RESUMEN
OBJECTIVE: Neurobehavioral dysregulation (NBD), a core clinical feature of traumatic encephalopathy syndrome, encompasses neuropsychiatric symptoms reported among individuals with a history of repetitive head impact exposure, including contact sport athletes. The objective of this study was to examine the construct and subconstructs of NBD through a series of factor and cluster analyses. METHODS: Six clinician-scientists selected self-report questionnaire items relevant to NBD from seven available neuropsychiatric scales through a blinded voting process. These items were subjected to confirmatory factor analyses in a sample of 178 former college and professional American football players and 60 asymptomatic individuals without a history of repetitive head impact exposure. All participants were enrolled in the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Factor scores were generated on the basis of the optimal expert-informed model for NBD. Construct validity was assessed with neuropsychiatric scales not included in generation of the factor scores. Cluster analyses with NBD factor scores were used to examine symptom profiles. RESULTS: Factor analyses confirmed that NBD was composed of four subconstructs: explosivity, emotional dyscontrol, impulsivity, and affective lability. Cluster analyses indicated four distinct symptom profiles of NBD in this group of former football players: asymptomatic (N=80, 45%), short fuse (N=33, 19%), high affective lability (N=34, 19%), and high NBD (N=31, 17%). CONCLUSIONS: These findings characterize NBD as a multifaceted clinical construct with a heterogeneous presentation, providing a foundation for empirical work on the diagnostic criteria for traumatic encephalopathy syndrome and research on the neurobiological underpinnings of NBD.
RESUMEN
Traumatic brain injury (TBI) and Alzheimer's disease (AD) have overlapping mechanisms but it remains unknown if pathophysiological characteristics and cognitive trajectories in AD patients are influenced by TBI history. Here, we studied AD patients (stage MCI or dementia) with TBI history (ADTBI+, n=110), or without (ADTBI-, n=110) and compared baseline CSF concentrations of amyloid beta 1-42 (Aß42), phosphorylated tau181 (pTau181), total tau, neurofilament light chain (NfL), synaptosomal associated protein-25kDa (SNAP25), neurogranin (Ng), neuronal pentraxin-2 (NPTX2) and glutamate receptor-4 (GluR4), as well as differences in cognitive trajectories using linear mixed models. Explorative, analyses were repeated within stratified TBI groups by TBI characteristics (timing, severity, number). We found no differences in baseline CSF biomarker concentrations nor in cognitive trajectories between ADTBI+ and ADTBI- patients. TBI >5 years ago was associated with higher NPTX2 and a tendency for higher SNAP25 concentrations compared to TBI ≤ 5 years ago, suggesting that TBI may be associated with long-term synaptic dysfunction only when occurring before onset or in a pre-clinical disease stage of AD.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Lesiones Traumáticas del Encéfalo , Cognición , Proteínas tau , Humanos , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Lesiones Traumáticas del Encéfalo/líquido cefalorraquídeo , Lesiones Traumáticas del Encéfalo/complicaciones , Biomarcadores/líquido cefalorraquídeo , Masculino , Femenino , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Neurogranina/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Persona de Mediana Edad , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/etiología , Disfunción Cognitiva/diagnóstico , Anciano de 80 o más Años , Proteína 25 Asociada a Sinaptosomas/líquido cefalorraquídeo , Proteína C-Reactiva/líquido cefalorraquídeo , Proteínas del Tejido NerviosoRESUMEN
BACKGROUND AND OBJECTIVES: Outcome reporting bias occurs when publication of trial results is dependent on clinical significance, thereby threatening the validity of trial results. Research on immunomodulatory drugs in multiple sclerosis has thrived in recent years. We aim to comprehensively examine to what extent outcome reporting bias is present in these trials and the possible underlying factors. METHODS: We identified clinical trials evaluating the efficacy and safety of immunomodulatory drugs in patients with multiple sclerosis (MS) registered in ClinicalTrials.gov after September 2007 and completed before the end of 2018. Information about study design, type of funding, and primary and secondary outcome measures was extracted from the registry. Timing of registration in relation to study initiation and subsequent amendments to the planned outcomes were reviewed. Publications related to these trials were identified in several bibliographic databases using the trial registration number. Registered primary and secondary outcomes were recorded for each trial and compared with outcomes in the publication describing the main outcomes of the trial. RESULTS: A search of ClinicalTrials.gov identified 535 eligible registered clinical trials; of these, 101 had a matching publication. Discrepancies between registered and published primary and secondary outcomes were found in 95% of the trials, including discrepancies between the registered and published primary outcomes in 26 publications. Forty-four percent of the published secondary outcomes were not included in the registry. A similar proportion of registered and nonregistered reported primary efficacy outcomes were positive (favoring the intervention). Nonindustry-funded and open-label trials in MS were more prone to selective primary outcome reporting, although these findings did not reach statistical significance. Only two-thirds of the trials were registered in ClinicalTrials.gov before the trial start date, and 62% of trials made amendments in registered outcomes during or after the trial period. DISCUSSION: Selective outcome reporting is prevalent in trials of disease-modifying drugs in people with MS. We propose methods to diminish the occurrence of this bias in future research.
Asunto(s)
Ensayos Clínicos como Asunto , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Sesgo de Publicación , Agentes Inmunomoduladores/uso terapéutico , Evaluación de Resultado en la Atención de Salud , Sistema de Registros , Factores Inmunológicos/uso terapéuticoRESUMEN
BACKGROUND: Traumatic encephalopathy syndrome (TES) is defined as the clinical manifestation of the neuropathological entity chronic traumatic encephalopathy (CTE). A core feature of TES is neurobehavioral dysregulation (NBD), a neuropsychiatric syndrome in repetitive head impact (RHI)-exposed individuals, characterized by a poor regulation of emotions/behavior. To discover biological correlates for NBD, we investigated the association between biomarkers of inflammation (interleukin (IL)-1ß, IL-6, IL-8, IL-10, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) in cerebrospinal fluid (CSF) and NBD symptoms in former American football players and unexposed individuals. METHODS: Our cohort consisted of former American football players, with (n = 104) or without (n = 76) NBD diagnosis, as well as asymptomatic unexposed individuals (n = 55) from the DIAGNOSE CTE Research Project. Specific measures for NBD were derived (i.e., explosivity, emotional dyscontrol, impulsivity, affective lability, and a total NBD score) from a factor analysis of multiple self-report neuropsychiatric measures. Analyses of covariance tested differences in biomarker concentrations between the three groups. Within former football players, multivariable linear regression models assessed relationships among log-transformed inflammatory biomarkers, proxies for RHI exposure (total years of football, cumulative head impact index), and NBD factor scores, adjusted for relevant confounding variables. Sensitivity analyses tested (1) differences in age subgroups (< 60, ≥ 60 years); (2) whether associations could be identified with plasma inflammatory biomarkers; (3) associations between neurodegeneration and NBD, using plasma neurofilament light (NfL) chain protein; and (4) associations between biomarkers and cognitive performance to explore broader clinical symptoms related to TES. RESULTS: CSF IL-6 was higher in former American football players with NBD diagnosis compared to players without NBD. Furthermore, elevated levels of CSF IL-6 were significantly associated with higher emotional dyscontrol, affective lability, impulsivity, and total NBD scores. In older football players, plasma NfL was associated with higher emotional dyscontrol and impulsivity, but also with worse executive function and processing speed. Proxies for RHI exposure were not significantly associated with biomarker concentrations. CONCLUSION: Specific NBD symptoms in former American football players may result from multiple factors, including neuroinflammation and neurodegeneration. Future studies need to unravel the exact link between NBD and RHI exposure, including the role of other pathophysiological pathways.
Asunto(s)
Lesiones Traumáticas del Encéfalo , Encefalopatía Traumática Crónica , Fútbol Americano , Humanos , Anciano , Persona de Mediana Edad , Encefalopatía Traumática Crónica/patología , Interleucina-6 , BiomarcadoresRESUMEN
In the last decades, numerous post-mortem case series have documented chronic traumatic encephalopathy (CTE) in former contact-sport athletes, though reports of CTE pathology in former soccer players are scarce. This study presents a clinicopathological case of a former professional soccer player with young-onset dementia. The patient experienced early onset progressive cognitive decline and developed dementia in his mid-50 s, after playing soccer for 12 years at a professional level. While the clinical picture mimicked Alzheimer's disease, amyloid PET imaging did not provide evidence of elevated beta-amyloid plaque density. After he died in his mid-60 s, brain autopsy showed severe phosphorylated tau (p-tau) abnormalities fulfilling the neuropathological criteria for high-stage CTE, as well as astrocytic and oligodendroglial tau pathology in terms of tufted astrocytes, thorn-shaped astrocytes, and coiled bodies. Additionally, there were TAR DNA-binding protein 43 (TDP-43) positive cytoplasmic inclusions in the frontal lobe and hippocampus, and Amyloid Precursor Protein (APP) positivity in the axons of the white matter. A systematic review of the literature revealed only 13 other soccer players with postmortem diagnosis of CTE. Our report illustrates the complex clinicopathological correlation of CTE and the need for disease-specific biomarkers.
Asunto(s)
Enfermedad de Alzheimer , Encefalopatía Traumática Crónica , Fútbol , Deportes , Masculino , Humanos , Encéfalo/diagnóstico por imagenRESUMEN
Introduction: Traumatic brain injury (TBI) has been associated with a greater risk of developing Alzheimer's disease (AD). Less is known about the clinical features of AD patients with TBI history. The objective of this study was to examine whether a history of TBI and specific injury characteristics are associated with differences in age of disease onset, cognitive features, and neuropsychiatric symptoms (NPSs) in AD patients. Methods: Biomarker-proven AD patients (CSF or amyloid PET) were selected from the Amsterdam Dementia Cohort. TBI events were classified by age at injury (TBI <25 or ≥25 years) and TBI severity (loss of consciousness, multiple events). Cognitive composite scores were calculated from results of a neuropsychological test battery. NPSs were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q). Linear regression analyses were utilized to examine associations between TBI, TBI characteristics, and clinical outcome measures. Results: Among the 1,755 selected AD patients (mean age = 65.2 years), 166 (9.5%) had documented ≥1 TBI in their medical history. Overall, TBI history was not related to differences in age of disease onset, but age at injury <25 years old was associated with 2.3 years earlier age at symptom onset (B = -2.34, p = 0.031). No significant associations were found between TBI history or TBI characteristics and differences in cognition or NPSs. Conclusion: Our results underscore previous findings on the vulnerability of the brain during critical maturation phases and suggest that an early TBI may contribute to lower resilience to neurodegenerative changes.
RESUMEN
BACKGROUND: Repetitive head injury in contact sports is associated with cognitive, neurobehavioral, and motor impairments and linked to a unique neurodegenerative disorder: chronic traumatic encephalopathy (CTE). As the clinical presentation is variable, risk factors are heterogeneous, and diagnostic biomarkers are not yet established, the diagnostic process of CTE remains a challenge. The general objective of the NEwTON study is to establish a prospective cohort of individuals with high risk for CTE, to phenotype the study population, to identify potential fluid and neuroimaging biomarkers, and to measure clinical progression of the disease. The present paper explains the protocol and design of this case-finding study. METHODS: NEwTON is a prospective study that aims to recruit participants at risk for CTE, with features of the traumatic encephalopathy syndrome (exposed participants), and healthy unexposed control individuals. Subjects are invited to participate after diagnostic screening at our memory clinic or recruited by advertisement. Exposed participants receive a comprehensive baseline screening, including neurological examination, neuropsychological tests, questionnaires and brain MRI for anatomical imaging, diffusion tensor imaging (DTI), resting-state functional MRI (rsfMRI), and quantitative susceptibility mapping (QSM). Questionnaires include topics on life-time head injury, subjective cognitive change, and neuropsychiatric symptoms. Optionally, blood and cerebrospinal fluid are obtained for storage in the NEwTON biobank. Patients are informed about our brain donation program in collaboration with the Netherlands Brain Brank. Follow-up takes place annually and includes neuropsychological assessment, questionnaires, and optional blood draw. Testing of control subjects is limited to baseline neuropsychological tests, MRI scan, and also noncompulsory blood draw. RESULTS: To date, 27 exposed participants have finished their baseline assessments. First baseline results are expected in 2023. CONCLUSIONS: The NEwTON study will assemble a unique cohort with prospective observational data of male and female individuals with high risk for CTE. This study is expected to be a primary explorative base and designed to share data with international CTE-related cohorts. Sub-studies may be added in the future with this cohort as backbone.