National Institute of Neurological Disorders and Stroke Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome.

OBJECTIVE: To develop evidence-informed, expert consensus research diagnostic criteria for traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic traumatic encephalopathy (CTE). METHODS: A panel of 20 expert clinician-scientists in neurology, neuropsychology, psychiatry, neurosurgery, and physical medicine and rehabilitation, from 11 academic institutions, participated in a modified Delphi procedure to achieve consensus, initiated at the First National Institute of Neurological Disorders and Stroke Consensus Workshop to Define the Diagnostic Criteria for TES, April, 2019. Before consensus, panelists reviewed evidence from all published cases of CTE with neuropathologic confirmation, and they examined the predictive validity data on clinical features in relation to CTE pathology from a large clinicopathologic study (n = 298). RESULTS: Consensus was achieved in 4 rounds of the Delphi procedure. Diagnosis of TES requires (1) substantial exposure to repetitive head impacts (RHIs) from contact sports, military service, or other causes; (2) core clinical features of cognitive impairment (in episodic memory and/or executive functioning) and/or neurobehavioral dysregulation; (3) a progressive course; and (4) that the clinical features are not fully accounted for by any other neurologic, psychiatric, or medical conditions. For those meeting criteria for TES, functional dependence is graded on 5 levels, ranging from independent to severe dementia. A provisional level of certainty for CTE pathology is determined based on specific RHI exposure thresholds, core clinical features, functional status, and additional supportive features, including delayed onset, motor signs, and psychiatric features. CONCLUSIONS: New consensus diagnostic criteria for TES were developed with a primary goal of facilitating future CTE research. These criteria will be revised as updated clinical and pathologic information and in vivo biomarkers become available.

The Second NINDS/NIBIB Consensus Meeting to Define Neuropathological Criteria for the Diagnosis of Chronic Traumatic Encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder associated with exposure to head trauma. In 2015, a panel of neuropathologists funded by the NINDS/NIBIB defined preliminary consensus neuropathological criteria for CTE, including the pathognomonic lesion of CTE as "an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern," based on review of 25 tauopathy cases. In 2016, the consensus panel met again to review and refine the preliminary criteria, with consideration around the minimum threshold for diagnosis and the reproducibility of a proposed pathological staging scheme. Eight neuropathologists evaluated 27 cases of tauopathies (17 CTE cases), blinded to clinical and demographic information. Generalized estimating equation analyses showed a statistically significant association between the raters and CTE diagnosis for both the blinded (OR = 72.11, 95% CI = 19.5-267.0) and unblinded rounds (OR = 256.91, 95% CI = 63.6-1558.6). Based on the challenges in assigning CTE stage, the panel proposed a working protocol including a minimum threshold for CTE diagnosis and an algorithm for the assessment of CTE severity as "Low CTE" or "High CTE" for use in future clinical, pathological, and molecular studies.

Reducing Events of Noncompliance in Neurology Human Subjects Research: the Effect of Human Subjects Research Protection Training and Site Initiation Visits.

In an effort to minimize protocol noncompliance in neurological research studies that can potentially compromise patient safety, delay completion of the study, and result in premature termination and added costs, we determined the effect of investigator trainings and site initiation visits (SIVs) on the occurrence of noncompliance events. Results of protocol audits conducted at the National Institute of Neurological Disorders and Stroke from 2003 to 2019 on 97 research protocols were retrospectively analyzed. Based on the depth of auditing and provision of investigator research training, audit data were separated into four arms: 1) Early Period, 2003 to 2012; 2) Middle Period, 2013 to 2016; and Late Period, 2017 to 2019, further divided into 3) Late Period without SIVs; and 4) Late Period with SIVs. Events of noncompliance were classified by the type of protocol deviation, the category, and the cause. In total, 952 events occurred across 1080 participants. Protocols audited during the Middle Period, compared to the Early Period, showed a decrease in the percentage of protocols with at least 1 noncompliance event. Protocols with SIVs had a further decrease in major, minor, procedural, eligibility, and policy events. Additionally, protocols audited during the Early Period had on average 0.46 major deviations per participant, compared to 0.26 events in protocols audited during the Middle Period, and 0.08 events in protocols audited during the Late Period with SIVs. Protocol deviations and noncompliance events in neurological clinical trials can be reduced by targeted investigator trainings and SIVs. These measures have major impacts on the integrity, safety, and effectiveness of human subjects research in neurology.

Prognostic Validation of the NINDS Common Data Elements for the Radiologic Reporting of Acute Traumatic Brain Injuries: A CENTER-TBI Study.

The aim of this study is to investigate the prognostic value of using the National Institute of Neurological Disorders and Stroke (NINDS) standardized imaging-based pathoanatomic descriptors for the evaluation and reporting of acute traumatic brain injury (TBI) lesions. For a total of 3392 patients (2244 males and 1148 females, median age = 51 years) enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, we extracted 96 Common Data Elements (CDEs) from the structured reports, spanning all three levels of pathoanatomic information (i.e., 20 "basic," 60 "descriptive," and 16 "advanced" CDE variables per patient). Six-month clinical outcome scores were dichotomized into favorable (Glasgow Outcome Scale Extended [GOS-E] = 5-8) versus unfavorable (GOS-E = 1-4). Regularized logistic regression models were constructed and compared using the optimism-corrected area under the curve (AUC). An abnormality was reported for the majority of patients (64.51%). In 79.11% of those patients, there was at least one coexisting pathoanatomic lesion or associated finding. An increase in lesion severity, laterality, and volume was associated with more unfavorable outcomes. Compared with the full set of pathoanatomic descriptors (i.e., all three categories of information), reporting "basic" CDE information provides at least equal discrimination between patients with favorable versus unfavorable outcome (AUC = 0.8121 vs. 0.8155, respectively). Addition of a selected subset of "descriptive" detail to the basic CDEs could improve outcome prediction (AUC = 0.8248). Addition of "advanced" or "emerging/exploratory" information had minimal prognostic value. Our results show that the NINDS standardized-imaging based pathoanatomic descriptors can be used in large-scale studies and provide important insights into acute TBI lesion patterns. When used in clinical predictive models, they can provide excellent discrimination between patients with favorable and unfavorable 6-month outcomes. If further validated, our findings could support the development of structured and itemized templates in routine clinical radiology.

Development of Common Data Elements for Use in Chiari Malformation Type I Clinical Research: An NIH/NINDS Project.

The management of Chiari I malformation (CMI) is controversial because treatment methods vary and treatment decisions rest on incomplete understanding of its complex symptom patterns, etiologies, and natural history. Validity of studies that attempt to compare treatment of CMI has been limited because of variable terminology and methods used to describe study subjects. The goal of this project was to standardize terminology and methods by developing a comprehensive set of Common Data Elements (CDEs), data definitions, case report forms (CRFs), and outcome measure recommendations for use in CMI clinical research, as part of the CDE project at the National Institute of Neurological Disorders and Stroke (NINDS) of the US National Institutes of Health. A working group, comprising over 30 experts, developed and identified CDEs, template CRFs, data dictionaries, and guidelines to aid investigators starting and conducting CMI clinical research studies. The recommendations were compiled, internally reviewed, and posted online for external public comment. In October 2016, version 1.0 of the CMI CDE recommendations became available on the NINDS CDE website. The recommendations span these domains: Core Demographics/Epidemiology; Presentation/Symptoms; Co-Morbidities/Genetics; Imaging; Treatment; and Outcome. Widespread use of CDEs could facilitate CMI clinical research trial design, data sharing, retrospective analyses, and consistent data sharing between CMI investigators around the world. Updating of CDEs will be necessary to keep them relevant and applicable to evolving research goals for understanding CMI and its treatment.

A common data language for clinical research studies: the National Institute of Neurological Disorders and Stroke and American Academy for Cerebral Palsy and Developmental Medicine Cerebral Palsy Common Data Elements Version 1.0 recommendations.

To increase the efficiency and effectiveness of clinical research studies, cerebral palsy (CP) specific Common Data Elements (CDEs) were developed through a partnership between the National Institute of Neurological Disorders and Stroke (NINDS) and the American Academy of Cerebral Palsy and Developmental Medicine (AACPDM). International experts reviewed existing NINDS CDEs and tools used in studies of children and young people with CP. CDEs were compiled, subjected to internal review, and posted online for external public comment in September 2016. Guided by the International Classification of Functioning, Disability and Health framework, CDEs were categorized into six domains: (1) participant characteristics; (2) health, growth, and genetics; (3) neuroimaging; (4) neuromotor skills and functional assessments; (5) neurocognitive, social, and emotional assessments; and (6) engagement and quality of life. Version 1.0 of the NINDS/AACPDM CDEs for CP is publicly available on the NINDS CDE and AACPDM websites. Global use of CDEs for CP will standardize data collection, improve data quality, and facilitate comparisons across studies. Ongoing collaboration with international colleagues, industry, and people with CP and their families will provide meaningful feedback and updates as additional evidence is obtained. These CDEs are recommended for NINDS-funded research for CP. WHAT THIS PAPER ADDS: This is the first comprehensive Common Data Elements (CDEs) for children and young people with CP for clinical research. The CDEs for children and young people with CP include common definitions, the standardization of case report forms, and measures. The CDE guides the standardization for data collection and outcome evaluation in all types of studies with children and young people with CP. The CDE ultimately improves data quality and data sharing.

Common Data Elements for Concussion in Tertiary Care: Phase One in Ontario.

BACKGROUND: Standardized data collection for traumatic brain injury (TBI) (including concussion) using common data elements (CDEs) has strengthened clinical care and research capacity in the United States and Europe. Currently, Ontario healthcare providers do not collect uniform data on adult patients diagnosed with concussion. OBJECTIVE: The Ontario Concussion Care Strategy (OCCS) is a collaborative network of multidisciplinary healthcare providers, brain injury advocacy groups, patient representatives, and researchers with a shared vision to improve concussion care across the province, starting with the collection of standardized data. METHODS: The International Framework of Functioning Disability and Health was selected as the conceptual framework to inform the selection of CDEs. The CDEs recommended by the OCCS were identified using key literature, including the National Institute of Neurological Disorders and Stroke-Zurich Consensus Statements for concussion in sport and the Ontario Neurotrauma Foundation Concussion/mTBI clinical guidelines. RESULTS: The OCCS has recommended and piloted CDEs for Ontario that are readily available at no cost, clinically relevant, patient friendly, easy to interpret, and recognized by the international scientific community. CONCLUSIONS: The implementation of CDEs can help to shift Ontario toward internationally recognized standard data collection, and in so doing yield a more comprehensive evidence-based approach to care while also supporting rigorous research.

Validation of the National Institute of Neurological Disorders and Stroke Criteria for Psychosis in Parkinson Disease.

OBJECTIVES: Parkinson disease (PD) psychosis is a condition associated with several negative outcomes. Despite its impact, there is a lack of validated diagnostic tools for this condition. In this study, we aim to verify the validity of the proposed NINDS criteria for PD psychosis and explore its possible applications in clinical practice. DESIGN, SETTINGS, PARTICIPANTS: We prospectively selected 104 subjects with idiopathic PD referred to a movement disorder clinic for a cross-sectional evaluation. MEASUREMENTS: A neurological evaluation confirmed idiopathic PD and classified PD psychosis according to the NINDS criteria. A psychiatrist then classified the subject according to DSM-IV-TR criteria for psychosis, considered the reference standard. We used Cohen's kappa (κ) to quantify reliability between methods. Finally, we designed models assigning a weighted score to each characteristic psychotic symptom from the NINDS criteria (criterion A), and plotted receiver operating curves for each model. RESULTS: Of the total sample, 52 (50%) met proposed criteria for NINDS PD psychosis and 16 (15.6%) met reference standard criteria. Inter-rater reliability showed only a fair agreement (κ = 0.30). By using a scoring approach for each NINDS criteria item and a cutoff total score for the diagnosis of PD psychosis, we significantly increased the agreement for diagnosis reliability (κ = 0.72), with sensitivity of 94% and specificity of 91%. CONCLUSIONS: Although the NINDS criteria had limited reliability for diagnosing PD psychosis, a scoring approach for symptoms showed good reliability, with sensitivity and specificity above 90%. This scoring approach may be an accurate tool for identifying patients with PD psychosis.

Acute Ischemic Stroke with Very Early Clinical Improvement: A National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Trials Exploratory Analysis.

BACKGROUND: A high proportion of patients excluded from recombinant tissue plasminogen activator (rt-PA) treatment because of rapid improvement occurring before treatment decision had incomplete recovery. The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Trials dataset allows for systematic analyses of very early postrandomization improvement (VEPRIM) in stroke severity as a National Institutes of Health Stroke Scale (NIHSS) score was available for all subjects enrolled in the study at baseline (NIHSSB) and at 2 hours after randomization (NIHSS2H). We explored various definitions of VEPRIM to characterize predictive values for clinical outcomes. METHODS: Post hoc analyses of the NINDS rt-PA Stroke Trials were conducted. VEPRIM was defined as the difference between the NIHSSB and the NIHSS2H scores using 3 approaches: raw, percent, and normalized change. We assessed the association between VEPRIM and 3-month favorable outcome (mRS score of 0-1), symptomatic intracerebral hemorrhage (sICH), and death. RESULTS: In the 624 subjects, every VEPRIM definition was independently associated with an increased probability of favorable outcome: for each unit of change within the VEPRIM definitions, there were 2%-24% (all P < .05) relative increased probability of favorable outcome, 2%-15% (all P < .05) decreased likelihood of death, and 2%-13% (all P < .05) decreased likelihood of sICH. Adjusting for NIHSSB and prestroke mRS scores, there was a significant rt-PA treatment effect for improvement seen for all 3 VEPRIM definitions. CONCLUSIONS: VEPRIM predicted favorable outcomes independent of definition and treatment arm. Patients with VEPRIM by any definition, while doing better than patients without VEPRIM, also derived increased clinical benefit when treated with rt-PA compared to placebo. Even with VEPRIM, a substantial percentage of patients had unfavorable outcomes.

Agreement between TOAST and CCS ischemic stroke classification: the NINDS SiGN study.

OBJECTIVE: The objective of this study was to assess the level of agreement between stroke subtype classifications made using the Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS) systems. METHODS: Study subjects included 13,596 adult men and women accrued from 20 US and European genetic research centers participating in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN). All cases had independently classified TOAST and CCS stroke subtypes. Kappa statistics were calculated for the 5 major ischemic stroke subtypes common to both systems. RESULTS: The overall agreement between TOAST and CCS was moderate (agreement rate, 70%; κ = 0.59, 95% confidence interval [CI] 0.58-0.60). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large-artery atherosclerosis (κ = 0.71, 95% CI 0.69-0.73) and lowest for small-artery occlusion (κ = 0.56, 95% CI 0.54-0.58). CONCLUSION: Agreement between TOAST and CCS diagnoses was moderate. Caution is warranted when comparing or combining results based on the 2 systems. Replication of study results, for example, genome-wide association studies, should utilize phenotypes determined by the same classification system, ideally applied in the same manner.

Performance of the NINDS-CSN 5-minute protocol in a national population-based sample.

In 2006, the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network (NINDS-CSN) Vascular Cognitive Impairment Harmonization Standards recommended a 5-Minute Protocol as a brief screening instrument for vascular cognitive impairment (VCI). We report demographically adjusted norms for the 5-Minute Protocol and its relation to other measures of cognitive function and cerebrovascular risk factors. We performed a cross-sectional analysis of 7199 stroke-free adults in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study on the NINDS-CSN 5-Minute Protocol score. Total scores on the 5-Minute Protocol were inversely correlated with age and positively correlated with years of education, and performance on the Six-Item Screener, Word List Learning, and Animal Fluency (all p-values <.001). Higher cerebrovascular risk on the Framingham Stroke Risk Profile (FSRP) was associated with lower total 5-Minute Protocol scores (p <.001). The 5-Minute Protocol also differentiated between participants with and without confirmed stroke and with and without stroke symptom histories (p <.001). The NINDS-CSN 5-Minute Protocol is a brief, easily administered screening measure that is sensitive to cerebrovascular risk and offers a valid method of screening for cognitive impairment in populations at risk for VCI.

Regression analysis of ordinal stroke clinical trial outcomes: an application to the NINDS t-PA trial.

BACKGROUND: The modified Rankin scale (mRS) is the most common functional outcome assessed in stroke trials. The proportional odds model is commonly used to analyze this ordinal outcome but it requires a restrictive assumption that a single odds ratio applies across the entire outcome scale. AIMS: The study aims to model the effect of tissue-type plasminogen activator on ordinal mRS, test model assumptions, and compare fits and predictive ability of the statistical models. METHODS: Several ordinal regression methods are presented and applied to a re-analysis of the 1995 NINDS tissue-type plasminogen activator study. Violations of the proportional odds assumption are demonstrated using graphs and statistical tests, and the partial proportional odds model is introduced and recommended as an alternative for the analysis of mRS. RESULTS: The partial proportional odds model relaxes the assumptions about treatment effect on the ordinal outcome scale and provides a better fit to the data than the commonly used proportional odds model (likelihood ratio test chi-square = 8·05, P = 0·005). It provides easily interpretable odds ratios and it is able to detect efficacy at the lower end and a lack of efficacy at the upper end of the mRS scale. Further, it provides lower prediction error than the proportional odds model (0·002 versus 0·005). CONCLUSIONS: Assuming proportional odds when it does not hold can mask differential treatment effects at the upper end of the ordinal mRS scale and has implications for reduced power when studies are designed under this assumption.

Twenty-five years of progress: the view from NIMH and NINDS.

As directors of two NIH institutes supporting neuroscience research, we explore the gap between 25 years of stunning progress in fundamental neuroscience and the persistent needs of those with brain disorders. We conclude that closing this gap will require a more detailed comprehension of brain function, a rethinking of how we approach translational science, a focus on human neurobiology, and a continuing commitment to build a diverse, innovative neuroscience workforce. In contrast to many other areas of medicine, we lack basic knowledge about our organ of interest. The next phase of progress on brain disorders will require a significantly deeper understanding of fundamental neurobiology.

Traumatic brain injury rehabilitation: analysis of common data elements.

Physical medicine rehabilitation interventions for post-acute traumatic brain injury (TBI) are heterogeneous and subject to differences based on multi-disciplinary treatment plans [1]. There is no universal knowledge representation (KR) model for TBI rehabilitation which impedes data collection, aggregation, computation, and sharing. This paper describes results of an analysis of the National Institute for Neurological Disorders and Stroke (NINDS) TBI "Common Data Elements" (CDE) clinical data standardization set. We conducted this to understand current TBI rehabilitation KR and as a foundational step toward the creation of a domain ontology. A content coverage study was performed on the "Treatment/Intervention" sub-set of CDEs. Results show that coverage of the CDEs is broad but lacks depth to represent the context of data collection in the TBI rehabilitation process. Next steps will be development of a KR model and identification and validation of domain concepts for a foundational ontology.

Common data elements in epilepsy research: development and implementation of the NINDS epilepsy CDE project.

The Common Data Element (CDE) Project was initiated in 2006 by the National Institute of Neurological Disorders and Stroke (NINDS) to develop standards for performing funded neuroscience-related clinical research. CDEs are intended to standardize aspects of data collection; decrease study start-up time; and provide more complete, comprehensive, and equivalent data across studies within a particular disease area. Therefore, CDEs will simplify data sharing and data aggregation across NINDS-funded clinical research, and where appropriate, facilitate the development of evidenced-based guidelines and recommendations. Epilepsy-specific CDEs were established in nine content areas: (1) Antiepileptic Drugs (AEDs) and Other Antiepileptic Therapies (AETs), (2) Comorbidities, (3) Electrophysiology, (4) Imaging, (5) Neurological Exam, (6) Neuropsychology, (7) Quality of Life, (8) Seizures and Syndromes, and (9) Surgery and Pathology. CDEs were developed as a dynamic resource that will accommodate recommendations based on investigator use, new technologies, and research findings documenting emerging critical disease characteristics. The epilepsy-specific CDE initiative can be viewed as part of the larger international movement toward "harmonization" of clinical disease characterization and outcome assessment designed to promote communication and research efforts in epilepsy. It will also provide valuable guidance for CDE improvement during further development, refinement, and implementation. This article describes the NINDS CDE Initiative, the process used in developing Epilepsy CDEs, and the benefits of CDEs for the clinical investigator and NINDS.