Faculty Bibliography

Background/UNASSIGNED:Medical residents must sustain acute sleep deprivation, which can lead to nonfatal and fatal consequences in hospitals due to cognitive decline. Anodal transcranial direct current stimulation (a-tDCS) is a safe noninvasive neuromodulation technique that can induce depolarization of neurons. Previous studies in pilots have shown benefits against fatigue increasing wakefulness and cognitive performance. However, the effects of a-tDCS on cognition in acute sleep deprived healthcare workers remains unknown. Purpose/UNASSIGNED:To evaluate cognitive changes in sleep deprived medical residents after one session of a-tDCS. Methods/UNASSIGNED:Open clinical test-re-test study including 13 medical residents with acute sleep deprivation. Subjects received 1 session of bifrontal a-tDCS (2mAx20min), anodal over the left dorsolateral prefrontal region. Pre-and-post treatment subjects were tested with Beck anxiety inventory, Beck depression and HVLT tests, Rey´s and Taylor´s figures, Trail Making A/B, Stroop, Aleatory Digit retention test (WAIS), Digits and symbols and MoCA tests. Post-intervention was added the Executive functions and Frontal Lobes Neuropsychological Battery (BANFE2) test and changing the Taylor figure for Reyfigure. Results/UNASSIGNED:Twelve medical residents were analyzed; 8 men and 4 women, 29.5 (+/-2.2) years mean age. All had a mean of 21.6 (+/-1.3) hours of sleep deprivation. There were no serious adverse events. We found statistically significant difference in Rey´s/Taylor´s figures (p=0.002), Trail Making Test (p=0.005), WAIS IV symbols (p=0.003), Word Stroop (p=0.021). BANFE-2 showed that the main affected area was the orbito-medial prefrontal region. Conclusion/UNASSIGNED:a-tDCS appears safe and improves working memory, attention, response time and distractors elimination in acute sleep deprived medical residents.

The World Trade Center Environmental Health Center (WTC EHC), is a federally designated clinical center of excellence for surveillance and treatment of WTC disaster exposed community members (WTC Survivors). Cognitive impairment (CI) has been extensively described in WTC responders and a concern for progressive impairment in all WTC disaster exposed groups has been raised. Cognitive status, however, has not been systematically characterized in the WTC Survivor population. We describe cognitive status in a subgroup of the Survivor population referred for mental health evaluation (N = 480) in the WTC EHC as measured by scores on the Montreal Cognitive Assessment (MoCA) instrument, and examine their association with WTC exposures and individual-level covariates including PTSD and depression screening inventory scores. In regression analyses, probable cognitive impairment (MoCA score < 26) was found in 59% of the study subjects and was significantly associated with age, race/ethnicity, education, income, depression and PTSD scores. Being caught in the dust cloud on 11 September 2011 was significantly associated with cognitive impairment even after controlling for the above. These data suggest an association with cognitive dysfunction in WTC Survivors with exposure to the toxic dust/fumes and psychological stress from the 9/11 terrorist attack and warrant further systematic study.

OBJECTIVE:Carotid artery plaque burden, indirectly measured by the degree of stenosis, quantifies future embolic risk. In natural history studies, patients with moderate degrees of stenosis have a lower stroke risk than those with severe stenosis. However, patients with symptomatic carotid stenosis who have experienced TIA or stroke are found to have both moderate and severe degrees of stenosis. We sought to examine the association carotid artery stenosis severity with outcomes in symptomatic patients undergoing carotid interventions including carotid endarterectomy (CEA), transfemoral carotid artery stenting (CAS) and transcervical carotid artery revascularization (TCAR). METHODS:The Society for Vascular Surgery Quality Initiative database was queried for all patients undergoing CAS, CEA and TCAR between 2003 and 2020. Patients were stratified into two groups based on the severity of stenosis - non-severe (0 - 69%) and severe (≥ 70%). Primary endpoints were periprocedural neurologic events (strokes and transient ischemic attacks (TIAs)). Secondary endpoints were periprocedural death, myocardial infarction (MI) and composite outcomes of stroke/death and stroke/death/MI per reporting standards for carotid interventions. RESULTS:Of 29,614 symptomatic patients included in the analysis, 5,296 (17.9%) patients underwent TCAR, 7,844 (26.5%) underwent CAS, and 16,474 (55.6%) underwent CEA for symptomatic carotid artery stenosis. In the CEA cohort, the neurologic event rate was similarly significantly lower in patients with severe stenosis when compared to those with non-severe stenosis (2.6% vs. 3.2%, P=.024). In the TCAR cohort, the periprocedural neurologic even rate was lower in patients with severe stenosis when compared to those with non-severe stenosis (3% vs. 4.3%, P=.033). There was no similar difference noted in the CAS cohort, with periprocedural neurologic event rates of 3.8% in the severe group versus 3.5% in the non-severe group (P=.518). On multivariable analysis, severe stenosis was associated with significantly decreased odds of post procedural neurologic events in patients undergoing CEA (odds ratio [OR] 0.75, 95% confidence interval [CI], 0.6 - 0.92; P=.007) and TCAR (OR .83; CI, .69 - 0.99; P=.039), but not CAS. CONCLUSION/CONCLUSIONS:Severe carotid stenosis as opposed to more moderate degrees of stenosis was associated with decreased rates of periprocedural stroke and TIAs in symptomatic patients undergoing TCAR and CEA, but not CAS. The finding of increased rates of periprocedural neurologic events in symptomatic patients with lesser degrees of stenosis undergoing TCAR and CEA warrants further evaluation with a particular focus on plaque morphology and brain physiology, and their inherent risks with carotid revascularization procedures.

OBJECTIVE:Prolonged post-stroke cardiac rhythm monitoring (PCM) reveals a substantial proportion of ischemic stroke (IS) patients with atrial fibrillation (AF) not detected by conventional rhythm monitoring strategies. We aim to evaluate the association between PCM and the institution of stroke preventive strategies and stroke recurrence. METHODS:We searched MEDLINE and SCOPUS databases to identify studies reporting stroke recurrence rates in patients with history of recent IS or transient ischemic attack (TIA) receiving PCM compared with patients receiving conventional cardiac rhythm monitoring. Pairwise meta-analyses were performed under the random-effects model. To explore for differences between the monitoring strategies we combined direct and indirect evidence for any given pair of monitoring devices assessed within a randomized controlled trial (RCT). RESULTS:We included 8 studies (5 RCTs, 3 observational; 2994 patients). Patients receiving PCM after their index event had a higher rate of AF detection and anticoagulant initiation in both RCTs (RR=3.91, 95%CI:2.54-6.03 & RR=2.16, 95%CI:1.66-2.80) and observational studies (RR=2.06, 95%CI:1.57-2.70 & RR=2.01; 95%CI:1.43-2.83), respectively. PCM was associated with a lower risk of recurrent stroke during follow-up in observational studies (RR=0.29; 95%CI:0.15-0.59), but not in RCTs (RR=0.72, 95%CI:0.49-1.07). In the indirect analyses of RCTs the likelihood of AF detection and anticoagulation initiation was higher for implantable loop recorders compared with both Holter monitors and external loop recorders. CONCLUSIONS:PCM after an IS or TIA can lead to higher rates of AF detection and anticoagulant initiation. Currently, there is no solid RCT evidence supporting that PCM may be associated with lower stroke recurrence risk.

Background/UNASSIGNED:. Methods/UNASSIGNED:Patients with PoMS (N=215; aged 10-<18 years) were randomised to once-daily oral fingolimod (N=107) or once-weekly intramuscular IFN β-1a (N=108). HRQoL outcomes were assessed using the 23-item Pediatric Quality of Life (PedsQL) scale that comprises Physical and Psychosocial Health Summary Scores (including Emotional, Social and School Functioning). A post hoc inferential analysis evaluated changes in self-reported or parent-reported PedsQL scores from baseline up to 2 years between treatment groups using an analysis of covariance model. Results/UNASSIGNED:Treatment with fingolimod showed improvements versus IFN β-1a on the PedsQL scale in both the self-reported and parent-reported Total Scale Scores (4.66 vs -1.16, p≤0.001 and 2.71 vs -1.02, p≤0.05, respectively). The proportion of patients achieving a clinically meaningful improvement in the PedsQL Total Scale Score was two times higher with fingolimod versus IFN β-1a per the self-reported scores (47.5% vs 24.2%, p=0.001), and fingolimod was favoured versus IFN β-1a per the parent-reported scores (37.8% vs 24.7%, p=non-significant). Group differences in self-reported Total Scale Scores in favour of fingolimod were most pronounced among patients who had ≥2 relapses in the year prior to study entry or who showed improving or stable Expanded Disability Status Scale scores during the study. Conclusion/UNASSIGNED:Fingolimod improved HRQoL compared with IFN β-1a in patients with PoMS as evidenced by the self-reported and parent-reported PedsQL scores.

Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. Our unbiased proteomics analysis of melanoma short-term cultures revealed that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. We showed that melanoma cells require amyloid beta (AB) for growth and survival in the brain parenchyma. Melanoma-secreted AB activates surrounding astrocytes to a pro-metastatic, anti-inflammatory phenotype and prevents phagocytosis of melanoma by microglia. Finally, we demonstrate that pharmacological inhibition of AB decreases brain metastatic burden.

OBJECTIVE:A recent FDA warning concerning an arrhythmogenic potential of lamotrigine created concern in the neurological community. This warning was based on in vitro studies, but no clinically relevant risk was considered. This rapid systematic review aims to elucidate the risk of lamotrigine on sudden death or electrocardiogram abnormalities. METHODS:We conducted a systematic search of Ovid Medline and Ovid Embase, including randomized controlled trials and observational studies, studies of people with or without epilepsy, with one of the following outcome measures: SUDEP and sudden cardiac death, as well as the development or worsening of electrocardiogram abnormalities. All titles and abstracts were independently screened, and the full texts of relevant studies were obtained. We re-evaluated the sudden death definitions used in all included studies, as some could have used unclear or overlapping definitions. We used the American Academy of Neurology risk of bias tool to evaluate the class of evidence and the GRADE approach to evaluate our confidence in the evidence. RESULTS:We included 26 studies with 24,962 participants, of whom 2,326 used lamotrigine. Twelve studies showed no significant risk of SUDEP for lamotrigine users. One study reporting on sudden cardiac death and three studies with unclear sudden death definitions did not report an elevated risk of death in lamotrigine users compared to controls. In 10 studies reporting on electrocardiogram parameters, there was no statistically significant increased risk among lamotrigine users except for two studies. These two studies reported either "slight increases" in PR interval or an increased PQ interval that the primary study authors felt to be more related to structural cardiac differences rather than an effect of lamotrigine. One study was rated class II while all others were class III or IV. We had "very low confidence" in the evidence following the GRADE assessment. None of the studies examined the risk of lamotrigine in people with pre-existing cardiac conditions. CONCLUSION/CONCLUSIONS:There is insufficient evidence to support or refute that lamotrigine is associated with sudden death or electrocardiogram changes, in people with or without epilepsy as compared to ASM or placebo. This is due to the high risk of bias in most studies and low precision and inconsistency in the reported results.

OBJECTIVE:The aim of this study was to describe the processes and outcomes associated with patients at five sites in the Adult Hydrocephalus Clinical Research Network (AHCRN) who had undergone evaluation and treatment for suspected idiopathic normal pressure hydrocephalus (iNPH) and had 1-year postoperative follow-up. METHODS:Subjects with possible iNPH who had been prospectively enrolled in the AHCRN registry between November 19, 2014, and December 31, 2018, were evaluated by CSF drainage via either lumbar puncture or external lumbar drainage, consistent with recommendations of the international iNPH guidelines. Standardized clinical evaluations of gait, cognition, urinary symptoms, depression, and functional outcomes were conducted at baseline, before and after CSF drainage, and at 4-month intervals after shunt surgery. Complications of CSF drainage and shunt surgery were recorded. RESULTS:Seventy-four percent (424/570) of patients with possible iNPH had CSF drainage, and 46% of them (193/424) underwent shunt surgery. The mean change in gait velocity with CSF drainage was 0.18 m/sec in patients who underwent shunt surgery versus 0.08 m/sec in patients who did not. For shunt surgery patients, gait velocity increased by 54% from 0.67 m/sec before CSF drainage to 0.96 m/sec 8-12 months after surgery, and 80% of patients had an increase of at least 0.1 m/sec by the first postoperative visit. Evaluation of cognition, urinary symptoms, depression, and functional outcomes also revealed improvement after shunt surgery. Of 193 patients who had undergone shunt surgery, 176 (91%) had no complications and 17 (9%) had 28 complications. Eleven patients (6%) had 14 serious complications that resulted in the need for surgery or an extended hospital stay. The 30-day reoperation rate was 3%. CONCLUSIONS:Using criteria recommended by the international iNPH guidelines, the authors found that evaluation and treatment of iNPH are safe and effective. Testing with CSF drainage and treatment with shunt surgery are associated with a high rate of sustained improvement and a low rate of complications for iNPH in the 1st year after shunt surgery. Patients who had undergone shunt surgery for iNPH experienced improvement in gait, cognitive function, bladder symptoms, depression, and functional outcome measures. Gait velocity, which is an easily measured, objective, continuous variable, should be used as a standard outcome measure to test a patient's response to CSF drainage and shunt surgery in iNPH.

BACKGROUND:F-THK5117, we previously reported that the ventricular CSF clearance of the PET tracer was reduced in AD and associated with elevated brain Aβ levels. METHODS:C-PiB to estimate CSF clearance calculated from early dynamic PET frames in 9 normal controls and 15 AD participants. RESULTS:F-THK5351) and brain Aβ load (r =  - 0.64, n = 24, p < 0.01). With a larger sample size, we extended our observations to show that reduced CSF clearance is associated with reductions in cortical thickness and cognitive performance. CONCLUSIONS:Overall, the findings support the hypothesis that failed CSF clearance is a feature of AD that is related to Aβ deposition and to the pathology of AD. Longitudinal studies are needed to determine whether failed CSF clearance is a predictor of progressive amyloidosis or its consequence.

BACKGROUND:Multiple sclerosis (MS) affects over 2.5 million individuals worldwide, yet much of the disease course is unknown. Hemispheric vulnerability in MS may elucidate part of this process but has not yet been studied. The current study assessed neuropsychological functioning as it relates to hemispheric vulnerability in MS. METHODS:Verbal IQ, as measured by verbal comprehension index (VCI), nonverbal IQ, as measured by perceptual reasoning index (PRI) and memory acquisition were compared in right-handed (dextral) and non-right-handed (non-dextral) persons with MS (PwMS). RESULTS:Linear mixed-effects modeling indicated a significant main effect of handedness, F(1, 195.35) = 3.95, p = .048, for a composite measure of VCI, PRI, and memory acquisition, with better performance for dextral PwMS. In examining differences for specific neuropsychological measures, the largest effect size between dextral and non-dextral participants was seen in PRI (d = 0.643), F(1,341) = 12.163, p = .001. No significant interaction effect between handedness and IQ was found, F(3, 525.60) = 0.75, p = .523. CONCLUSIONS:Dextral PwMS perform better than non-dextral PwMS when assessing neuropsychological performance for memory and IQ combined. Results are suggestive of increased vulnerability in the left brain to the pathological process of MS.