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Developing methods to detect and diagnose chronic traumatic encephalopathy during life: rationale, design, and methodology for the DIAGNOSE CTE Research Project

Alosco, Michael L; Mariani, Megan L; Adler, Charles H; Balcer, Laura J; Bernick, Charles; Au, Rhoda; Banks, Sarah J; Barr, William B; Bouix, Sylvain; Cantu, Robert C; Coleman, Michael J; Dodick, David W; Farrer, Lindsay A; Geda, Yonas E; Katz, Douglas I; Koerte, Inga K; Kowall, Neil W; Lin, Alexander P; Marcus, Daniel S; Marek, Kenneth L; McClean, Michael D; McKee, Ann C; Mez, Jesse; Palmisano, Joseph N; Peskind, Elaine R; Tripodis, Yorghos; Turner, Robert W; Wethe, Jennifer V; Cummings, Jeffrey L; Reiman, Eric M; Shenton, Martha E; Stern, Robert A
BACKGROUND:Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been neuropathologically diagnosed in brain donors exposed to repetitive head impacts, including boxers and American football, soccer, ice hockey, and rugby players. CTE cannot yet be diagnosed during life. In December 2015, the National Institute of Neurological Disorders and Stroke awarded a seven-year grant (U01NS093334) to fund the "Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project." The objectives of this multicenter project are to: develop in vivo fluid and neuroimaging biomarkers for CTE; characterize its clinical presentation; refine and validate clinical research diagnostic criteria (i.e., traumatic encephalopathy syndrome [TES]); examine repetitive head impact exposure, genetic, and other risk factors; and provide shared resources of anonymized data and biological samples to the research community. In this paper, we provide a detailed overview of the rationale, design, and methods for the DIAGNOSE CTE Research Project. METHODS:The targeted sample and sample size was 240 male participants, ages 45-74, including 120 former professional football players, 60 former collegiate football players, and 60 asymptomatic participants without a history of head trauma or participation in organized contact sports. Participants were evaluated at one of four U.S. sites and underwent the following baseline procedures: neurological and neuropsychological examinations; tau and amyloid positron emission tomography; magnetic resonance imaging and spectroscopy; lumbar puncture; blood and saliva collection; and standardized self-report measures of neuropsychiatric, cognitive, and daily functioning. Study partners completed similar informant-report measures. Follow-up evaluations were intended to be in-person and at 3 years post-baseline. Multidisciplinary diagnostic consensus conferences are held, and the reliability and validity of TES diagnostic criteria are examined. RESULTS:Participant enrollment and all baseline evaluations were completed in February 2020. Three-year follow-up evaluations began in October 2019. However, in-person evaluation ceased with the COVID-19 pandemic, and resumed as remote, 4-year follow-up evaluations (including telephone-, online-, and videoconference-based cognitive, neuropsychiatric, and neurologic examinations, as well as in-home blood draw) in February 2021. CONCLUSIONS:Findings from the DIAGNOSE CTE Research Project should facilitate detection and diagnosis of CTE during life, and thereby accelerate research on risk factors, mechanisms, epidemiology, treatment, and prevention of CTE. TRIAL REGISTRATION:NCT02798185.
PMCID:8357968
PMID: 34384490
ISSN: 1758-9193
CID: 5004422

Addressing neuropsychological diagnostics in adults with epilepsy: Introducing the International Classification of Cognitive Disorders in Epilepsy: The IC CODE Initiative

Norman, Marc; Wilson, Sarah J; Baxendale, Sallie; Barr, William; Block, Cady; Busch, Robyn M; Fernandez, Alberto; Hessen, Erik; Loring, David W; McDonald, Carrie R; Hermann, Bruce P
This paper addresses the absence of an international diagnostic taxonomy for cognitive disorders in patients with epilepsy. Initiated through the 2020 Memorandum of Understanding between the International League Against Epilepsy and the International Neuropsychological Society, neuropsychological representatives from both organizations met to address the problem and consequences of the absence of an international diagnostic taxonomy for cognitive disorders in epilepsy, overview potential solutions, and propose specific solutions going forward. The group concluded that a classification of cognitive disorders in epilepsy, including an overall taxonomy and associated operational criteria, was clearly lacking and sorely needed. This paper reviews the advantages and shortcomings of four existing cognitive diagnostic approaches, including taxonomies derived from the US National Neuropsychology Network, DSM-V Neurocognitive Disorders, the Mild Cognitive Impairment classification from the aging/preclinical dementia literature, and the Research Domain Criteria Initiative. We propose a framework to develop a consensus-based classification system for cognitive disorders in epilepsy that will be international in scope and be applicable for clinical practice and research globally and introduce the International Classification of Cognitive Disorders in Epilepsy (IC-CODE) project.
PMCID:8166800
PMID: 34033259
ISSN: 2470-9239
CID: 4907072

The Utility of the Repeatable Battery of Neuropsychological Status in Patients with Temporal and Non-temporal Lobe Epilepsy

Maiman, Moshe; Del Bene, Victor A; Farrell, Eileen; MacAllister, William S; Sheldon, Sloane; Rentería, Miguel Arce; Slugh, Mitchell; Gazzola, Deana M; Barr, William B
OBJECTIVE:The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a brief neuropsychological battery that has been validated in the assessment of dementia and other clinical populations. The current study examines the utility of the RBANS in patients with epilepsy. METHODS:Ninety-eight patients with epilepsy completed the RBANS as part of a more comprehensive neuropsychological evaluation. Performance on the RBANS was evaluated for patients with a diagnosis of temporal lobe epilepsy (TLE; n = 51) and other epilepsy patients (non-TLE, n = 47) in comparison to published norms. Multivariate analysis of variance compared group performances on RBANS indices. Rates of impairment were also compared across groups using cutoff scores of ≤1.0 and ≤1.5 standard deviations below the normative mean. Exploratory hierarchical regressions were used to examine the relations between epilepsy severity factors (i.e., age of onset, disease duration, and number of antiepileptic drugs [AEDs]) and RBANS performance. RESULTS:TLE and non-TLE patients performed below the normative sample across all RBANS indices. Those with TLE performed worse than non-TLE patients on the Immediate and Delayed Memory indices and exhibited higher rates of general cognitive impairment. Number of AEDs was the only epilepsy severity factor that significantly predicted RBANS total performance, accounting for 14% of the variance. CONCLUSIONS:These findings suggest that the RBANS has utility in evaluating cognition in patients with epilepsy and can differentiate TLE and non-TLE patients. Additionally, number of AEDs appears to be associated with global cognitive performance in adults with epilepsy.
PMID: 31761928
ISSN: 1873-5843
CID: 4215572

Getting Physical: A Specific Boost for Cognition in Epilepsy? [Comment]

Barr, William B
PMID: 34025265
ISSN: 1535-7597
CID: 4888782

Cognitive phenotypes in temporal lobe epilepsy utilizing data- and clinically driven approaches: Moving toward a new taxonomy

Reyes, Anny; Kaestner, Erik; Ferguson, Lisa; Jones, Jana E; Seidenberg, Michael; Barr, William B; Busch, Robyn M; Hermann, Bruce P; McDonald, Carrie R
OBJECTIVE:To identify cognitive phenotypes in temporal lobe epilepsy (TLE) and test their reproducibility in a large, multi-site cohort of patients using both data-driven and clinically driven approaches. METHOD/METHODS:Four-hundred seven patients with TLE who underwent a comprehensive neuropsychological evaluation at one of four epilepsy centers were included. Scores on tests of verbal memory, naming, fluency, executive function, and psychomotor speed were converted into z-scores based on 151 healthy controls (HCs). For the data-driven method, cluster analysis (k-means) was used to determine the optimal number of clusters. For the clinically driven method, impairment was defined as >1.5 standard deviations below the mean of the HC, and patients were classified into groups based on the pattern of impairment. RESULTS:Cluster analysis revealed a three-cluster solution characterized by (a) generalized impairment (29%), (b) language and memory impairment (28%), and (c) no impairment (43%). Based on the clinical criteria, the same broad categories were identified, but with a different distribution: (a) generalized impairment (37%), (b) language and memory impairment (30%), and (c) no impairment (33%). There was a 82.6% concordance rate with good agreement (κ = .716) between the methods. Forty-eight patients classified as having a normal profile based on cluster analysis were classified as having generalized impairment (n = 16) or an isolated language/memory impairment (n = 32) based on the clinical criteria. Patients with generalized impairment had a longer disease duration and patients with no impairment had more years of education. However, patients demonstrating the classic TLE profile (ie, language and memory impairment) were not more likely to have an earlier age at onset or mesial temporal sclerosis. SIGNIFICANCE/CONCLUSIONS:We validate previous findings from single-site studies that have identified three unique cognitive phenotypes in TLE and offer a means of translating the patterns into a clinical diagnostic criteria, representing a novel taxonomy of neuropsychological status in TLE.
PMID: 32363598
ISSN: 1528-1167
CID: 4437072

Counterpoint: Links between traumatic brain injury and dementia remain poorly defined

Barr, William B
There has been considerable public interest in the topic of traumatic brain injury (TBI) as a risk factor for development of late-life dementia. A review was performed on empirical studies examining the relationship between these two conditions. Although results from a number of studies clearly demonstrate that TBI is a positive risk factor for developing dementia, there are an equivalent number of studies that obtain inconclusive or negative findings. Inconsistencies across studies are often the result of methodological findings including the nature of the investigational design, choice of comparison groups, and criteria used to define cases. In many studies, the diagnosis of TBI is obtained retrospectively in a manner that is subject to bias. Accurate identification of dementia cases is often compromised by the use of inappropriately brief follow-up periods and variations in diagnostic methods. There remains no universally accepted neurobiological mechanism to explain the transition from acute TBI to the chronic effects of dementia. Studies of specialty populations, including athletes and military personnel are beset by secular and cohort effects, raising questions about the applicability of findings to the general population. No existing studies have been able to exclude the possible effects of confounding medical or lifestyle factors in facilitating the onset of dementia following TBI. Although the research findings suggest a general association between TBI and dementia, the specifics of the relationship remain poorly defined.
PMID: 32008038
ISSN: 1873-5843
CID: 4301162

Ten things every neurologist needs to know about neuropsychological assessments and interventions in people with epilepsy

Baxendale, Sallie A; Wilson, Sarah J; Baker, Gus A; Barr, William; Helmstaedter, Christoph; Hermann, Bruce P; Langfitt, John; Reuner, Gitta; Rzezak, Patricia; Samson, Séverine; Smith, Mary-Lou
This paper describes ten core features of a neuropsychological assessment with the aim of helping neurologists understand the unique contribution the evaluation can make within the wider context of diagnostic methods in epilepsy. The possibilities, limitations and cautions associated with the investigation are discussed under the headings below: 1. A neuropsychological assessment is a collaborative investigation. 2. Assessment prior to treatment allows for the accurate assessment of treatment effects. 3. The nature of an underlying lesion and its neurodevelopmental context play an important role in shaping the associated neuropsychological deficit. 4. Cognitive and behavioural impairments result from the essential comorbidities of epilepsy which can be considered as much a disorder of cognition and behaviour as of seizures. 5. Patient's subjective complaints can help us understand objective cognitive impairments and their underlying neuroanatomy, resulting in improved patient care. At other times, patient complaints reflect other factors and require careful interpretation. 6. The results from a neuropsychological assessment can be used to maximise the educational and occupational potentials of people with epilepsy. 7. Not all patients are able to engage with a neuropsychological assessment. 8. There are limitations in assessments conducted in a second language with tests that have been standardized on different populations to that of the patient. 9. Adequate intervals between assessments maximise sensitivity to meaningful change. 10. Patients should be fully informed about the purpose of the assessment and have realistic expectations of the outcome prior to referral.
PMID: 31610070
ISSN: 1468-1331
CID: 4140272

Believers versus deniers: The radicalization of sports concussion and chronic traumatic encephalopathy (CTE) science.

Barr, William B.
Unprecedented media coverage of concussion in sport has led to increased fears regarding the potential negative effects of participation in contact sports including North American football and ice hockey. Initial responses of professional sports leagues to implementation of acute concussion management practices and reports of a neurodegenerative condition known as chronic traumatic encephalopathy (CTE) developing in retired players caused an atmosphere of distrust whereby the leagues were accused of maintaining cover-ups analogous to what had been seen in association with studies of tobacco and smoking. This article reviews the important role that psychology has played in the study of sports concussion and in the establishment of methods currently used to diagnose and track concussion symptoms. Results of existing studies have shown that the neurobiological effects of concussion are rather short-lived with development of persisting symptoms in some individuals associated more with psychosocial factors than underlying physiological effects. With regard to CTE, the status of the science remains preliminary with little definitive information known about its epidemiology or cause. In the midst of the ongoing controversy, a polarized climate has developed in association with concussion and CTE, divided by believers in the dangers of long-term consequences and deniers who question the status of the existing science. The conclusion is that it is important for psychology to extend its scope of study to provide increased understanding of the social factors underlying the current polarized climate while continuing to provide the public with an accurate and reliable account of the existing science. (PsycInfo Database Record (c) 2020 APA, all rights reserved)Public Significance Statement"”Continued media reporting of the sports concussion and its potential long-term effects has been accompanied by public concerns about the safety of contact sports and potential development of chronic traumatic encephalopathy (CTE). Controversies have emerged about the status of the science, creating polarization on the topic. Psychology has provided significant contributions to our scientific knowledge on sports concussion and has the potential to provide a key to understanding the factors underlying division on these topics. (PsycInfo Database Record (c) 2020 APA, all rights reserved)Une couverture médiatique sans précédent des commotions cérébrales dans le sport a entraîné une augmentation des craintes quant aux effets négatifs potentiels de la participation aux sports de contact, notamment au football et au hockey sur glace en Amérique du Nord. Les premières réponses des ligues sportives professionnelles à la mise en Å“uvre de pratiques de gestion des commotions aiguës et les déclarations de maladie neurodégénérative connue sous le nom d"™encéphalopathie traumatique chronique (CTE) en développement chez les joueurs retraités ont provoqué une atmosphère de méfiance où les ligues ont été accusées de dissimulations de manière similaire à ce qui avait été observé avec les études sur le tabac et le tabagisme. Le présent article examine le rôle important que la psychologie a joué dans l"™Ã©tude des commotions liées au sport et dans l"™Ã©tablissement de méthodes actuellement utilisées pour diagnostiquer et surveiller les symptômes de commotion cérébrale. Les résultats des études existantes ont montré que les effets neurobiologiques de commotion cérébrale sont plutôt de courte durée avec l"™apparition de symptômes persistants, chez certaines personnes, plutôt associés à des facteurs psychosociaux qu"™aux effets physiologiques sous-jacents. En ce qui concerne la CTE, le statut de la science reste préliminaire, avec peu de renseignements définitifs connus sur son épidémiologie ou sa cause. Au cÅ“ur de la controverse actuelle, un climat polarisé s"™est développé en lien avec la commotion cérébrale et la CTE, divisé par les croyants aux dangers des conséquences à long terme et les négateurs qui remettent en question le statut de la science existante. En conclusion, il est important pour la psychologie d"™Ã©tendre sa portée d"™Ã©tude afin de mieux comprendre les facteurs sociaux sous-jacents au climat polarisé actuel tout en continuant à fournir au public un compte rendu exact et fiable de la science existante. (PsycInfo Database Record (c) 2020 APA, all rights reserved)
SCOPUS:85103483814
ISSN: 0708-5591
CID: 4860412

Memory Decline Following Epilepsy Surgery: Can We Predict Who Will Pay the Price?

Barr, William B
[Box: see text].
PMCID:7020522
PMID: 31876174
ISSN: 1535-7597
CID: 4627432

Challenges in the neuropsychological assessment of ethnic minorities

Chapter by: Rabin, Laura A; Brodale, Donald L; Elbulok-Charcape, Milushka M; Barr, William B
in: Clinical cultural neuroscience: An integrative approach to cross-cultural neuropsychology by Pedraza, Otto [Ed]
New York, NY, US: Oxford University Press, 2020
pp. 55-80
ISBN: 9780190619305
CID: 4374302