Immunosuppressive Drug-Resistant Armored T-Cell Receptor T Cells for Immune Therapy of HCC in Liver Transplant Patients.

BACKGROUND AND AIMS: HBV-specific T-cell receptor (HBV-TCR) engineered T cells have the potential for treating HCC relapses after liver transplantation, but their efficacy can be hampered by the concomitant immunosuppressive treatment required to prevent graft rejection. Our aim is to molecularly engineer TCR-T cells that could retain their polyfunctionality in such patients while minimizing the associated risk of organ rejection. APPROACH AND RESULTS: We first analyzed how immunosuppressive drugs can interfere with the in vivo function of TCR-T cells in liver transplanted patients with HBV-HCC recurrence receiving HBV-TCR T cells and in vitro in the presence of clinically relevant concentrations of immunosuppressive tacrolimus (TAC) and mycophenolate mofetil (MMF). Immunosuppressive Drug Resistant Armored TCR-T cells of desired specificity (HBV or Epstein-Barr virus) were then engineered by concomitantly electroporating mRNA encoding specific TCRs and mutated variants of calcineurin B (CnB) and inosine-5'-monophosphate dehydrogenase (IMPDH), and their function was assessed through intracellular cytokine staining and cytotoxicity assays in the presence of TAC and MMF. Liver transplanted HBV-HCC patients receiving different immunosuppressant drugs exhibited varying levels of activated (CD39+ Ki67+ ) peripheral blood mononuclear cells after HBV-TCR T-cell infusions that positively correlate with clinical efficacy. In vitro experiments with TAC and MMF showed a potent inhibition of TCR-T cell polyfunctionality. This inhibition can be effectively negated by the transient overexpression of mutated variants of CnB and IMPDH. Importantly, the resistance only lasted for 3-5 days, after which sensitivity was restored. CONCLUSIONS: We engineered TCR-T cells of desired specificities that transiently escape the immunosuppressive effects of TAC and MMF. This finding has important clinical applications for the treatment of HBV-HCC relapses and other pathologies occurring in organ transplanted patients.

Duration of American Football Play and Chronic Traumatic Encephalopathy.

OBJECTIVE: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to contact and collision sports, including American football. We hypothesized a dose-response relationship between duration of football played and CTE risk and severity. METHODS: In a convenience sample of 266 deceased American football players from the Veterans Affairs-Boston University-Concussion Legacy Foundation and Framingham Heart Study Brain Banks, we estimated the association of years of football played with CTE pathological status and severity. We evaluated the ability of years played to classify CTE status using receiver operating characteristic curve analysis. Simulation analyses quantified conditions that might lead to selection bias. RESULTS: In total, 223 of 266 participants met neuropathological diagnostic criteria for CTE. More years of football played were associated with having CTE (odds ratio [OR] = 1.30 per year played, 95% confidence interval [CI] = 1.19-1.41; p = 3.8 × 10-9 ) and with CTE severity (severe vs mild; OR = 1.14 per year played, 95% CI = 1.07-1.22; p = 3.1 × 10-4 ). Participants with CTE were 1/10th as likely to have played <4.5 years (negative likelihood ratio [LR] = 0.102, 95% CI = 0.100-0.105) and were 10 times as likely to have played >14.5 years (positive LR = 10.2, 95% CI = 9.8-10.7) compared with participants without CTE. Sensitivity and specificity were maximized at 11 years played. Simulation demonstrated that years played remained adversely associated with CTE status when years played and CTE status were both related to brain bank selection across widely ranging scenarios. INTERPRETATION: The odds of CTE double every 2.6 years of football played. After accounting for brain bank selection, the magnitude of the relationship between years played and CTE status remained consistent. ANN NEUROL 2020;87:116-131.

Use of Expression Profiles of HBV-DNA Integrated Into Genomes of Hepatocellular Carcinoma Cells to Select T Cells for Immunotherapy.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is often associated with hepatitis B virus (HBV) infection. Cells of most HBV-related HCCs contain HBV-DNA fragments that do not encode entire HBV antigens. We investigated whether these integrated HBV-DNA fragments encode epitopes that are recognized by T cells and whether their presence in HCCs can be used to select HBV-specific T-cell receptors (TCRs) for immunotherapy. METHODS: HCC cells negative for HBV antigens, based on immunohistochemistry, were analyzed for the presence of HBV messenger RNAs (mRNAs) by real-time polymerase chain reaction, sequencing, and Nanostring approaches. We tested the ability of HBV mRNA-positive HCC cells to generate epitopes that are recognized by T cells using HBV-specific T cells and TCR-like antibodies. We then analyzed HBV gene expression profiles of primary HCCs and metastases from 2 patients with HCC recurrence after liver transplantation. Using the HBV-transcript profiles, we selected, from a library of TCRs previously characterized from patients with self-limited HBV infection, the TCR specific for the HBV epitope encoded by the detected HBV mRNA. Autologous T cells were engineered to express the selected TCRs, through electroporation of mRNA into cells, and these TCR T cells were adoptively transferred to the patients in increasing numbers (1 × 104-10 × 106 TCR+ T cells/kg) weekly for 112 days or 1 year. We monitored patients' liver function, serum levels of cytokines, and standard blood parameters. Antitumor efficacy was assessed based on serum levels of alpha fetoprotein and computed tomography of metastases. RESULTS: HCC cells that did not express whole HBV antigens contained short HBV mRNAs, which encode epitopes that are recognized by and activate HBV-specific T cells. Autologous T cells engineered to express TCRs specific for epitopes expressed from HBV-DNA in patients' metastases were given to 2 patients without notable adverse events. The cells did not affect liver function over a 1-year period. In 1 patient, 5 of 6 pulmonary metastases decreased in volume during the 1-year period of T-cell administration. CONCLUSIONS: HCC cells contain short segments of integrated HBV-DNA that encodes epitopes that are recognized by and activate T cells. HBV transcriptomes of these cells could be used to engineer T cells for personalized immunotherapy. This approach might be used to treat a wider population of patients with HBV-associated HCC.

Contact sport participation and chronic traumatic encephalopathy are associated with altered severity and distribution of cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) consists of beta-amyloid deposition in the walls of the cerebrovasculature and is commonly associated with Alzheimer's disease (AD). However, the association of CAA with repetitive head impacts (RHI) and with chronic traumatic encephalopathy (CTE) is unknown. We evaluated the relationship between RHI from contact sport participation, CTE, and CAA within a group of deceased contact sport athletes (n = 357), a community-based cohort (n = 209), and an AD cohort from Boston University AD Center (n = 241). Unsupervised hierarchal cluster analysis demonstrated a unique cluster (n = 11) with increased CAA in the leptomeningeal vessels compared to the intracortical vessels (p < 0.001) comprised of participants with significantly greater frequencies of CTE (7/11) and history of RHI. Overall, participants with CTE (n = 251) had more prevalent (p < 0.001) and severe (p = 0.010) CAA within the frontal leptomeningeal vessels compared to intracortical vessels. Compared to those with AD, participants with CTE had more severe CAA in frontal than parietal lobes (p < 0.001) and more severe CAA in leptomeningeal than intracortical vessels (p = 0.002). The overall frequency of CAA in participants with CTE was low, and there was no significant association between contact sport participation and the presence of CAA. However, in those with CAA, a history of contact sports was associated with increased CAA severity in the frontal leptomeningeal vessels (OR = 4.01, 95% CI 2.52-6.38, p < 0.001) adjusting for AD, APOE ε4 status, and age. Participants with CAA had increased levels of sulcal tau pathology and decreased levels of the synaptic marker PSD-95 (p's < 0.05), and CAA was a predictor of dementia (OR = 1.75, 95% CI 1.02-2.99, p = 0.043) adjusting for age, sex, and comorbid pathology. Overall, contact sport participation and CTE were associated with more severe frontal and leptomeningeal CAA, and CAA was independently associated with worse pathological and clinical outcomes.

Food allergies are associated with increased disease activity in multiple sclerosis.

OBJECTIVE: The association between allergy and multiple sclerosis (MS) is still unclear. In our study, we assessed the association between a self-reported history of allergic conditions with MS clinical and MRI disease activity. METHODS: A subset of 1349 patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) study completed a self-administered questionnaire on environmental, food and drug allergies. Patients were distributed among four allergy groups: (1) environmental, (2) food, (3) drug, (4) no known allergies (NKA). Clinical (number of attacks, expanded disability status scale (EDSS), MS severity score (MSSS)) and radiological variables (presence of gadolinium-enhancing lesions and lesion count), and their associations with the different allergy groups or those with NKA, were assessed. RESULTS: The food allergy group had a 1.38 times higher rate for cumulative number of attacks compared with the NKA group (P=0.0062); this difference remained significant in the adjusted analysis (relapse rate ratio 1.27, P=0.0305). The food allergy group showed more than twice the likelihood (OR 2.53, P=0.0096) of having gadolinium-enhancing lesions on MRI. The environmental and drug allergy groups did not show significant differences when compared with the NKA group. The EDSS and MSSS were not affected by any type of allergy. CONCLUSIONS: MS patients with food allergy had more relapses and a higher likelihood of gadolinium-enhancing lesions compared with patients with no known allergy. Future prospective studies are needed to confirm our findings and investigate underlying biological mechanisms, which may unveil new therapeutic and preventative strategies for MS.

Oral contraceptives and MS disease activity in a contemporary real-world cohort.

BACKGROUND: There is uncertainty regarding the effect of oral hormonal contraceptives (OC) on multiple sclerosis (MS) course. OBJECTIVE: To evaluate the hypothesis that OC use is associated with decreased risk of relapses in an observational study of women of childbearing age with new-onset MS starting a first-line injectable disease-modifying therapy (DMT). METHODS: From our CLIMB longitudinal observational study, we identified 162 women with MS or CIS with known OC use who initiated injectable DMT within two years of symptom onset, and categorized OC use at DMT onset as past, ever or never. Our primary analysis was comparison of annualized relapse rate from baseline DMT start across the three OC use categories using a negative binomial regression model. RESULTS: In this cohort of 162 women, 81 were treated with interferon therapy and 81 with glatiramer acetate. Mean ages for current-, past-, and never-OC users were 31.4 ( n = 46), 40.3 ( n = 66), and 37.9 ( n = 50) years, respectively ( p < 0.05); mean disease duration (1.0 years) and median baseline EDSS (1.0) did not differ between groups. Prior OC users had significantly lower relapse rates than never-users ( p = 0.031); the lower annualized relapse rate in current-users relative to never-users was not significant ( p = 0.91). Annualized relapse rate was not significantly different across the OC groups ( p = 0.057, three-group comparison). RESULTS: These observations provide reassurance for women newly diagnosed that OC use, past or current, does not appear to be associated with greater risk of relapses.

A longitudinal uncontrolled study of cerebral gray matter volume in patients receiving natalizumab for multiple sclerosis.

OBJECTIVE: Brain atrophy in multiple sclerosis (MS) selectively affects gray matter (GM), which is highly relevant to disability and cognitive impairment. We assessed cerebral GM volume (GMV) during one year of natalizumab therapy. DESIGN/METHODS: Patients with relapsing-remitting (n = 18) or progressive (n = 2) MS had MRI ∼1 year apart during natalizumab treatment. At baseline, patients were on natalizumab for (mean ± SD) 16.6 ± 10.9 months with age 38.5 ± 7.4 and disease duration 9.7 ± 4.3 years. RESULTS: At baseline, GMV was 664.0 ± 56.4 ml, Expanded Disability Status Scale (EDSS) score was 2.3 ± 2.0, timed 25-foot walk (T25FW) was 6.1±3.4 s; two patients (10%) had gadolinium (Gd)-enhancing lesions. At follow-up, GMV was 663.9 ± 60.2 mL; EDSS was 2.6 ± 2.1 and T25FW was 5.9 ± 2.9 s. One patient had a mild clinical relapse during the observation period (0.052 annualized relapse rate for the entire cohort). No patients had Gd-enhancing lesions at follow-up. Linear mixed-effect models showed no significant change in annualized GMV [estimated mean change per year 0.338 mL, 95% confidence interval -9.66, 10.34, p = 0.94)], GM fraction (p = 0.92), whole brain parenchymal fraction (p = 0.64), T2 lesion load (p = 0.64), EDSS (p = 0.26) or T25FW (p = 0.79). CONCLUSIONS: This pilot study shows no GM atrophy during one year of natalizumab MS therapy. We also did not detect any loss of whole brain volume or progression of cerebral T2 hyperintense lesion volume during the observation period. These MRI results paralleled the lack of clinical worsening.

Using multiple imputation to efficiently correct cerebral MRI whole brain lesion and atrophy data in patients with multiple sclerosis.

Automated segmentation of brain MRI scans into tissue classes is commonly used for the assessment of multiple sclerosis (MS). However, manual correction of the resulting brain tissue label maps by an expert reader remains necessary in many cases. Since automated segmentation data awaiting manual correction are "missing", we proposed to use multiple imputation (MI) to fill-in the missing manually-corrected MRI data for measures of normalized whole brain volume (brain parenchymal fraction-BPF) and T2 hyperintense lesion volume (T2LV). Automated and manually corrected MRI measures from 1300 patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) were identified. Simulation studies were conducted to assess the performance of MI with missing data both missing completely at random and missing at random. An imputation model including the concurrent automated data as well as clinical and demographic variables explained a high proportion of the variance in the manually corrected BPF (R(2)=0.97) and T2LV (R(2)=0.89), demonstrating the potential to accurately impute the missing data. Further, our results demonstrate that MI allows for the accurate estimation of group differences with little to no bias and with similar precision compared to an analysis with no missing data. We believe that our findings provide important insights for efficient correction of automated MRI measures to obviate the need to perform manual correction on all cases.

A state-space approach for longitudinal outcomes: An application to neuropsychological outcomes.

Longitudinal assessments are crucial in evaluating the disease state and trajectory in patients with neurodegenerative diseases. Neuropsychological outcomes measured over time often have a non-linear trajectory with autocorrelated residuals and a skewed distribution. We propose the adjusted local linear trend model, an extended state-space model in lieu of the commonly used linear mixed-effects model in modeling longitudinal neuropsychological outcomes. Our contributed model has the capability to utilize information from the stochasticity of the data while accounting for subject-specific trajectories with the inclusion of covariates and unequally spaced time intervals. The first step of model fitting involves a likelihood maximization step to estimate the unknown variances in the model before parsing these values into the Kalman filter and Kalman smoother recursive algorithms. Results from simulation studies showed that the adjusted local linear trend model is able to attain lower bias, lower standard errors, and high power, particularly in short longitudinal studies with equally spaced time intervals, as compared to the linear mixed-effects model. The adjusted local linear trend model also outperforms the linear mixed-effects model when data is missing completely at random, missing at random, and, in certain cases, even in data with missing not at random.

Immunological alterations after immunotherapy with short lived HBV-TCR T cells associates with long-term treatment response in HBV-HCC.

The application of hepatitis B virus (HBV)-T-cell receptor (TCR) T-cell immunotherapy in patients with HBV-related hepatocellular carcinoma (HBV-HCC) has been apathetic, as the expression of HBV antigens by both normal HBV-infected hepatocytes and HCC cells with HBV-DNA integration increases the risk of on-target off-tumor severe liver inflammatory events. To increase the safety of this immunotherapeutic approach, we developed messenger RNA (mRNA) HBV-TCR-redirected T cells that-due to the transient nature of mRNA-are functionally short lived and can be infused in escalating doses. The safety of this approach and its clinical potential against primary HBV-HCC have never been analyzed in human trials; thus, we studied the clinical and immunological parameters of 8 patients with chronic HBV infection and diffuse nonoperable HBV-HCC treated at weekly intervals with escalating doses (1 × 104 , 1 × 105 , 1 × 106 , and 5 × 106 TCR+ T cells/kg body weight) of T cells modified with HBV-TCR encoding mRNA. The treatment was well tolerated with no severe systemic inflammatory events, cytokine storm, or neurotoxicity observed in any of these patients throughout treatment. Instead, we observed a destruction of the tumor lesion or a prolonged stable disease in 3 of 8 patients. Importantly, the patients without clinically relevant reductions of HCC did not display any detectable peripheral blood immunological alterations. In contrast, signs of transient localized liver inflammation, activation of the T-cell compartment, and/or elevations of serum chemokine (C-X-C motif) ligand (CXCL) 9 and CXCL10 levels were detected in patients with long-term clinical benefit. Conclusion: We show that despite the reduced in vivo half-life (3-4 days), adoptive transfer of mRNA HBV-TCR T cells into patients with HBV-HCC show long-term clinical benefit that was associated with transient immunological alterations.

A magnetic resonance spectroscopy investigation in symptomatic former NFL players.

The long-term neurologic consequences of exposure to repetitive head impacts (RHI) are not well understood. This study used magnetic resonance spectroscopy (MRS) to examine later-life neurochemistry and its association with RHI and clinical function in former National Football League (NFL) players. The sample included 77 symptomatic former NFL players and 23 asymptomatic individuals without a head trauma history. Participants completed cognitive, behavior, and mood measures. N-acetyl aspartate, glutamate/glutamine, choline, myo-inositol, creatine, and glutathione were measured in the posterior (PCG) and anterior (ACG) cingulate gyrus, and parietal white matter (PWM). A cumulative head impact index (CHII) estimated RHI. In former NFL players, a higher CHII correlated with lower PWM creatine (r = -0.23, p = 0.02). Multivariate mixed-effect models examined neurochemical differences between the former NFL players and asymptomatic individuals without a history of head trauma. PWM N-acetyl aspartate was lower among the former NFL players (mean diff. = 1.02, p = 0.03). Between-group analyses are preliminary as groups were recruited based on symptomatic status. The ACG was the only region associated with clinical function, including positive correlations between glutamate (r = 0.32, p = 0.004), glutathione (r = 0.29, p = 0.02), and myo-inositol (r = 0.26, p = 0.01) with behavioral/mood symptoms. Other positive correlations between ACG neurochemistry and clinical function emerged (i.e., behavioral/mood symptoms, cognition), but the positive directionality was unexpected. All analyses controlled for age, body mass index, and education (for analyses examining clinical function). In this sample of symptomatic former NFL players, there was a direct effect between RHI and reduced cellular energy metabolism (i.e., lower creatine). MRS neurochemicals associated with neuroinflammation also correlated with behavioral/mood symptoms.

Time between expanded disability status scale (EDSS) scores.

BACKGROUND: Although the expanded disability status scale (EDSS) is the most commonly used measure of disability for multiple sclerosis, measurement of disability accumulation is complex due to the unequal steps of the scale. OBJECTIVE: To estimate the time between EDSS scores in a large MS cohort from a single center and determine the impact of functional system scores on EDSS transitions. METHODS: 31,394 clinical visits with EDSS scores from 2054 subjects in the CLIMB longitudinal cohort study were included in our analysis. The time to each EDSS score and the time between each EDSS score were calculated using the nonparametric maximum likelihood estimate for interval censored data. For each initial EDSS value, the association between functional status scores and subsequent EDSS value was assessed using a mixed effects linear regression model, and the association with time to EDSS increase was assessed using a Cox proportional hazards model. RESULTS: The median time until EDSS 2, 3, 4, 5 and 6 in all subjects were 4.8, 15.1, 28.2, 31.2, and 32.4 years, respectively. The time intervals showed that the disability accumulation intervals from EDSS 4 to 6 were much shorter than the accumulation intervals from EDSS 0 to 3 or from EDSS 6 to 8. For EDSS of 1 or 1.5, pyramidal, cerebellar, sensory, bowel-bladder and mental system scores were associated with higher subsequent EDSS values. For higher EDSS values, only pyramidal and bowel-bladder scores maintained the association. CONCLUSIONS: Time between specific EDSS levels varies considerably. Certain functional system scores have greater predictive power for future EDSS-related disability despite same present EDSS level. These findings will assist in adaptation of the EDSS as an outcome measure to assess MS-related disability in clinical trials.

Factors Influencing Choice of Radiology and Relationship to Resident Job Satisfaction.

PURPOSE: Identify when current radiology residents initially became interested in radiology, which factors influenced their decision to pursue a career in radiology, and which factors correlate with job satisfaction. METHODS: An online survey was distributed to United States radiology residents between December 7, 2016 and March 31, 2017. Respondents identified the most appealing aspects of radiology during medical school, identified experiences most influential in choosing radiology, and scored job satisfaction on visual analog scales. Relative importance was compared with descriptive statistics. Satisfaction scores were compared across factors with analysis of variance and post-hoc Tukey tests. RESULTS: 488 radiology residents responded (age 30.8 ± 3.2 years; 358 male, 129 female, 1 unknown; 144 PGY2, 123 PGY3, 103 PGY4, 118 PGY5). The most influential aspects in choosing radiology were the intellectual (n=187, 38%), imaging (n=100, 20%), and procedural (n=96, 20%) components and potential lifestyle (n=69, 14%). Radiology clerkship reading room shadowing (n=143, 29%), radiologist mentor (n=98, 20%), non-radiology clerkship imaging exposure (n=77, 16%), and radiology clerkship interventions exposure (n=75, 15%) were most influential. Choosing radiology because of potential lifestyle correlated with less job satisfaction than choosing radiology for intellectual (p=0.0004) and imaging (p=0.0003) components. CONCLUSION: Recruitment of medical students into radiology may be most effective when radiology clerkships emphasize the intellectual and imaging components of radiology through reading room shadowing and exposure to interventions. Choosing radiology for lifestyle correlates with less job satisfaction, at least during residency.

Interactive Effects of Racial Identity and Repetitive Head Impacts on Cognitive Function, Structural MRI-Derived Volumetric Measures, and Cerebrospinal Fluid Tau and Aß.

BACKGROUND: Factors of increased prevalence among individuals with Black racial identity (e.g., cardiovascular disease, CVD) may influence the association between exposure to repetitive head impacts (RHI) from American football and later-life neurological outcomes. Here, we tested the interaction between racial identity and RHI on neurobehavioral outcomes, brain volumetric measures, and cerebrospinal fluid (CSF) total tau (t-tau), phosphorylated tau (p-tau181), and Aß1 - 42 in symptomatic former National Football League (NFL) players. METHODS: 68 symptomatic male former NFL players (ages 40-69; n = 27 Black, n = 41 White) underwent neuropsychological testing, structural MRI, and lumbar puncture. FreeSurfer derived estimated intracranial volume (eICV), gray matter volume (GMV), white matter volume (WMV), subcortical GMV, hippocampal volume, and white matter (WM) hypointensities. Multivariate generalized linear models examined the main effects of racial identity and its interaction with a cumulative head impact index (CHII) on all outcomes. Age, years of education, Wide Range Achievement Test, Fourth Edition (WRAT-4) scores, CVD risk factors, and APOEε4 were included as covariates; eICV was included for MRI models. P-values were false discovery rate adjusted. RESULTS: Compared to White former NFL players, Black participants were 4 years younger (p = 0.04), had lower WRAT-4 scores (mean difference = 8.03, p = 0.002), and a higher BMI (mean difference = 3.09, p = 0.01) and systolic blood pressure (mean difference = 8.15, p = 0.03). With regards to group differences on the basis of racial identity, compared to White former NFL players, Black participants had lower GMV (mean adjusted difference = 45649.00, p = 0.001), lower right hippocampal volume (mean adjusted difference = 271.96, p = 0.02), and higher p-tau181/t-tau ratio (mean adjusted difference = -0.25, p = 0.01). There was not a statistically significant association between the CHII with GMV, right hippocampal volume, or p-tau181/t-tau ratio. However, there was a statistically significant Race x CHII interaction for GMV (b = 2206.29, p = 0.001), right hippocampal volume (b = 12.07, p = 0.04), and p-tau181/t-tau ratio concentrations (b = -0.01, p = 0.004). CONCLUSION: Continued research on racial neurological disparities could provide insight into risk factors for long-term neurological disorders associated with American football play.

Association of White Matter Rarefaction, Arteriolosclerosis, and Tau With Dementia in Chronic Traumatic Encephalopathy.

IMPORTANCE: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head impacts, including those from US football, that presents with cognitive and neuropsychiatric disturbances that can progress to dementia. Pathways to dementia in CTE are unclear and likely involve tau and nontau pathologic conditions. OBJECTIVE: To investigate the association of white matter rarefaction and cerebrovascular disease with dementia in deceased men older than 40 years who played football and had CTE. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study involves analyses of data from the ongoing Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Study, which is conducted via and included brain donors from the Veterans Affairs-Boston University-Concussion Legacy Foundation brain bank between 2008 and 2017. An original sample of 224 men who had played football and were neuropathologically diagnosed with CTE was reduced after exclusion of those younger than 40 years and those missing data. EXPOSURES: The number of years of football play as a proxy for repetitive head impacts. MAIN OUTCOMES AND MEASURES: Neuropathological assessment of white matter rarefaction and arteriolosclerosis severity (on a scale of 0-3, where 3 is severe); number of infarcts, microinfarcts, and microbleeds; and phosphorylated tau accumulation determined by CTE stage and semiquantitative rating of dorsolateral frontal cortex (DLFC) neurofibrillary tangles (NFTs) (none or mild vs moderate or severe). Informant-based retrospective clinical interviews determined dementia diagnoses via diagnostic consensus conferences. RESULTS: A total of 180 men were included. The mean (SD) age of the sample at death was 67.9 (12.7) years. Of 180, 120 [66.7%]) were found to have had dementia prior to death. Moderate to severe white matter rarefaction (84 of 180 [46.6%]) and arteriolosclerosis (85 of 180 [47.2%]) were common; infarcts, microinfarcts, and microbleeds were not. A simultaneous equations regression model controlling for age and race showed that more years of play was associated with more severe white matter rarefaction (ß, 0.16 [95% CI, 0.02-0.29]; P = .03) and greater phosphorylated tau accumulation (DLFC NFTs: ß, 0.15 [95% CI, 0.004-0.30]; P = .04; CTE stage: ß, 0.27 [95% CI, 0.14-0.41]; P < .001). White matter rarefaction (ß, 0.16 [95% CI, 0.02-0.29]; P = .03) and DLFC NFTs (ß, 0.16 [95% CI, 0.03-0.28]; P = .01) were associated with dementia. Arteriolosclerosis and years of play were not associated, but arteriolosclerosis was independently associated with dementia (ß, 0.21 [95% CI, 0.07-0.35]; P = .003). CONCLUSIONS AND RELEVANCE: Among older men who had played football and had CTE, more years of football play were associated with more severe white matter rarefaction and greater DLFC NFT burden. White matter rarefaction, arteriolosclerosis, and DLFC NFTs were independently associated with dementia. Dementia in CTE is likely a result of neuropathologic changes, including white matter rarefaction and phosphorylated tau, associated with repetitive head impact and pathologic changes not associated with head trauma, such as arteriolosclerosis.

Brain and spinal cord MRI lesions in primary progressive vs. relapsing-remitting multiple sclerosis.

BACKGROUND: Primary progressive (PP) multiple sclerosis (MS) is considered a clinically distinct entity from the spectrum of relapsing-remitting (RR) forms of the disease. OBJECTIVE: To compare the presence of brain and spinal cord lesions between PP and RR subjects. METHODS: We studied people with PPMS [n = 40, 17 (42.5%) men, age 50.7 ±â€¯7.7 years, disease duration 10.1 ±â€¯7.4 years, Expanded Disability Status Scale (EDSS) score 4.6 ±â€¯2.1] and RRMS [n = 40, 12 (30%) men, age 47.9 ±â€¯4.2, disease duration 13.7 ±â€¯5.9, EDSS 1.7 ±â€¯1.3]. MRI of the brain and full spinal cord at 1.5T was analyzed to define patients having: 1. brain only, 2. spinal cord only, or 3. brain and spinal cord MS lesions. RESULTS: Lesions in the brain only were less common in PP (n = 1, 2.5% of people) than RR (n = 10, 25%) (Fisher's exact p = 0.007). Lesions in the spinal cord only (PP: n = 6, 15%, RR: n = 3, 7.5%, p = 0.481) or brain plus spinal cord (PP: n = 33, 83%, RR: n = 27, 68%, p = 0.196) were similar between groups. PP had higher EDSS and timed 25-ft walk (Wilcoxon tests, both p < 0.001), higher age (t-test p = 0.049), lower disease duration (t-test, p = 0.02), and a similar sex ratio (Fisher's exact p = 0.352) vs. RR. CONCLUSIONS: We report a topographic difference in MRI lesion involvement between PPMS and RRMS. Lesions restricted to the brain are more common in RRMS. These findings provide support to the notion that PP may have features distinctive from the RR spectrum of the disease. Longitudinal comparisons and quantitative MRI analysis would be necessary to confirm and extend these results.

Nailfold Capillary Morphology in Alzheimer's Disease Dementia.

BACKGROUND: Cerebrovascular disease (CVD) is highly comorbid with Alzheimer's disease (AD), yet its role is not entirely understood. Nailfold video capillaroscopy (NVC) is a noninvasive method of live imaging the capillaries near the fingernail's cuticle and may help to describe further vascular contributions to AD. OBJECTIVE: To examine finger nailfold capillary morphology using NVC in subjects with AD dementia, mild cognitive impairment (MCI), and normal cognition (NC). METHODS: We evaluated nailfold capillary hemorrhages, avascular zones ≥100 microns, and degree of tortuosity in 28 NC, 15 MCI, and 18 AD dementia subjects using NVC. Tortuosity was measured with a semi-quantitative rating scale. To assess the relation between nailfold capillary morphological features and diagnostic grouping, univariate and multivariable logistic regression models were fit to the data. RESULTS: 56% of subjects with AD dementia compared to 14% with NC and 13% with MCI displayed moderate to severe tortuosity. Greater severity of tortuosity was associated with 10.6-fold (95% confidence interval [CI]: 2.4, 46.2; p = 0.0018) and 7.4-fold (95% CI: 1.3, 41.3; p = 0.023) increased odds of AD dementia relative to NC and MCI, respectively, after adjusting for multiple covariates. CONCLUSION: Greater nailfold capillary tortuosity was found in participants with AD dementia compared to those with MCI or NC. These data provide preliminary evidence of a systemic microvasculopathy in AD that may be noninvasively and inexpensively evaluated through NVC.

White matter signal abnormalities in former National Football League players.

INTRODUCTION: Later-life brain alterations in former tackle football players are poorly understood, particularly regarding their relationship with repetitive head impacts (RHIs) and clinical function. We examined white matter signal abnormalities (WMSAs) and their association with RHIs and clinical function in former National Football League (NFL) players. METHODS: Eighty-six clinically symptomatic former NFL players and 23 same-age reportedly asymptomatic controls without head trauma exposure underwent magnetic resonance imaging and neuropsychological testing. FreeSurfer calculated WMSAs. A cumulative head impact index quantified RHIs. RESULTS: In former NFL players, increased volume of WMSAs was associated with higher cumulative head impact index scores (P = .043) and worse psychomotor speed and executive function (P = .015). Although former NFL players had greater WMSA volume than controls (P = .046), these findings are inconclusive due to recruitment of controls based on lack of clinical symptoms and head trauma exposure. DISCUSSION: In former NFL players, WMSAs may reflect long-term microvascular and nonmicrovascular pathologies from RHIs that negatively impact cognition.

Age at First Exposure to Repetitive Head Impacts Is Associated with Smaller Thalamic Volumes in Former Professional American Football Players.

Thalamic atrophy has been associated with exposure to repetitive head impacts (RHI) in professional fighters. The aim of this study is to investigate whether or not age at first exposure (AFE) to RHI is associated with thalamic volume in symptomatic former National Football League (NFL) players at risk for chronic traumatic encephalopathy (CTE). Eighty-six symptomatic former NFL players (mean age = 54.9 ± 7.9 years) were included. T1-weighted data were acquired on a 3T magnetic resonance imager, and thalamic volumes were derived using FreeSurfer. Mood and behavior, psychomotor speed, and visual and verbal memory were assessed. The association between thalamic volume and AFE to playing football and to number of years playing was calculated. Decreased thalamic volume was associated with more years of play (left: p = 0.03; right: p = 0.03). Younger AFE was associated with decreased right thalamic volume (p = 0.014). This association remained significant after adjusting for total years of play. Decreased left thalamic volume was associated with worse visual memory (p = 0.014), whereas increased right thalamic volume was associated with fewer mood and behavior symptoms (p = 0.003). In our sample of symptomatic former NFL players at risk for CTE, total years of play and AFE were associated with decreased thalamic volume. The effect of AFE on right thalamic volume was almost twice as strong as the effect of total years of play. Our findings confirm previous reports of an association between thalamic volume and exposure to RHI. They suggest further that younger AFE may result in smaller thalamic volume later in life.

Automated versus manual segmentation of brain region volumes in former football players.

Objectives: To determine whether or not automated FreeSurfer segmentation of brain regions considered important in repetitive head trauma can be analyzed accurately without manual correction. Materials and methods: 3 T MR neuroimaging was performed with automated FreeSurfer segmentation and manual correction of 11 brain regions in former National Football League (NFL) players with neurobehavioral symptoms and in control subjects. Automated segmentation and manually-corrected volumes were compared using an intraclass correlation coefficient (ICC). Linear mixed effects regression models were also used to estimate between-group mean volume comparisons and to correlate former NFL player brain volumes with neurobehavioral factors. Results: Eighty-six former NFL players (55.2 ±â€¯8.0 years) and 22 control subjects (57.0 ±â€¯6.6 years) were evaluated. ICC was highly correlated between automated and manually-corrected corpus callosum volumes (0.911), lateral ventricular volumes (right 0.980, left 0.967), and amygdala-hippocampal complex volumes (right 0.713, left 0.731), but less correlated when amygdalae (right -0.170, left -0.090) and hippocampi (right 0.539, left 0.637) volumes were separately delineated and also less correlated for cingulate gyri volumes (right 0.639, left 0.351). Statistically significant differences between former NFL player and controls were identified in 8 of 11 regions with manual correction but in only 4 of 11 regions without such correction. Within NFL players, manually corrected brain volumes were significantly associated with 3 neurobehavioral factors, but a different set of 3 brain regions and neurobehavioral factor correlations was observed for brain region volumes segmented without manual correction. Conclusions: Automated FreeSurfer segmentation of the corpus callosum, lateral ventricles, and amygdala-hippocampus complex may be appropriate for analysis without manual correction. However, FreeSurfer segmentation of the amygdala, hippocampus, and cingulate gyrus need further manual correction prior to performing group comparisons and correlations with neurobehavioral measures.