Faculty Bibliography

OBJECTIVE:To investigate the efficacy and safety of aceneuramic acid extended-release (Ace-ER), a treatment intended to replace deficient sialic acid, in patients with GNE myopathy. METHODS:UX001-CL301 was a phase 3, double-blind, placebo-controlled, randomized, international study evaluating the efficacy and safety of Ace-ER in patients with GNE myopathy. Participants who could walk ≥200 meters in a 6-minute walk test at screening were randomized 1:1, and stratified by sex, to receive Ace-ER 6 g/d or placebo for 48 weeks and assessed every 8 weeks. The primary endpoint was change in muscle strength over 48 weeks measured by upper extremity composite (UEC) score. Key secondary endpoints included change in lower extremity composite (LEC) score, knee extensor strength, and GNE myopathy-Functional Activity Scale (GNEM-FAS) mobility domain score. Safety assessments included adverse events (AEs), vital signs, and clinical laboratory results. RESULTS:= 0.5387). At week 48, there was no significant difference between treatments for the change in key secondary endpoints: LEC LSM difference (CI) -1.49 (-5.83 to 2.86); knee extension strength -0.40 (-2.38 to 1.58); and GNEM-FAS mobility domain score -0.72 (-2.01 to 0.57). Gastrointestinal events were the most common AEs. CONCLUSIONS:Ace-ER was not superior to placebo in improving muscle strength and function in patients with GNE myopathy. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class I evidence that for patients with GNE myopathy, Ace-ER does not improve muscle strength compared to placebo.

OBJECTIVE:To test the hypothesis that in patients with spontaneous intracerebral hemorrhage (ICH), perihemorrhagic edema to hematoma ratio (rPHE) on admission CT scan (aCT) is unaffected by home statin use when time from symptom onset to aCT is controlled for. METHODS:In a single-center prospective cohort of 176 consecutive ICH patients, 2 investigators independently determined hematoma and perihemorrhagic edema (PHE) volumes by using semiautomated validated software. rPHE were dichotomized at the median ratio (>0.75 vs ≤0.75). We used binary logistic regression to test for associations with rPHE. RESULTS:= 0.68) associated with rPHE. CONCLUSION/CONCLUSIONS:Use of statins before hospital admission for ICH is not associated with reduced rPHE on admission CT. In future studies, imaging timing relative to ICH onset needs to be controlled for in order to avoid confounding.

Phosphatidylinositol 3-kinase signaling promotes cell growth and survival and is frequently activated in infiltrative gliomas. Activating mutations in PIK3CA gene are observed in 6-15% of glioblastomas, although their clinical significance is largely undescribed. The objective of this study was to examine whether PIK3CA mutations are associated with a specific clinical phenotype in glioblastoma. We retrospectively reviewed 157 consecutive newly diagnosed glioblastoma patients from December 2009 to June 2012 who underwent molecular profiling consisting of targeted hotspot genotyping, fluorescence in situ hybridization for gene amplification, and methylation-specific PCR for O⁶-methylguanine-DNA methyltransferase promoter methylation. Molecular alterations were correlated with clinical features, imaging and outcome. The Cancer Genome Atlas data was analyzed as a validation set. There were 91 males; median age was 58 years (range, 23-85). With a median follow-up of 20.9 months, median progression-free survival (PFS) and estimated overall survival (OS) were 11.9 and 24.0 months, respectively. Thirteen patients (8.3%) harbored PIK3CA mutation, which was associated with younger age (mean 49.4 vs. 58.1 years, p = 0.02). PIK3CA mutation correlated with shorter PFS (median 6.9 vs. 12.4 months, p = 0.01) and OS (median 21.2 vs. 24.2 months, p = 0.049) in multivariate analysis. A significant association between PIK3CA mutation and more disseminated disease at diagnosis, as defined by gliomatosis, multicentric lesions, or distant leptomeningeal lesions, was observed (46.2% vs. 11.1%, p = 0.004). In conclusion, despite the association with younger age, PIK3CA activating mutations are associated with earlier recurrence and shorter survival in adult glioblastoma. The aggressive course of these tumors may be related to their propensity for disseminated presentation.

OBJECTIVE:The Mobile Universal Lexicon Evaluation System (MULES) is a test of rapid picture naming under investigation. Measures of rapid automatic naming (RAN) have been used for over 50 years to capture aspects of vision and cognition. MULES was designed as a series of 54 grouped color photographs (fruits, random objects, animals) that integrates saccades, color perception and contextual object identification. We examined MULES performance in youth, collegiate and professional athletes at pre-season baseline and at the sidelines following concussion. METHODS:Our study teams administered the MULES to youth, collegiate and professional athletes during pre-season baseline testing. Sideline post-concussion time scores were compared to pre-season baseline scores among athletes with concussion to determine degrees and directions of change. RESULTS:Among 681 athletes (age 17 ± 4 years, range 6-37, 38% female), average test times at baseline were 41.2 ± 11.2 s. The group included 280 youth, 357 collegiate and 44 professional athletes; the most common sports were ice hockey (23%), soccer (17%) and football (11%). Age was a predictor of MULES test times, with longer times noted for younger participants (P < .001, linear regression). Consistent with other timed performance measures, significant learning effects were noted for the MULES during baseline testing with trial 1 test times (mean 49.2 ± 13.1 s) exceeding those for trial 2 (mean 41.3 ± 11.2 s, P < .0001, paired t-test). Among 17 athletes with concussion during the sports seasons captured to date (age 18 ± 3 years), all showed increases (worsening) of MULES time scores from pre-season baseline (median increase 11.2 s, range 0.6-164.2, P = .0003, Wilcoxon signed-rank test). The Symptom Severity Score from the SCAT5 Symptom Evaluation likewise worsened from pre-season baseline following injury among participants with concussion (P = .002). CONCLUSIONS:Concussed athletes demonstrate worsening performance on the MULES test compared to their baseline time scores. This test samples a wide network of brain pathways and complements other vision-based measures for sideline concussion assessment. The MULES test demonstrates capacity to identify athletes with sports-related concussion.

OBJECTIVES/OBJECTIVE:To identify factors associated with medical students becoming neurologists because, despite the increasing burden of neurologic disorders, there is a growing neurologist shortage. METHODS:Deidentified data from the Association of American Medical Colleges Matriculating Student Questionnaire (MSQ) and Graduation Questionnaire (GQ) were obtained for the graduation years 2013 to 2014 through 2016 to 2017. Logistic regression was used to assess demographic characteristics and responses to training and career-related questions in association with specialty choice (intent to enter neurology). RESULTS:Of the 51,816 students with complete data, 1,456 (2.8%) indicated an intent to enter a neurology residency. Factors associated with an increased likelihood of entering neurology were a student's rating of excellent for their basic neuroscience course and neurology clerkship, participation in an MD/PhD program, majoring in neuroscience or psychology as an undergraduate, a selection response of "content of the specialty was a strong influence on career choice," and indicating interest in neurology on the MSQ. Factors associated with a decreased likelihood of entering neurology were a higher-priority response on the GQ for salary, work/life balance, and personal fit of the specialty. CONCLUSION/CONCLUSIONS:Data from surveys at the entry into and graduation from medical school suggest several approaches to increase the number of medical students entering neurology, including a focus on the student-reported quality of the basic neuroscience course and neurology clerkships, targeted engagement with MD/PhD students, and mentoring programs for students interested in neurology. Efforts to improve salaries for neurologists, to reduce medical school debt, and to improve work/life balance may also help to attract more students.

We examined whether time to onset of paresthesia was associated with indicators of severity of World Trade Center (WTC) exposure. We analyzed data from 3411 patients from the Bellevue Hospital-WTC Environmental Health Center. Paresthesia was defined as present if the symptom occurred in the lower extremities with frequency "often" or "almost continuous." We plotted hazard functions and used the log-rank test to compare time to onset of paresthesia between different exposure groups. We also used Cox regression analysis to examine risk factors for time-to-paresthesia after 9/11/2001 and calculate hazard ratios adjusted for potential confounders. We found significantly elevated hazard ratios for paresthesia for (a) working in a job that required cleaning of WTC dust in the workplace; and (b) being heavily exposed to WTC dust on September 11, 2001, after adjusting for age, race/ethnicity, depression, anxiety, post-traumatic stress disorder, and body mass index. These observational data are consistent with the hypothesis that exposure to WTC dust or some other aspect of cleaning WTC dust in the workplace, is associated with neuropathy and paresthesia. Further neurological evaluations of this and other WTC-exposed populations is warranted.

Parkinson's disease (PD) is the second most common degenerative disorder. Although the disease was described more than 200 years ago, its pathogenetic mechanisms have not yet been fully described. In recent years, the discovery of the association between mutations of the GBA gene (encoding for the lysosomal enzyme glucocerebrosidase) and PD facilitated a better understating of this disorder. GBA mutations are the most common genetic risk factor of the disease. However, mutations of this gene can be found in different phenotypes, such as Gaucher's disease (GD), PD, dementia with Lewy bodies (DLB) and rapid eye movements (REM) sleep behavior disorders (RBDs). Understanding the pathogenic role of this mutation and its different manifestations is crucial for geneticists and scientists to guide their research and to select proper cohorts of patients. Moreover, knowing the implications of the GBA mutation in the context of PD and the other associated phenotypes is also important for clinicians to properly counsel their patients and to implement their care. With the present review we aim to describe the genetic, clinical, and therapeutic features related to the mutation of the GBA gene.

BACKGROUND:Damage to the cerebellum can affect neural structures involved in locomotion, causing gait and balance disorders. However, the integrity of cerebellum does not seem to be critical in managing sudden and unexpected environmental changes such as disturbances during walking. The cerebellum also plays a functional role in motor learning. Only a few effective therapies exist for individuals with cerebellar ataxia. With these in mind, we aimed at investigating: (1) corrective response of participants with cerebellar ataxia (CA) to unexpected gait perturbations; and (2) the effectiveness of a perturbation-based training to improve their dynamic stability during balance recovery responses and steady walking. Specifically, we hypothesized that: (1) CA group can show a corrective behavior similar to that of a healthy control group; (2) the exposure to a perturbation-based treatment can exploit residual learning capability, thus improving their dynamic stability during balance recovery responses and steady locomotion. METHODS:Ten participants with cerebellar ataxia and eight age-matched healthy adults were exposed to a single perturbation-based training session. The Active Tethered Pelvic Assist Device applied unexpected waist-pull perturbations while participants walked on a treadmill. Spatio-temporal parameters and dynamic stability were determined during corrective responses and steady locomotion, before and after the training. The ANalysis Of VAriance was the main statistical test used to assess the effects of group (healthy vs CA) and training (baseline vs post) on spatio-temporal parameters of the gait and margin of stability. RESULTS:Data analysis revealed that individuals with cerebellar ataxia behaved differently from healthy volunteers: (1) they retained a wider base of support during corrective responses and steady gait both before and after the training; (2) due to the training, patients improved their anterior-posterior margin of stability during steady walking only. CONCLUSIONS:Our results revealed that participants with cerebellar ataxia could still rely on their learning capability to modify the gait towards a safer behavior. However, they could not take advantage from their residual learning capability while managing sudden and unexpected perturbations. Accordingly, the proposed training paradigm can be considered as a promising approach to improve balance control during steady walking in these individuals.

Rett syndrome (RTT), a rare neurodevelopmental disorder caused by mutations in the MECP2 gene, is typified by profound cognitive impairment and severe language impairment, rendering it very difficult to accurately measure auditory processing capabilities behaviorally in this population. Here we leverage the mismatch negativity (MMN) component of the event-related potential to measure the ability of RTT patients to decode and store occasional duration deviations in a stream of auditory stimuli. Sensory memory for duration, crucial for speech comprehension, has not been studied in RTT.High-density electroencephalography was successfully recorded in 18 females with RTT and 27 age-matched typically developing (TD) controls (aged 6-22 years). Data from seven RTT and three TD participants were excluded for excessive noise. Stimuli were 1 kHz tones with a standard duration of 100 ms and deviant duration of 180 ms. To assess the sustainability of sensory memory, stimulus presentation rate was varied with stimulus onset asynchronies (SOAs) of 450, 900, and 1800 ms. MMNs with maximum negativity over fronto-central scalp and a latency of 220-230 ms were clearly evident for each presentation rate in the TD group, but only for the shortest SOA in the RTT group. Repeated-measures ANOVA revealed a significant group by SOA interaction. MMN amplitude correlated with age in the TD group only. MMN amplitude was not correlated with the Rett Syndrome Severity Scale. This study indicates that while RTT patients can decode deviations in auditory duration, the span of this sensory memory system is severely foreshortened, with likely implications for speech decoding abilities.