Citations

AbstractBackgroundTraumatic encephalopathy syndrome (TES) is the proposed clinical syndrome of the neurodegenerative disease chronic traumatic encephalopathy (CTE). As part of the 2021 TES NINDS consensus diagnostic criteria, certainty levels of underlying CTE neuropathology can be determined (i.e., suggestive, possible, probable) partially based on the presence/absence of supportive psychiatric features including but not limited to depression, anxiety, and apathy. These are ‘supportive’ because of their non‐specificity and unclear biological correlates in this setting. We examined the association between CSF biomarkers of amyloid, tau, neurodegeneration, microglial activation and neuroinflammation and supportive psychiatric features of TES in former American football players.MethodThe sample included 180 male former football players (120 professional, 60 college) from the DIAGNOSE CTE Research Project. Participants completed a lumbar puncture, and CSF assays were conducted for biomarkers of amyloid (Aβ40, Aβ42), p‐tau (p‐tau181, p‐tau231, p‐tau217), neurodegeneration (total tau), axonal degeneration (NfL), microglial activation (strem2) and neuroinflammation (GFAP, IL‐6). Biomarkers were log‐transformed. The Apathy Evaluation Scale (AES), Beck Depression Inventory‐II (BDI‐II) and the Beck Anxiety Inventory (BAI) self‐report questionnaires were completed by participants. Multivariable regression models tested the association between each CSF biomarker and each scale, controlling for age, race, body mass index, revised Framingham stroke risk profile and Alcohol Use Disorders Identification Test. P‐values were adjusted for multiple comparisons using false discovery rate methods.Result140 participants had successful LPs and available CSF for assays. 33(22%) reported moderate/severe anxiety, 34(22%) reported moderate/severe depression, and 51(33%) had an elevated AES score. Higher CSF concentrations of IL‐6 were associated with higher scores on the BAI (unstandardized‐β=0.016, 95%CI [0.017, 0.026], padj=0.004), BDI‐II (unstandardized‐β=0.013, 95%CI [0.004, 0.021], padj=0.008) and AES (unstandardized‐β=0.014, 95%CI [0.006,0.022], padj=0.002). There were no significant relationships between other biomarkers with the BDI‐II, BAI or AES.ConclusionIn this sample of former American football players, there were significant associations between IL‐6 (a proinflammatory cytokine) and reported symptoms of depression, anxiety, and apathy. CSF biomarkers of amyloid, tau and neurodegeneration had no associations, highlighting the role of neuroinflammatory processes in the manifestation of psychiatric symptoms of TES. Continued research on the biological correlates of TES features will inform future iterations of the criteria.

AbstractBackgroundClinically meaningful cognitive impairment has typically been defined as a single impaired test score, but this approach is prone to false‐positive errors. Examining two test scores at a lower threshold (i.e., using neuropsychological criteria) can improve diagnostic reliability and has shown stronger associations with biomarkers of Alzheimer’s disease. Cognitive impairment in episodic memory and/or executive functioning is a core feature of traumatic encephalopathy syndrome (TES). However, there remains a need to improve the specificity of TES criteria. We applied 1‐ vs. 2‐test criteria for cognitive impairment in former American football players to examine whether 2‐test criteria showed stronger associations with biomarkers of tau, axonal injury, and neurodegeneration.Method169 male former American football players from the DIAGNOSE CTE Research Project completed neuropsychological assessment, lumbar puncture, and MRI (see Table). Episodic memory measures were delayed recall from Craft Story, Brief Visuospatial Memory Test, and NAB List Learning. Executive functioning measures were FAS, Stroop Interference, NAB Mazes, and Trails B. Cerebrospinal fluid (CSF) was measured using Lumipulse technology (p‐tau, t‐tau) and an in‐house ELISA (neurofilament light [NfL]). Hippocampal volumes were extracted from structural MRI using Freesurfer 7.1. Cognitive impairment was identified by 1‐test criteria (≥1.5 SD below norms on one test in either domain) and 2‐test criteria (>1 SD below norms on two tests within a domain). Regressions adjusting for age, race, education, and APOE ε4 status assessed whether meeting 1‐ or 2‐test criteria, separately, predicted log‐transformed CSF p‐tau181, p‐tau231, t‐tau, and NfL, and hippocampal volumes.Result37 of the 99 football players that were impaired by 1‐test criteria did not meet 2‐test criteria, and four uniquely met 2‐test but not 1‐test criteria (see Figure). Cognitive impairment by 2‐test but not 1‐test criteria predicted higher log‐CSF NfL (2‐test: B = 0.24, p = .007; 1‐test: B = 0.06, p = .53), smaller left hippocampal volume (2‐test: B = ‐195.84, p = .01; 1‐test: B = ‐131.52, p = .08), and smaller right hippocampal volume (2‐test: B = ‐161.19, p = .045; 1‐test: B = ‐134.88, p = .08). Neither criterion predicted p‐tau181, p‐tau231, or t‐tau.Conclusion2‐test criteria demonstrated stronger associations between cognitive impairment and markers of axonal injury and neurodegeneration. Incorporating multiple test scores to identify cognitive impairment could improve diagnostic specificity in TES.

AbstractBackgroundTraumatic encephalopathy syndrome (TES) is the proposed clinical syndrome of chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head impacts in contact/collision sports. A core clinical feature of TES is cognitive impairment, particularly in memory and executive functions. Cognitive intraindividual variability (IIV) is the extent of variability in neuropsychological test performance (i.e., dispersion of test scores) and is believed to be an indicator of disruption in executive control, linked to altered fronto‐subcortical circuits. Here, we examined cognitive IIV as a method to detect subtle executive dysfunction in TES that may not be captured by traditional neuropsychological measures.MethodThe sample included former American football players (120 professional, 60 college); participants were males, aged 45‐74. Participants completed a baseline neuropsychological test battery (n = 8 excluded for suboptimal performance validity). A multidisciplinary diagnostic consensus conference classified participants using the 2021 NINDS Consensus Diagnostic Criteria for TES (see Table‐1): (1) No‐TES (n = 62); (2) TES‐CTE Suggestive (n = 35); (3) TES‐CTE Possible (n = 21); (4) TES‐CTE Probable (n = 54). TES‐CTE Possible and Probable were combined. The coefficient of variation (CoV) was used to measure cognitive IIV (CoV = iSD/iOTBM, iOTBM = average T‐score across neuropsychological tests; iSD = standard deviation of iOTBM). A higher CoV indicates greater score dispersion. To avoid circularity, memory and executive tests used for classifying TES groups were intentionally excluded from the CoV calculation. Analysis of covariance compared the TES groups on CoV, controlling for age, education, and race.ResultResults showed a significant difference in CoV between TES groups, F(2, 165) = 8.20 p<.001, partial η2 = .09. The TES‐CTE Possible/Probable group had the highest CoV (M = .226, SE = .007), compared with the TES‐no (M = .192, SE = .008, p<.001) and TES‐CTE Suggestive groups (M = .178, SE = .011, p<.001). CoV did not significantly differ between the TES‐no and TES‐CTE suggestive groups (Mdiff = 0.014, SE = .013, p = .293).ConclusionThe TES‐CTE possible/probable group had the highest cognitive IIV with ∼23% dispersion (vs. ∼18‐19% in TES‐no and TES‐CTE suggestive groups), suggesting greater cognitive variability in those with the greatest likelihood for having underlying CTE (based on TES criteria). This finding emphasizes the potential utility of exploring cognitive IIV as a method for detecting nuanced executive dysfunction in TES.

Abstract Former American football players are at risk for developing traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic traumatic encephalopathy (CTE). The objective of this study was to determine whether hyposmia is present in traumatic encephalopathy syndrome. The study included 119 former professional American football players, 60 former college football players, and 58 same-age asymptomatic unexposed men from the DIAGNOSE CTE Research Project. All subjects included in the analysis had completed the Brief Smell Identification Test (B-SIT). Traumatic encephalopathy syndrome and the level of CTE certainty were diagnosed using the 2021 NINDS consensus diagnostic criteria. TES is categorized antemortem by provisional levels of increasing CTE certainty: Suggestive, Possible, and Probable. Former players who had traumatic encephalopathy syndrome and Probable CTE had lower B-SIT scores than those with TES and Suggestive CTE. Hyposmia was more likely in the former players with TES who were either CTE Possible or Probable than in those who did not have TES or had TES but were less likely to have CTE, or CTE Suggestive. There was no difference in B-SIT scores between all former players versus unexposed men nor overall between the football players with and without TES. We conclude that lower B-SIT scores may be a clinical biomarker for underlying CTE in former American football players.

Abstract Aims Gender-affirming hormone therapy (GAHT) is used by some transgender individuals (TG), who comprise 1.4% of US population. However, the effects of GAHT on electrocardiogram (ECG) remain unknown. The objective is to assess the effects of GAHT on ECG changes in TG. Methods and results Twelve-lead ECGs of TG on GAHT at the Mayo Clinic were inspected using a validated artificial intelligence (AI) algorithm. The algorithm assigns a patient’s ECG male pattern probability on a scale of 0 (female) to 1 (male). In the primary analysis, done separately for transgender women (TGW) and transgender men (TGM), 12-lead ECGs were used to estimate the male pattern probability before and after GAHT. In a subanalysis, only patients with both pre- and post-GAHT EGCs were included. Further, the autopopulated PR, QRS, and QTc intervals were compared before and after GAHT. Among TGW (n = 86), the probability (mean ± SD) of an ECG male pattern was 0.84 ± 0.25 in the pre-GAHT group, and it was lowered to 0.59 ± 0.36 in the post-GAHT group (n = 173, P &lt; 7.8 × 10−10). Conversely, among TGM, male pattern probability was 0.16 ± 0.28 (n = 47) in the pre-GAHT group, and it was higher at 0.41 ± 0.38 in the post-GAHT group (n = 53, P &lt; 2.4×10−4). The trend persisted in the subanalysis. Furthermore, both the PR (P = 5.68 × 10−4) and QTc intervals (P = 6.65×10−6) prolonged among TGW. Among TGM, the QTc interval shortened (P = 4.8 × 10−2). Conclusion Among TG, GAHT is associated with ECG changes trending towards gender congruence, as determined by the AI algorithm and ECG intervals. Prospective studies are warranted to understand GAHT effects on cardiac structure and function.

AbstractINTRODUCTIONBlood‐based biomarkers offer a promising approach for the detection of neuropathologies from repetitive head impacts (RHI). We evaluated plasma biomarkers of amyloid, tau, neurodegeneration, and inflammation in former football players.METHODSThe sample included 180 former football players and 60 asymptomatic, unexposed male participants (aged 45–74). Plasma assays were conducted for beta‐amyloid (Aβ) 40, Aβ42, hyper‐phosphorylated tau (p‐tau) 181+231, total tau (t‐tau), neurofilament light (NfL), glial fibrillary acidic protein (GFAP), interleukin‐6 (IL‐6), Aβ42/p‐tau181 and Aβ42/Aβ40 ratios. We evaluated their ability to differentiate the groups and associations with RHI proxies and traumatic encephalopathy syndrome (TES).RESULTSP‐tau181 and p‐tau231(padj = 0.016) were higher and Aβ42/p‐tau181 was lower(padj = 0.004) in football players compared to controls. Discrimination accuracy for p‐tau was modest (area under the curve [AUC] = 0.742). Effects were not attributable to AD‐related pathology. Younger age of first exposure (AFE) correlated with higher NfL (padj = 0.03) and GFAP (padj = 0.033). Plasma GFAP was higher in TES‐chronic traumatic encephalopathy (TES‐CTE) Possible/Probable (padj = 0.008).DISCUSSIONPlasma p‐tau181 and p‐tau231, GFAP, and NfL may offer some usefulness for the characterization of RHI‐related neuropathologies.Highlights Former football players had higher plasma p‐tau181 and p‐tau231 and lower Aβ42/ptau‐181 compared to asymptomatic, unexposed men. Younger age of first exposure was associated with increased plasma NfL and GFAP in older but not younger participants. Plasma GFAP was higher in participants with TES‐CTE possible/probable compared to TES‐CTE no/suggestive.

AbstractThe tauopathies are defined by pathological tau protein aggregates within a spectrum of clinically heterogeneous neurodegenerative diseases. The primary tauopathies meet the definition of rare diseases in the United States. There is no approved treatment for primary tauopathies. In this context, designing the most efficient development programs to translate promising targets and treatments from preclinical studies to early‐phase clinical trials is vital. In September 2022, the Rainwater Charitable Foundation convened an international expert workshop focused on the translation of tauopathy therapeutics through early‐phase trials. Our report on the workshop recommends a framework for principled drug development and a companion lexicon to facilitate communication focusing on reproducibility and achieving common elements. Topics include the selection of targets, drugs, biomarkers, participants, and study designs. The maturation of pharmacodynamic biomarkers to demonstrate target engagement and surrogate disease biomarkers is a crucial unmet need.Highlights Experts provided a framework to translate therapeutics (discovery to clinical trials). Experts focused on the “5 Rights” (target, drug, biomarker, participants, trial). Current research on frontotemporal degeneration, progressive supranuclear palsy, and corticobasal syndrome therapeutics includes 32 trials (37% on biologics) Tau therapeutics are being tested in Alzheimer's disease; primary tauopathies have a large unmet need.

BACKGROUND: There has been a shift in the treatment of fistula-in-ano toward a focus on the preservation of continence while simultaneously eradicating the disease. The utilization of radially emitting diode laser catheters to ablate fistula tracks has been described since 2011, with heterogenous studies publishing success rates ranging from 20% to 89%. OBJECTIVE: Present the authors’ experience managing solitary transsphincteric fistulas of cryptoglandular origin with a radially emitting diode laser. DESIGN: Prospective nonrandomized single center trial with 12-month follow-up. SETTINGS: Quaternary referral academic health care center. PATIENTS: Forty-six adults with transsphincteric fistula-in-ano. INTERVENTIONS: All patients underwent radially emitting diode laser closure of fistula-in-ano. MAIN OUTCOME MEASURES: Clinical healing and fistula recurrence. RESULTS: Forty-six patients with a median age of 48 years (range, 26–85) underwent diode laser closure. Most were men (n = 28; 60%). Twenty-four patients (52%) had previous fistula repairs with a median of 1.5 (range, 1–7) repairs per patient. All were followed for 12 months. Successful closure after 1 laser treatment occurred in 43% of patients. Thirteen of 26 failure cases (50%) were able to undergo a delayed fistulotomy secondary to an anatomic change with the fistula becoming more superficial, moving out of the internal sphincter muscle after laser ablation, all of which healed. No patients experienced new or worsening (preexisting) fecal incontinence. Two patients (8%) continued treatment for abscesses/fistula branching. One patient (3%) experienced migration of the fistula from the base of the left labia to the introitus of the vagina and 1 experienced recurrence and worsening of their disease process with subsequent involvement of the coccyx (previous deep postanal space abscess). LIMITATIONS: Limitations to our study include its nonrandomized prospective nature, single center and surgeon experience, and small patient sample size. CONCLUSIONS: Radially emitting diode laser closure is a continence-preserving option to consider when treating transsphincteric fistula-in-ano. When the procedure fails, it does not fail poorly (open wounds, retracted flaps, incontinence, etc) and can be repeated. Complications can include abscess formation and fistula migration to adjacent anatomic locations (vagina). Even if unsuccessful, after treatment, the fistula can anatomically migrate distally, becoming more superficial and thus providing the opportunity to proceed with a delayed fistulotomy. See Video Abstract. CIERRE DE FÍSTULA ANAL TRANSESFINTÉRICA CON LÁSER DE DIODO DE EMISIÓN RADIAL ANTECEDENTES: Ha habido un cambio en el tratamiento de la fístula anal hacia un enfoque en la preservación de la continencia y al mismo tiempo en la erradicación de la enfermedad. La utilización de catéteres láser de diodo de emisión radial para extirpar los trayectos de las fístulas se describe desde el 2011 y estudios heterogéneos publican tasas de éxito que oscilan entre el 20 y el 89%. OBJETIVO: Presentar nuestra experiencia en el manejo de fístulas transesfinterianas solitarias de origen criptoglandular con láser de diodo de emisión radial. DISEÑO: Ensayo prospectivo, no aleatorizado, unicéntrico, con seguimiento de 12 meses. LUGARES: Centro de salud académico de referencia Cuaternario. PACIENTES: Cuarenta y seis adultos con fístula anal transesfintérica. INTERVENCIONES: Todos se sometieron a cierre de fístula anal con láser de diodo de emisión radial. MEDIDAS PRINCIPALES DEL RESULTADO: Curación clínica y recurrencia de la fístula. RESULTADOS: Cuarenta y seis pacientes con una mediana de edad de 48 años (rango, 26-85) se sometieron a cierre con láser de diodo. La mayoría eran hombres (n=28/60%). Veinticuatro (52%) habían tenido reparaciones previas de fístulas con una mediana de 1,5 (rango, 1-7) reparaciones por paciente. Todos fueron seguidos durante 12 meses. El cierre exitoso después de un tratamiento con láser se produjo en el 43%. Trece de 26 fracasos (50%) pudieron someterse a una fistulotomía tardía debido a un cambio anatómico en el que la fístula se volvió más superficial y salió del músculo del esfínter interno después de la ablación con láser, y todas sanaron. Ningún paciente experimentó incontinencia fecal nueva o que empeoró (preexistente). Dos (8%) continuaron tratamiento por abscesos/ramificación de fístulas. Una (3%) experimentó migración de la fístula desde la base de los labios izquierdos hasta el introito de la vagina y 1 experimentó recurrencia y empeoramiento de su proceso patológico con posterior afectación del cóccix (absceso previo en el espacio postanal profundo). LIMITACIONES: Las limitaciones de nuestro estudio incluyen su naturaleza prospectiva no aleatoria, la experiencia de un solo centro y del cirujano y el tamaño pequeño de la muestra de pacientes. CONCLUSIONES: El cierre con láser de diodo de emisión radial es una opción para preservar la continencia a considerar cuando se trata la fístula en el ano transesfintérica. Cuando el procedimiento fracasa, no fracasa mal (heridas abiertas, colgajos retraídos, incontinencia, etc.), y puede repetirse. Las complicaciones pueden incluir formación de abscesos y migración de fístulas a ubicaciones anatómicas adyacentes (vagina). Incluso si no tiene éxito, después del tratamiento la fístula puede migrar anatómicamente distal volviéndose más superficial y brindando así la oportunidad de proceder con una fistulotomía retrasada. (Traducción—Yesenia Rojas-Khalil)