NEWS FROM THE WORLD- Research Gaps and Controversies in Chronic Traumatic Encephalopathy A Review

Abstract

Importance  Scientific and lay interest in negative outcomes associated with exposure to repetitive brain trauma (RBT) continues to strengthen. Concerns about the association between RBT and dementia began more than a century ago, but have resurfaced in the last decade with the more recently described chronic traumatic encephalopathy (CTE). Chronic traumatic encephalopathy is a tauopathy associated with RBT that has become inextricably linked to conversations about sport-related concussion and mild traumatic brain injury. Accordingly, specific populations such as collision sport athletes and certain military personnel are of particular interest owing to their unique exposure to RBT. The gaps and controversies in our understanding of the epidemiologic factors, mechanism, and clinicopathological correlates of CTE reflect the current reliance on postmortem case series investigations. This review discusses the state of the science of CTE and raises considerations for researching and interpreting cognitive changes in members of at-risk populations.

Observations  The recent development of pathological diagnostic criteria for CTE represented an important step for differentiating CTE from other neurodegenerative diseases. By comparison, defining the clinical syndrome(s) associated with CTE and the necessary and sufficient symptoms needed for its diagnosis lags behind. The absence of validated in vivo biomarkers of pathological characteristics of CTE and longitudinal tracking with neuropsychological evaluation remains a significant hurdle. Attribution of candidate symptoms in retired athletes to CTE is complicated by the presence of multiple premorbid and comorbid factors affecting cognitive reserve that influence normal or expected cognitive functioning. This is a critical issue in appropriately defining reference groups for normative comparisons.

Conclusions and Relevance  Available data, while limited and complicated by selection bias, indicate that exposure to RBT represents the greatest risk factor for CTE pathological features, although clinicopathological correlates and the nature of onset and progression of symptoms are largely unknown. Considering aspects of cognitive reserve is likely essential for both interpreting cognitive outcomes associated with CTE and for developing preventive treatment programs. Research on CTE would benefit greatly from incorporating principles established within other areas of neurodegenerative disease and the nuances of clinicopathological considerations.

Jama Neurology 2017

NEWS FROM THE WORLD- Targeting Pioglitazone Hydrochloride Therapy After Stroke or Transient Ischemic Attack According to Pretreatment Risk for Stroke or Myocardial Infarction

Abstract

Importance  There is growing recognition that patients may respond differently to therapy and that the average treatment effect from a clinical trial may not apply equally to all candidates for a therapy.

Objective  To determine whether, among patients with an ischemic stroke or transient ischemic attack and insulin resistance, those at higher risk for future stroke or myocardial infarction (MI) derive more benefit from the insulin-sensitizing drug pioglitazone hydrochloride compared with patients at lower risk.

Design, Setting, and Participants  A secondary analysis was conducted of the Insulin Resistance Intervention After Stroke trial, a double-blind, placebo-controlled trial of pioglitazone for secondary prevention. Patients were enrolled from 179 research sites in 7 countries from February 7, 2005, to January 15, 2013, and were followed up for a mean of 4.1 years through the study’s end on July 28, 2015. Eligible participants had a qualifying ischemic stroke or transient ischemic attack within 180 days of entry and insulin resistance without type 1 or type 2 diabetes.

Interventions  Pioglitazone or matching placebo.

Main Outcomes and Measures  A Cox proportional hazards regression model was created using baseline features to stratify patients above or below the median risk for stroke or MI within 5 years. Within each stratum, the efficacy of pioglitazone for preventing stroke or MI was calculated. Safety outcomes were death, heart failure, weight gain, and bone fracture.

Results  Among 3876 participants (1338 women and 2538 men; mean [SD] age, 63 [11] years), the 5-year risk for stroke or MI was 6.0% in the pioglitazone group among patients at lower baseline risk compared with 7.9% in the placebo group (absolute risk difference, –1.9% [95% CI, –4.4% to 0.6%]). Among patients at higher risk, the risk was 14.7% in the pioglitazone group vs 19.6% for placebo (absolute risk difference, –4.9% [95% CI, –8.6% to 1.2%]). Hazard ratios were similar for patients below or above the median risk (0.77 vs 0.75; P = .92). Pioglitazone increased weight less among patients at higher risk but increased the risk for fracture more.

Conclusions and Relevance  After an ischemic stroke or transient ischemic attack, patients at higher risk for stroke or MI derive a greater absolute benefit from pioglitazone compared with patients at lower risk. However, the risk for fracture is also higher.

JAMA Neurology 2017

NEWS FROM THE WORLD- Survival End Points for Huntington Disease Trials Prior to a Motor Diagnosis

Abstract

Importance  Predictive genetic testing in Huntington disease (HD) enables therapeutic trials in HTTgene expansion mutation carriers prior to a motor diagnosis. Progression-free survival (PFS) is the composite of a motor diagnosis or a progression event, whichever comes first.

Objective  To determine if PFS provides feasible sample sizes for trials with mutation carriers who have not yet received a motor diagnosis.

Design, Setting, and Participants  This study uses data from the 2-phase, longitudinal cohort studies called Track and from a longitudinal cohort study called the Cooperative Huntington Observational Research Trial (COHORT). Track had 167 prediagnosis mutation carriers and 156 noncarriers, whereas COHORT had 366 prediagnosis mutation carriers and noncarriers. Track studies were conducted at 4 sites in 4 countries (Canada, France, England, and the Netherlands) from which data were collected from January 17, 2008, through November 17, 2014. The COHORT was conducted at 38 sites in 3 countries (Australia, Canada, and the United States) from which data were collected from February 14, 2006, through December 31, 2009. Results from the Track data were externally validated with data from the COHORT. The required sample size was estimated for a 2-arm prediagnosis clinical trial. Data analysis took place from May 1, 2016, to June 10, 2017.

Main Outcomes and Measures  The primary end point is PFS. Huntington disease progression events are defined for the Unified Huntington's Disease Rating Scale total motor score, total functional capacity, symbol digit modalities test, and Stroop word test.

Results  Of Track’s 167 prediagnosis mutation carriers, 93 (55.6%) were women, and the mean (SD) age was 40.06 (8.92) years; of the 156 noncarriers, 87 (55.7%) were women, and the mean (SD) age was 45.58 (10.30) years. Of the 366 COHORT participants, 229 (62.5%) were women and the mean (SD) age was 42.21 (12.48) years. The PFS curves of the Track mutation carriers showed good external validity with the COHORT mutation carriers after adjusting for initial progression. For required sample size, PFS with a motor diagnosis or total motor score progression required about 4 times fewer participants than a motor diagnosis alone. Including additional cognitive progression events further reduced the number. For example, a 3-year trial with 10% attrition and a treatment effect of 50% requires a total of 661 with motor diagnosis as the survival end point but only 177 with a total motor score PFS.

Conclusions and Relevance  Reasonably sized prediagnosis Huntington disease trials can be planned with PFS, and there is evidence of generalizability of this approach.

Jama Neurology 2017

NEWS FROM THE WORLD- Global, regional, and national burden of neurological disorders during 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015

Background

Comparable data on the global and country-specific burden of neurological disorders and their trends are crucial for health-care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study provides such information but does not routinely aggregate results that are of interest to clinicians specialising in neurological conditions. In this systematic analysis, we quantified the global disease burden due to neurological disorders in 2015 and its relationship with country development level.

Methods

We estimated global and country-specific prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) for various neurological disorders that in the GBD classification have been previously spread across multiple disease groupings. The more inclusive grouping of neurological disorders included stroke, meningitis, encephalitis, tetanus, Alzheimer's disease and other dementias, Parkinson's disease, epilepsy, multiple sclerosis, motor neuron disease, migraine, tension-type headache, medication overuse headache, brain and nervous system cancers, and a residual category of other neurological disorders. We also analysed results based on the Socio-demographic Index (SDI), a compound measure of income per capita, education, and fertility, to identify patterns associated with development and how countries fare against expected outcomes relative to their level of development.

Findings

Neurological disorders ranked as the leading cause group of DALYs in 2015 (250·7 [95% uncertainty interval (UI) 229·1 to 274·7] million, comprising 10·2% of global DALYs) and the second-leading cause group of deaths (9·4 [9·1 to 9·7] million], comprising 16·8% of global deaths). The most prevalent neurological disorders were tension-type headache (1505·9 [UI 1337·3 to 1681·6 million cases]), migraine (958·8 [872·1 to 1055·6] million), medication overuse headache (58·5 [50·8 to 67·4 million]), and Alzheimer's disease and other dementias (46·0 [40·2 to 52·7 million]). Between 1990 and 2015, the number of deaths from neurological disorders increased by 36·7%, and the number of DALYs by 7·4%. These increases occurred despite decreases in age-standardised rates of death and DALYs of 26·1% and 29·7%, respectively; stroke and communicable neurological disorders were responsible for most of these decreases. Communicable neurological disorders were the largest cause of DALYs in countries with low SDI. Stroke rates were highest at middle levels of SDI and lowest at the highest SDI. Most of the changes in DALY rates of neurological disorders with development were driven by changes in YLLs.

Interpretation

Neurological disorders are an important cause of disability and death worldwide. Globally, the burden of neurological disorders has increased substantially over the past 25 years because of expanding population numbers and ageing, despite substantial decreases in mortality rates from stroke and communicable neurological disorders. The number of patients who will need care by clinicians with expertise in neurological conditions will continue to grow in coming decades. Policy makers and health-care providers should be aware of these trends to provide adequate services.

Lancet Neurology 2017

NEWS FROM THE WORLD- Qualitative study of burnout, career satisfaction, and well-being among US neurologists in 2016

ABSTRACT

Objective: To understand the experience and identify drivers and mitigating factors of burnout and well-being among US neurologists.

Methods: Inductive data analysis was applied to free text comments (n = 676) from the 2016 American Academy of Neurology survey of burnout, career satisfaction, and well-being.

Results: Respondents providing comments were significantly more likely to be older, owners/partners of their practice, solo practitioners, and compensated by production than those not commenting. The 4 identified themes were (1) policies and people affecting neurologists (government and insurance mandates, remuneration, recertification, leadership); (2) workload and work–life balance (workload, electronic health record [EHR], work–life balance); (3) engagement, professionalism, work domains specific to neurology; and (4) solutions (systemic and individual), advocacy, other. Neurologists mentioned workload > professional identity > time spent on insurance and government mandates when describing burnout. Neurologists' patient and clerical workload increased work hours or work brought home, resulting in poor work–life balance. EHR and expectations of high patient volumes by administrators impeded quality of patient care. As a result, many neurologists reduced work hours and call provision and considered early retirement.

Conclusions: Our results further characterize burnout among US neurologists through respondents' own voices. They clarify the meaning respondents attributed to ambiguous survey questions and highlight the barriers neurologists must overcome to practice their chosen specialty, including multiple regulatory hassles and increased work hours. Erosion of professionalism by external factors was a common issue. Our findings can provide strategic direction for advocacy and programs to prevent and mitigate neurologist burnout and promote well-being and engagement.

Neurology 2017

NEWS FROM THE WORLD-Neurogranin, a synaptic protein, is associated with memory independent of Alzheimer biomarkers

ABSTRACT

Objective: To determine the association between synaptic functioning as measured via neurogranin in CSF and cognition relative to established Alzheimer disease (AD) biomarkers in neurologically healthy older adults.

Methods: We analyzed CSF concentrations of neurogranin, β-amyloid (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau) among 132 neurologically normal older adults (mean 64.5, range 55–85), along with bilateral hippocampal volumes and a measure of episodic memory (Auditory Verbal Learning Test, delayed recall). Univariable analyses examined the relationship between neurogranin and the other AD-related biomarkers. Multivariable regression models examined the relationship between neurogranin and delayed recall, adjusting for age and sex, and interaction terms (neurogranin × AD biomarkers).

Results: Higher neurogranin concentrations were associated with older age (ρ = 0.20, p = 0.02), lower levels of p-tau and t-tau, and smaller hippocampal volumes (p < 0.03), but not with CSF Aβ42 (p = 0.18). In addition, CSF neurogranin demonstrated a significant relationship with memory performance independent of the AD-related biomarkers; individuals with the lowest CSF neurogranin concentrations performed better on delayed recall than those with medium or high CSF neurogranin concentrations (p < 0.01). Notably, CSF p-tau, t-tau, and Aβ42 and hippocampal volumes were not significantly associated with delayed recall scores (p > 0.40), and did not interact with neurogranin to predict memory (p > 0.10).

Conclusions: Synaptic dysfunction (assessed via neurogranin) may be an early pathologic process in age-related neurodegeneration, and a sensitive marker of age-related cognitive abilities, potentially preceding or even acting independently from AD pathogenesis. Synaptic functioning may be a useful early marker of cognitive aging and possibly a target for future brain aging interventions.

Neurology 2017

NEWS FROM THE WORLD-Randomized open-label trial of dextromethorphan in Rett syndrome

ABSTRACT

Objective: To determine safety and perform a preliminary assessment of dose-dependent efficacy of dextromethorphan in normalizing electrographic spikes, clinical seizures, and behavioral and cognitive functions in girls with Rett syndrome.

Methods: We used a prospective randomized, open-label trial in fast metabolizers of dextromethorphan to examine the effect of dextromethorphan on core clinical features of Rett syndrome. Interictal spike activity and clinical seizures were determined using EEG and parent reporting. Cognitive data were obtained using the Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales, while behavioral data were obtained from parent-completed checklists, the Aberrant Behavior Checklist–Community Version, and the Screen for Social Interaction. Anthropometric data were obtained according to the National Health and Nutrition Examination Survey. The Rett Syndrome Severity Scale provided a clinical global impression of the effect of dextromethorphan on clinical severity.

Results: Dextromethorphan is safe for use in 3- to 15-year-old girls with Rett syndrome. Thirty-five girls were treated with 1 of 3 doses of dextromethorphan over a period of 6 months. Statistically significant dose-dependent improvements were seen in clinical seizures, receptive language, and behavioral hyperactivity. There was no significant improvement in global clinical severity as measured by the Rett Syndrome Severity Scale.

Conclusions: Dextromethorphan is a potent noncompetitive antagonist of the NMDA receptor channel that is safe for use in young girls with Rett syndrome. Preliminary evidence suggests that dextromethorphan may improve some core features of Rett syndrome.

Classification of evidence: This study provides Class IV evidence that dextromethorphan at various doses does not change EEG spike counts over 6 months, though precision was limited to exclude an important effect.

Neurology 2017