder- and setting-specific concerns, and measuring the potential impact of diagnostic accuracy and treatment efficacy data on interpretation of findings. METHOD: A literature search of multiple databases (e.g., PubMed) was conducted using key words and study inclusion criteria associated with the clinical questions. RESULTS: Ten group studies were accepted that addressed assessment of motor speech, language, and cognitive impairments; assessment of motor speech and language activity limitations/participation restrictions; and treatment of cognitive impairments and activity limitations/participation restrictions. In most cases, equivalence of outcomes was noted across service delivery methods. CONCLUSIONS: Limited findings, lack of diagnostic accuracy and treatment efficacy data, and heterogeneity of assessments and interventions precluded robust evaluation of clinical implications for telepractice equivalence and the broader area of telepractice efficacy. Future research is needed that will build upon current knowledge through replication. In addition, further evaluation at the impairment and activity limitation/participation restriction levels is needed.