Quiz Ref ID Chronic traumatic encephalopathy (CTE) is a progressive neurodegeneration associated with repetitive head trauma.^1-8 In 2013, based on a report of the clinical and pathological features of 68 men with CTE (including 36 football players from the current study), criteria for neuropathological diagnosis of CTE and a staging scheme of pathological severity were proposed.⁶ Two clinical presentations of CTE were described; in one, the initial features developed at a younger age and involved behavioral disturbance, mood disturbance, or both; in the other, the initial presentation developed at an older age and involved cognitive impairment.⁹ In 2014, a methodologically rigorous approach to assessing clinicopathological correlation in CTE was developed using comprehensive structured and semistructured informant interviews and online surveys conducted by a team of behavioral neurologists and neuropsychologists.¹⁰ In 2015, the neuropathological criteria for diagnosis of CTE were refined by a panel of expert neuropathologists organized by the National Institute of Neurological Disorders and Stroke and the National Institute of Biomedical Imaging and Bioengineering (NINDS-NIBIB).⁸

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.

OBJECTIVE: To evaluate the effect of a clinic-based screening and referral system (Well Child Care, Evaluation, Community Resources, Advocacy, Referral, Education [WE CARE]) on families’ receipt of community-based resources for unmet basic needs.METHODS: We conducted a cluster randomized controlled trial at 8 urban community health centers, recruiting mothers of healthy infants. In the 4 WE CARE clinics, mothers completed a self-report screening instrument that assessed needs for child care, education, employment, food security, household heat, and housing. Providers made referrals for families; staff provided requisite applications and telephoned referred mothers within 1 month. Families at the 4 control community health centers received the usual care. We analyzed the results with generalized mixed-effect models.RESULTS: Three hundred thirty-six mothers were enrolled in the study (168 per arm). The majority of families had household incomes <$20 000 (57%), and 68% had ≥2 unmet basic needs. More WE CARE mothers received ≥1 referral at the index visit (70% vs 8%; adjusted odds ratio [aOR] = 29.6; 95% confidence interval [CI], 14.7–59.6). At the 12-month visit, more WE CARE mothers had enrolled in a new community resource (39% vs 24%; aOR = 2.1; 95% CI, 1.2–3.7). WE CARE mothers had greater odds of being employed (aOR = 44.4; 95% CI, 9.8–201.4). WE CARE children had greater odds of being in child care (aOR = 6.3; 95% CI, 1.5–26.0). WE CARE families had greater odds of receiving fuel assistance (aOR = 11.9; 95% CI, 1.7–82.9) and lower odds of being in a homeless shelter (aOR = 0.2; 95% CI, 0.1–0.9).CONCLUSIONS: Systematically screening and referring for social determinants during well child care can lead to the receipt of more community resources for families.

The term “repetitive head impacts” (RHI) refers to the cumulative exposure to concussive and subconcussive events. Although RHI are believed to increase risk for later-life neurological consequences (including chronic traumatic encephalopathy), quantitative analysis of this relationship has not yet been examined because of the lack of validated tools to quantify lifetime RHI exposure. The objectives of this study were: 1) to develop a metric to quantify cumulative RHI exposure from football, which we term the “cumulative head impact index” (CHII); 2) to use the CHII to examine the association between RHI exposure and long-term clinical outcomes; and 3) to evaluate its predictive properties relative to other exposure metrics (i.e., duration of play, age of first exposure, concussion history). Participants included 93 former high school and collegiate football players who completed objective cognitive and self-reported behavioral/mood tests as part of a larger ongoing longitudinal study. Using established cutoff scores, we transformed continuous outcomes into dichotomous variables (normal vs. impaired). The CHII was computed for each participant and derived from a combination of self-reported athletic history (i.e., number of seasons, position[s], levels played), and impact frequencies reported in helmet accelerometer studies. A bivariate probit, instrumental variable model revealed a threshold dose-response relationship between the CHII and risk for later-life cognitive impairment ( p < 0.0001), self-reported executive dysfunction ( p < 0.0001), depression ( p < 0.0001), apathy ( p = 0.0161), and behavioral dysregulation ( p < 0.0001). Ultimately, the CHII demonstrated greater predictive validity than other individual exposure metrics.

The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood–brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood–brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath.

Objective To develop evidence-informed, expert consensus research diagnostic criteria for traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic traumatic encephalopathy (CTE). Methods A panel of 20 expert clinician-scientists in neurology, neuropsychology, psychiatry, neurosurgery, and physical medicine and rehabilitation, from 11 academic institutions, participated in a modified Delphi procedure to achieve consensus, initiated at the First National Institute of Neurological Disorders and Stroke Consensus Workshop to Define the Diagnostic Criteria for TES, April, 2019. Before consensus, panelists reviewed evidence from all published cases of CTE with neuropathologic confirmation, and they examined the predictive validity data on clinical features in relation to CTE pathology from a large clinicopathologic study (n = 298). Results Consensus was achieved in 4 rounds of the Delphi procedure. Diagnosis of TES requires (1) substantial exposure to repetitive head impacts (RHIs) from contact sports, military service, or other causes; (2) core clinical features of cognitive impairment (in episodic memory and/or executive functioning) and/or neurobehavioral dysregulation; (3) a progressive course; and (4) that the clinical features are not fully accounted for by any other neurologic, psychiatric, or medical conditions. For those meeting criteria for TES, functional dependence is graded on 5 levels, ranging from independent to severe dementia. A provisional level of certainty for CTE pathology is determined based on specific RHI exposure thresholds, core clinical features, functional status, and additional supportive features, including delayed onset, motor signs, and psychiatric features. Conclusions New consensus diagnostic criteria for TES were developed with a primary goal of facilitating future CTE research. These criteria will be revised as updated clinical and pathologic information and in vivo biomarkers become available.