Neuropathologic and Clinical Findings in Young Contact Sport Athletes Exposed to Repetitive Head Impacts.

Importance: Young contact sport athletes may be at risk for long-term neuropathologic disorders, including chronic traumatic encephalopathy (CTE). Objective: To characterize the neuropathologic and clinical symptoms of young brain donors who were contact sport athletes. Design, Setting, and Participants: This case series analyzes findings from 152 of 156 brain donors younger than 30 years identified through the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank who donated their brains from February 1, 2008, to September 31, 2022. Neuropathologic evaluations, retrospective telephone clinical assessments, and online questionnaires with informants were performed blinded. Data analysis was conducted between August 2021 and June 2023. Exposures: Repetitive head impacts from contact sports. Main Outcomes and Measures: Gross and microscopic neuropathologic assessment, including diagnosis of CTE, based on defined diagnostic criteria; and informant-reported athletic history and informant-completed scales that assess cognitive symptoms, mood disturbances, and neurobehavioral dysregulation. Results: Among the 152 deceased contact sports participants (mean [SD] age, 22.97 [4.31] years; 141 [92.8%] male) included in the study, CTE was diagnosed in 63 (41.4%; median [IQR] age, 26 [24-27] years). Of the 63 brain donors diagnosed with CTE, 60 (95.2%) were diagnosed with mild CTE (stages I or II). Brain donors who had CTE were more likely to be older (mean difference, 3.92 years; 95% CI, 2.74-5.10 years) Of the 63 athletes with CTE, 45 (71.4%) were men who played amateur sports, including American football, ice hockey, soccer, rugby, and wrestling; 1 woman with CTE played collegiate soccer. For those who played football, duration of playing career was significantly longer in those with vs without CTE (mean difference, 2.81 years; 95% CI, 1.15-4.48 years). Athletes with CTE had more ventricular dilatation, cavum septum pellucidum, thalamic notching, and perivascular pigment-laden macrophages in the frontal white matter than those without CTE. Cognitive and neurobehavioral symptoms were frequent among all brain donors. Suicide was the most common cause of death, followed by unintentional overdose; there were no differences in cause of death or clinical symptoms based on CTE status. Conclusions and Relevance: This case series found that young brain donors exposed to repetitive head impacts were highly symptomatic regardless of CTE status, and the causes of symptoms in this sample are likely multifactorial. Future studies that include young brain donors unexposed to repetitive head impacts are needed to clarify the association among exposure, white matter and microvascular pathologic findings, CTE, and clinical symptoms.

Three dimensional evaluation of cerebrovascular density and branching in chronic traumatic encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI) and characterized by perivascular accumulations of hyperphosphorylated tau protein (p-tau) at the depths of the cortical sulci. Studies of living athletes exposed to RHI, including concussive and nonconcussive impacts, have shown increased blood-brain barrier permeability, reduced cerebral blood flow, and alterations in vasoreactivity. Blood-brain barrier abnormalities have also been reported in individuals neuropathologically diagnosed with CTE. To further investigate the three-dimensional microvascular changes in individuals diagnosed with CTE and controls, we used SHIELD tissue processing and passive delipidation to optically clear and label blocks of postmortem human dorsolateral frontal cortex. We used fluorescent confocal microscopy to quantitate vascular branch density and fraction volume. We compared the findings in 41 male brain donors, age at death 31-89 years, mean age 64 years, including 12 donors with low CTE (McKee stage I-II), 13 with high CTE (McKee stage III-IV) to 16 age- and sex-matched non-CTE controls (7 with RHI exposure and 9 with no RHI exposure). The density of vessel branches in the gray matter sulcus was significantly greater in CTE cases than in controls. The ratios of sulcus versus gyrus vessel branch density and fraction volume were also greater in CTE than in controls and significantly above one for the CTE group. Hyperphosphorylated tau pathology density correlated with gray matter sulcus fraction volume. These findings point towards increased vascular coverage and branching in the dorsolateral frontal cortex (DLF) sulci in CTE, that correlates with p-tau pathology.

Vascular injury is associated with repetitive head impacts and tau pathology in chronic traumatic encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to repetitive head impacts (RHI) and characterized by perivascular hyperphosphorylated tau (p-tau) deposits. The role of vascular injury, blood-brain barrier leakage, and neuroinflammation in CTE pathogenesis is not well understood. We performed quantitative immunoassays for intercellular adhesion molecule 1 (ICAM1), vascular cellular adhesion molecule 1 (VCAM1), and C-reactive protein (CRP) within the postmortem dorsolateral frontal cortex of participants with and without a history of RHI and CTE (n = 156), and tested for associations with RHI, microgliosis, and tau pathology measures. Levels of vascular injury-associated markers ICAM1, VCAM1, and CRP were increased in CTE compared to RHI-exposed and -naïve controls. ICAM1 and CRP increased with RHI exposure duration (p < 0.01) and were associated with increased microglial density (p < 0.001) and tau pathology (AT8, p-tau396, p-tau202; p < 0.05). Histologically, there was significantly increased ICAM1 staining of the microvasculature, extracellular space, and astrocytes at the sulcal depths in high stage CTE compared to both low stage CTE and controls. Multifocal perivascular immunoreactivity for serum albumin was present in all RHI-exposed individuals. These findings demonstrate that vascular injury markers are associated with RHI exposure, duration, and microgliosis, are elevated in CTE, and increase with disease severity.

Neuroimmune proteins can differentiate between tauopathies.

BACKGROUND: Tauopathies are a group of neurodegenerative diseases where there is pathologic accumulation of hyperphosphorylated tau protein (ptau). The most common tauopathy is Alzheimer's disease (AD), but chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease (AGD) are significant health risks as well. Currently, it is unclear what specific molecular factors might drive each distinct disease and represent therapeutic targets. Additionally, there is a lack of biomarkers that can differentiate each disease in life. Recent work has suggested that neuroinflammatory changes might be specific among distinct diseases and offers a novel resource for mechanistic targets and biomarker candidates. METHODS: To better examine each tauopathy, a 71 immune-related protein multiplex ELISA panel was utilized to analyze anterior cingulate grey matter from 127 individuals neuropathologically diagnosed with AD, CTE, PSP, CBD, and AGD. A partial least square regression analysis was carried out to perform unbiased clustering and identify proteins that are distinctly correlated with each tauopathy correcting for age and gender. Receiver operator characteristic and binary logistic regression analyses were then used to examine the ability of each candidate protein to distinguish diseases. Validation in postmortem cerebrospinal fluid (CSF) from 15 AD and 14 CTE cases was performed to determine if candidate proteins could act as possible novel biomarkers. RESULTS: Five clusters of immune proteins were identified and compared to each tauopathy to determine if clusters were specific to distinct disease. Each cluster was found to correlate with either CTE, AD, PSP, CBD, or AGD. When examining which proteins were the strongest driver of each cluster, it was observed the most distinctive protein for CTE was CCL21, AD was FLT3L, and PSP was IL13. Individual proteins that were specific to CBD and AGD were not observed. CCL21 was observed to be elevated in CTE CSF compared to AD cases (p = 0.02), further validating the use as possible biomarkers. Sub-analyses for male only cases confirmed the results were not skewed by gender differences. CONCLUSIONS: Overall, these results highlight that different neuroinflammatory responses might underlie unique mechanisms in related neurodegenerative pathologies. Additionally, the use of distinct neuroinflammatory signatures could help differentiate between tauopathies and act as novel biomarker candidate to increase specificity for in-life diagnoses.

Fatal Microscopic Pulmonary Tumor Thromboemboli: Unusual Presentation of Occult Cervical Carcinoma. Two Case Reports and Review of the Literature.

Cor pulmonale (right heart failure) due to microscopic pulmonary tumor emboli (MPTE) can arise from a variety of malignancies including breast, lung, and liver and carries significant morbidity and mortality. Tumor cell aggregates spread hematogenously to the lungs and occlude small pulmonary vessels leading to pulmonary hypertension through either a mechanical process or inducing vascular remodeling as a downstream result of interactions between the embolus and the vessel wall. Its presentation includes unexplained dyspnea, hypoxemia, tachycardia, pulmonary hypertension, right heart failure, and in some cases sudden death. The symptoms may suggest the more common entity of pulmonary thromboembolism, particularly in the setting of previously known metastatic cancer; however, computed tomography scans may appear normal and ventilation-perfusion scans which are the preferable diagnostic modality are not always ordered. In most cases of MPTE, the presentation reflects metastasis of an already known and advanced tumor, but, in rare cases, it may be the primary manifestation of an occult malignancy. We present here 2 unique cases of MPTE in women with occult cervical cancer. In both cases, the malignancy was discovered and diagnosed at autopsy. Microscopic pulmonary tumor emboli can be easily overlooked, and therefore, forensic pathologists and other death investigators should be aware of it and trained to at least consider the possibility in appropriate situations. Thorough microscopic examination of apparently normal tissues may be necessary, particularly in cases of unexplained right heart failure and sudden death, even if the decedent has few or no identifiable risk factors for cancer.

Mild Traumatic Brain Injury in Mice Beneficially Alters Lung NK1R and Structural Protein Expression to Enhance Survival after Pseudomonas aeruginosa Infection.

Mild traumatic brain injury (mTBI) in a murine model increases survival to a bacterial pulmonary challenge compared with blunt tail trauma (TT). We hypothesize substance P and its receptor, the neurokinin 1 receptor (NK1R; official name TACR1), play a role in the increased survival of mTBI mice. Mice were subjected to mTBI or TT, and 48 hours after trauma, the levels of NK1R mRNA and protein were significantly up-regulated in mTBI lungs. Examination of the lung 48 hours after injury by microarray showed significant differences in the expression of 433 gene sets between groups, most notably genes related to intercellular proteins. Despite down-regulated gene expression of connective proteins, the presence of an intact pulmonary vasculature was supported by normal histology and bronchoalveolar lavage protein levels. To determine whether these mTBI-induced lung changes benefited in vivo responses, two chemotactic stimuli (a CXCL1 chemokine and a live Pseudomonas aeruginosa infection) were administered 48 hours after trauma. For both stimuli, mTBI mice recruited more neutrophils to the lung 4 hours after instillation (CXCL1: mTBI = 6.3 ± 1.3 versus TT = 3.3 ± 0.7 neutrophils/mL; Pseudomonas aeruginosa: mTBI = 9.4 ± 1.4 versus TT = 5.3 ± 1.1 neutrophils/mL). This study demonstrates that the downstream consequences of mTBI on lung NK1R levels and connective protein expression enhance neutrophil recruitment to a stimulus that may contribute to increased survival.

Fatal Pulmonary Thromboembolism in Patients with Diabetic Ketoacidosis: A Seven-Case Series and Review of the Literature.

Diabetes mellitus is a well-recognized risk factor for arterial thrombosis, however its relationship to venous thromboembolism (VTE) in adults is still debated. We report here seven cases of fatal pulmonary thromboembolism in adults with diabetic ketoacidosis as the underlying cause. In four of seven cases, there was no prior diagnosis of diabetes mellitus and patients were newly diagnosed either upon presenting to the hospital in diabetic ketoacidosis (DKA) or at the time of autopsy by the vitreous glucose concentration. None of the patients had family history, recent surgery, recent trauma, long distance travel, or other strong risk factors for VTE. Only two patients had a body mass index greater than 35 kg/m2 and the same two cases had hospital stays that ranged from three to five days. We believe that DKA is a frequently unrecognized and sometimes overlooked risk factor for VTE, particularly in the forensic setting where routine toxicology and vitreous glucose analysis may not be standard practices. We encourage forensic pathologists, medical examiners, and coroners to consider the possibility of diabetic ketoacidosis as a risk factor, and in some cases, the underlying etiology for pulmonary thromboembolism. Additionally, we recommend vitreous glucose testing be performed if there are any signs of DKA or diabetes present, such as acetone in the blood.

Mental health issues among college students: who gets referred for psychopharmacology evaluation?

OBJECTIVE: To describe diagnostic and psychotropic medication prescription characteristics among college students referred by college counseling centers for psychopharmacologic evaluation. PARTICIPANTS: Participants were 540 college students referred by 6 college counseling centers in Massachusetts between November 2005 and May 2011. METHODS: Students completed self-report measures of depression, anxiety, suicidal ideation and attempts, and substance use. Information regarding DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) diagnosis, previous history of medication prescription, and current psychotropic medication(s) prescribed by the consulting psychiatrist was obtained from medical records. RESULTS: Depression, anxiety, and attention-deficit/hyperactivity disorder (ADHD) were the most common psychiatric problems identified in students. Half of these students had been prescribed mediation prior to evaluation. Antidepressant medication was the most frequently prescribed medication. A large proportion of students reported previous thoughts of suicide, and 12% had made at least 1 suicide attempt. CONCLUSIONS: Depression, anxiety, and ADHD are common among students referred by college counseling centers for medication evaluation and treatment.

Population-based initiatives in college mental health: students helping students to overcome obstacles.

College students' need for mental health care has increased dramatically, leaving campus counseling and mental health centers struggling to meet the demand. This has led to the investigation and development of extra-center, population-based interventions. Student-to-student support programs are but one example. Students themselves are a plentiful, often-untapped resource that extends the reach of mental health services on campus. Student-to-student programs capitalize on students' natural inclination to assist their peers. A brief review of the prevalence and effects of mental disorders in the college population is provided, followed by a broad overview of the range of peer-to-peer programs that can be available on college campuses. Two innovative programs are highlighted: (1) a hospital- and community-based program, the College Mental Health Program (CMHP) at McLean Hospital, and 2) the Student Support Network (SSN) at Worcester Polytechnic Institute. The subsequent section reviews the literature on peer-to-peer programs for students with serious and persistent mental illness for which there is a small but generally positive body of research. This lack of an empirical basis in college mental health leads the authors to argue for development of broad practice-research networks.

Military service member and veteran self reports of efficacy of cranial electrotherapy stimulation for anxiety, posttraumatic stress disorder, insomnia, and depression.

Cranial electrotherapy stimulation (CES) is being prescribed for service members and veterans for the treatment of anxiety, posttraumatic stress disorder (PTSD), insomnia and depression. The purpose of this study was to examine service members' and veterans' perceptions of the effectiveness and safety of CES treatment. Service members and veterans (N=1,514) who had obtained a CES device through the Department of Defense or Veterans Affairs Medical Center from 2006-2011 were invited to participate in the web based survey via email. One hundred fifty-two participants returned questionnaires. Data were analyzed using descriptive statistics. Participants reported clinical improvement of 25% or more from using CES for anxiety (66.7%), PTSD (62.5%), insomnia (65.3%) and depression (53.9%). The majority of these participants reported clinical improvement of 50% or more. Respondents also perceived CES to be safe (99.0%). Those individuals who were not taking any prescription medication rated CES more effective than the combined CES and prescription medication group. CES provides service members and veterans with a safe, noninvasive, nondrug, easy to use treatment for anxiety, PTSD, insomnia, and depression that can be used in the clinical setting or self-directed at home.

Cranial electrotherapy stimulation for treatment of anxiety, depression, and insomnia.

Cranial electrotherapy stimulation is a prescriptive medical device that delivers a mild form of electrical stimulation to the brain for the treatment of anxiety, depression, and insomnia. It is supported by more than 40 years of research demonstrating its effectiveness in several mechanistic studies and greater than 100 clinical studies. Adverse effects are rare (<1%), mild, and self-limiting, consisting mainly of skin irritation under the electrodes and headaches. Often used as a stand-alone therapy, because results are usually seen from the first treatment, cranial electrotherapy stimulation may also be used as an adjunctive therapy.

Preoperative breast MRI in the surgical treatment of ductal carcinoma in situ.

Accurate determination of the size or extent of ductal carcinoma in situ (DCIS) by imaging is uncertain, and incomplete resection of tumor results in involved margins in up to 81% of cases. This study examined the accuracy of magnetic resonance imaging (MRI) for assessment of DCIS size, and evaluated the effect of preoperative breast MRI on achievement of tumor-free surgical margins after breast-conserving surgery (BCS). One-hundred and fifty-eight female patients with DCIS were identified from a prospective database: 60 patients (62 cases) had preoperative breast MRI, and 98 patients did not have MRI. The accuracy of tumor size assessed by MRI was determined by comparison with histopathologic size. All patients underwent BCS initially. The rate of involved margins after resection was compared in MRI and no-MRI groups. The overall correlation between MRI size and histopathologic size was high (p < 0.0001). MRI assessment of size was significantly more accurate when DCIS was high grade (p < 0.0001) or intermediate grade (p = 0.005) versus low grade (p = 0.187). The rate of tumor-involved margins was not significantly different in MRI and no-MRI groups (30.7% and 24.7%, respectively; p = 0.414). The rate of mastectomy was significantly higher in the MRI group than the no-MRI group (17.7% versus 4.1%; p = 0.004). These findings indicate that MRI can detect DCIS, especially when lesions are high or intermediate grade, but that MRI does not accurately predict the size of DCIS. In this study, MRI did not improve the surgeon's ability to achieve clear margins following BCS.

MRI versus ultrasonography and mammography for preoperative assessment of breast cancer.

Mammography and ultrasonography are traditional for preoperative estimation of breast cancer size; magnetic resonance imaging (MRI) is more recent but not as well studied. We compared ultrasonography, mammography, and MRI for preoperative imaging of primary breast cancer presenting as a mass in patients treated at our center over a 2-year period. Of the 61 breast cancers with all three imaging modalities performed, 52 were infiltrating ductal cancer, 5 were infiltrating lobular cancer, 2 were ductal carcinoma in situ, and 2 were other histologic types. When pathologic size was used to determine the accuracy of imaging assessments, the Pearson correlation coefficient was better for MRI (r = 0.80) than ultrasonography (r = 0.57) or mammography (r = 0.26). Mean tumor size was 2.1 cm by mammography, 1.73 cm by ultrasonography, 2.65 cm by MRI, and 2.76 cm by pathology. MRI-based tumor size was within 1 cm of pathologic size in 44 (72%) tumors, > 1 cm above pathologic size in 6 (10%) tumors, and > 1 cm below pathologic size in 11 (18%) tumors. We conclude that MRI is more accurate than either ultrasonography or mammography for assessment of the size of primary breast cancer presenting as a mass.

Breast core-needle biopsy: clinical trial of relaxation technique versus medication versus no intervention for anxiety reduction.

PURPOSE: To evaluate effectiveness of oral anxiolytic medication versus relaxation technique for anxiety reduction in women undergoing breast core-needle biopsy (CNB). MATERIALS AND METHODS: The institutional review board reviewed and approved the study. Informed consent was obtained from 143 consecutive women scheduled for breast CNB. Women were randomized as follows: no anxiety intervention (usual care group), relaxation therapy with an audiotape of classical music and ocean sounds during CNB (relaxation group), and 0.5-mg of alprazolam administered orally 15 minutes before CNB (medication group). Anxiety before, during, and 24 hours after the procedure was assessed with State-Trait Anxiety Inventory and self-reported visual analog scale from 0 (no anxiety) to 10 (worst anxiety). Data analysis was performed with statistical software. Descriptive statistics were computed for all variables. Group differences were determined with analysis of variance. Differences in mean values were assessed with Bonferroni multiple comparison procedure. Categorical demographic differences were assessed with chi(2) statistic. RESULTS: Preprocedural State-Trait Anxiety Inventory scores indicated that women were not inherently anxious: usual care group, score of 44.63; relaxation group, 45.74; and medication group, 49.1. Scores represented significantly elevated anxiety for women in all three groups when compared with the normative value of 35.12 (P < .0001), with no statistically significant differences between the scores of the three groups. Women in medication group reported significant reductions in anxiety (-44%) from levels determined before the procedure to levels determined during the procedure (P = .02) and significant reduction during the procedure when compared with changes in usual care (+15%) and relaxation (-8%) groups (P = .02). Women in all three groups reported significant reduction in anxiety from levels determined before the procedure to levels determined at 24 hours after it (P < .0001). There was no significant difference (P = .95) in 24-hour postprocedural anxiety levels among the three groups. CONCLUSION: Use of oral anxiolytic medication before breast CNB can significantly reduce anxiety women experience during the procedure.

Conservative excision of wire-bracketed breast carcinomas: a community hospital's experience.

We report our experience with excision of hooked-wire bracketed breast carcinomas in a community hospital setting. The mammographic and pathology reports from 36 nonpalpable or minimally palpable breast cancers were retrieved from a single surgical oncologist's office records and a number of factors that might influence a successful initial surgical excision were examined. The median lesion size was 1 cm. The radiographic abnormalities were microcalcifications only in 14 cases (39%), combined mass/density and microcalcifications in 9 cases (25%), and mass/density without microcalcifications in 13 cases (36%). The median number of bracketing wires placed was two. A prior fine-needle aspiration (FNA) or core biopsy was performed in 29 of the 36 cases (81%). Of these, 27 were positive for malignancy. The tumor was considered to be inadequately excised if it was present within 5 mm of any surgical margin; this outcome occurred in 21 of the 36 cases (58%). Fifteen cases (42%) had tumor involving either the margin or extending to within 1 mm of the margin. Inadequately excised lesions were more commonly seen with increasing tumor size, a radiographic appearance of microcalcifications without an associated mass, and a pathologic diagnosis of ductal carcinoma in situ (DCIS). An intraoperative consult led to taking additional marginal tissue in 23 cases and was successful in achieving final clear histologic margins in 8 of these (35%). Our experience suggests that there are at least two ways to optimize the adequacy of conservative excision of nonpalpable or difficult-to-palpate breast cancers using standard modalities presently available in most community hospitals. These are (a) having the pathologist and radiologist available for intraoperative consultation and (b) obtaining a tissue diagnosis of malignancy preoperatively. The use of bracketing wires to better delineate the margins of tissue to be excised may also be helpful, but this needs to be further evaluated in a randomized study.

The use of cranial electrotherapy stimulation in the management of chronic pain: A review.

Cranial Electrotherapy Stimulation (CES) has a growing history of applications in rehabilitation medicine in the United States dating back to early 1970. As a recognized non-drug treatment of anxiety, depression and insomnia, CES gained its first major application in the field of addiction treatment and rehabilitation. By the mid 1980s research was showing additional important uses of CES in the treatment of closed head injured patients, and in paraplegic and quadriplegic patients. The most recent research is showing CES to be highly effective in the management of chronic pain patients. It may be elevating the pain threshold due to its stress reducing effects when anxiety and depression are reduced below clinical levels. Modern theorists of a pain neuromatrix in the cerebral cortex may provide an additional basis for understanding CES mechanisms in the control of pain related disorders.