Faculty Bibliography

INTRODUCTION/BACKGROUND:The ability to deploy transcranial direct current stimulation (tDCS) at home is a key usability advantage to support scaling for pivotal clinical trials. We have established a home-based tDCS protocol for use in clinical trials termed remotely supervised (RS)-tDCS. OBJECTIVE:To report the tolerability and feasibility of tDCS sessions completed to date using RS-tDCS in clinical trials. METHODS:We analyzed tolerability (i.e., adverse events, AEs) reported in six Class I/II/III trials using RS-tDCS to study symptom outcomes over 10 to 60 daily applications. Across the six clinical trials, 308 participants (18-78 years old) completed an average of 23 sessions for a total of 6779 RS-tDCS administrations. The majority of participants were diagnosed with multiple sclerosis, and open-label trials included those diagnosed with a range of other conditions (e.g., Parkinson's disease, post-stroke aphasia, traumatic brain injury, cerebellar ataxia), with minimum-to-severe neurologic disability. Clinical trial feasibility (i.e., treatment fidelity and blinding integrity) was examined using two Class I randomized controlled trials (RCTs). RESULTS:No serious AEs occurred. Across administrations, three sessions (0.04%) were aborted due to discomfort, but no participant discontinued due to tolerability. The AEs most commonly reported by participants were tingling (68%), itching (41%) and warmth sensation (42%) at the electrode site, and these were equally reported in active and sham tDCS conditions. The two Class I RCTs resulted in rapid enrollment, high fidelity to treatment completion, and blinding integrity. CONCLUSIONS:At-home RS-tDCS is tolerable, including when used over extended periods of time. Home-based RS-tDCS is feasible and can enable Class I tDCS clinical trial designs.

BACKGROUND:The optimal endovascular strategy for reperfusing distal medium-vessel occlusions (DMVO) remains unknown. This study evaluates angiographic and clinical outcomes of thrombectomy strategies in DMVO stroke of the posterior circulation. METHODS:TOPMOST (Treatment for Primary Medium Vessel Occlusion Stroke) is an international, retrospective, multicenter, observational registry of patients treated for DMVO between January 2014 and June 2020. This study analyzed endovascularly treated isolated primary DMVO of the posterior cerebral artery in the P2 and P3 segment. Technical feasibility was evaluated with the first-pass effect defined as a modified Thrombolysis in Cerebral Infarction Scale score of 3. Rates of early neurological improvement and functional modified Rankin Scale scores at 90 days were compared. Safety was assessed by the occurrence of symptomatic intracranial hemorrhage and intervention-related serious adverse events. RESULTS:<0.025). Symptomatic intracranial hemorrhage occurred in 2.8% (4) of all cases. CONCLUSIONS:Both first-pass aspiration and stent retriever thrombectomy for primary isolated posterior circulation DMVO seem to be safe and technically feasible leading to similar favorable rates of angiographic and clinical outcome.

We describe an educational intervention for neurology residents aimed at developing feedback skills. An objective structured clinical examination case was designed to simulate the provision of feedback to a medical student. After the simulated case session, residents received structured, individualized feedback on their performance and then participated in a group discussion about feedback methods. Survey data were collected from the standardized medical student regarding residents' performance and from residents for assessments of their performance and of the OSCE case. This manuscript aims to describe this educational intervention and to demonstrate the feasibility of this approach for feedback skills development.

BACKGROUND/UNASSIGNED:Multiple sclerosis (MS) is a neuroinflammatory disease with debilitating manifestations that may predispose patients to hip fracture and osteoarthritis, and may affect recovery from total hip arthroplasty (THA). With increased longevity of MS patients and growth in demand for arthroplasty in this population, it is important to understand outcomes of THA in patients with MS. AIM/UNASSIGNED:We sought to compare outcomes of THA among persons with MS and without MS. METHODS/UNASSIGNED:International Classification of Diseases, Ninth Revision Procedure Coding System (ICD-9-PCS) codes for hip arthroplasty (815.1) were used to identify all patients in the New York Statewide Planning and Research Cooperative System (SPARCS) database who underwent THA between 2000 and 2014. Patients with MS, the primary exposure, were identified using ICD-9-Clinical Modification (CM) code 340. The study outcomes of length of stay (days), discharge disposition, index admission mortality, 90-day readmission, 1-year revision arthroplasty, and 1-year all-cause mortality were evaluated using multivariable regression analyses inclusive of basic demographics, admission source, disposition, payer, comorbidity, and socioeconomic status (SES). RESULTS/UNASSIGNED: = 0.035). However, MS patients had similar risk for 90-day readmission and one-year all-cause mortality as compared with non-MS patients. CONCLUSIONS/UNASSIGNED:Although patients with MS who underwent THA had a 90-day complication risk that was similar to those without MS, the risk for requiring revision surgery was more than 2-fold higher. Additional studies are needed to understand the reasons for revision surgery and for developing strategies to mitigate the risk of complications.

Amyloid plaques contain many proteins in addition to beta amyloid (Aβ). Previous studies examining plaque-associated proteins have shown these additional proteins are important; they provide insight into the factors that drive amyloid plaque development and are potential biomarkers or therapeutic targets for Alzheimer's disease (AD). The aim of this study was to comprehensively identify proteins that are enriched in amyloid plaques using unbiased proteomics in two subtypes of early onset AD: sporadic early onset AD (EOAD) and Down Syndrome (DS) with AD. We focused our study on early onset AD as the drivers of the more aggressive pathology development in these cases is unknown and it is unclear whether amyloid-plaque enriched proteins differ between subtypes of early onset AD. Amyloid plaques and neighbouring non-plaque tissue were microdissected from human brain sections using laser capture microdissection and label-free LC-MS was used to quantify the proteins present. 48 proteins were consistently enriched in amyloid plaques in EOAD and DS. Many of these proteins were more significantly enriched in amyloid plaques than Aβ. The most enriched proteins in amyloid plaques in both EOAD and DS were: COL25A1, SMOC1, MDK, NTN1, OLFML3 and HTRA1. Endosomal/lysosomal proteins were particularly highly enriched in amyloid plaques. Fluorescent immunohistochemistry was used to validate the enrichment of four proteins in amyloid plaques (moesin, ezrin, ARL8B and SMOC1) and to compare the amount of total Aβ, Aβ40, Aβ42, phosphorylated Aβ, pyroglutamate Aβ species and oligomeric species in EOAD and DS. These studies showed that phosphorylated Aβ, pyroglutamate Aβ species and SMOC1 were significantly higher in DS plaques, while oligomers were significantly higher in EOAD. Overall, we observed that amyloid plaques in EOAD and DS largely contained the same proteins, however the amount of enrichment of some proteins was different in EOAD and DS. Our study highlights the significant enrichment of many proteins in amyloid plaques, many of which may be potential therapeutic targets and/or biomarkers for AD.

BACKGROUND:The neutrophil-lymphocyte ratio (NLR) is emerging as an important biomarker of acute physiologic stress in a myriad of medical conditions, and is a confirmed poor prognostic indicator in COVID-19. OBJECTIVE:We sought to describe the role of NLR in predicting poor outcome in COVID-19 patients undergoing mechanical thrombectomy for acute ischemic stroke. METHODS:We analyzed NLR in COVID-19 patients with large vessel occlusion (LVO) strokes enrolled into an international 12-center retrospective study of laboratory-confirmed COVID-19, consecutively admitted between March 1, 2020 and May 1, 2020. Increased NLR was defined as ≥7.2. Logistic regression models were generated. RESULTS:Incidence of LVO stroke was 38/6698 (.57%). Mean age of patients was 62 years (range 27-87), and mortality rate was 30%. Age, sex, and ethnicity were not predictive of mortality. Elevated NLR and poor vessel recanalization (Thrombolysis in Cerebral Infarction (TICI) score of 1 or 2a) synergistically predicted poor outcome (likelihood ratio 11.65, p  =  .003). Patients with NLR > 7.2 were 6.8 times more likely to die (OR 6.8, CI95% 1.2-38.6, p  =  .03) and almost 8 times more likely to require prolonged invasive mechanical ventilation (OR 7.8, CI95% 1.2-52.4, p  =  .03). In a multivariate analysis, NLR > 7.2 predicted poor outcome even when controlling for the effect of low TICI score on poor outcome (NLR p  =  .043, TICI p  =  .070). CONCLUSIONS:We show elevated NLR in LVO patients with COVID-19 portends significantly worse outcomes and increased mortality regardless of recanalization status. Severe neuro-inflammatory stress response related to COVID-19 may negate the potential benefits of successful thrombectomy.

BACKGROUND:Moyamoya disease may present with either hemorrhagic or ischemic strokes. Surgical bypass has previously demonstrated superiority when compared to natural history and medical treatment alone. The best bypass option (direct vs. indirect), however, remains controversial in regard to adult ischemic symptomatic moyamoya disease. Multiple studies have demonstrated clinical as well as angiographic effectiveness of direct bypass in adult hemorrhagic moyamoya disease. In particular, there are limited data regarding strategies in the setting of failed indirect bypass with recurrent hemorrhagic strokes. Here, we describe a salvage procedure. METHODS:We describe a case of a 52-year-old man who presented with hemorrhagic moyamoya disease and failed previous bilateral encephaloduroarteriosynangiosis (EDAS) procedures at an outside institution. On a 3-year follow-up diagnostic cerebral angiogram, no synangiosis was noted on the right side and only minimal synangiosis was present on the left. The left hemisphere was significant for a left parietal hypoperfusion state. We performed a salvage left proximal superficial temporal artery to distal parietal M4 middle cerebral artery bypass using the descending branch of the lateral circumflex artery as an interposition graft with preservation of the existing EDAS sites. RESULTS:The patient underwent the procedure successfully and recovered well with resolution of headaches and no further strokes or hemorrhages on the 1-year follow-up magnetic resonance imaging of the brain. CONCLUSIONS:This case presents the use of a salvage direct bypass technique for recurrent symptomatic hemorrhagic moyamoya disease after failed EDAS. The strategy, approach, and technical nuances of this unique case have implications for revascularization options.

STUDY OBJECTIVES/OBJECTIVE:Alterations in sleep spindles have been linked to cognitive impairment. This finding has contributed to a growing interest in identifying sleep-based biomarkers of cognition and neurodegeneration, including sleep spindles. However, flexibility surrounding spindle definitions and algorithm parameter settings present a methodological challenge. The aim of this study was to characterize how spindle detection parameter settings influence the association between spindle features and cognition and to identify parameters with the strongest association with cognition. METHODS:Adult patients (n=167, 49 ± 18 years) completed the NIH Toolbox Cognition Battery after undergoing overnight diagnostic polysomnography recordings for suspected sleep disorders. We explored 1000 combinations across seven parameters in Luna, an open-source spindle detector, and used four features of detected spindles (amplitude, density, duration, and peak frequency) to fit linear multiple regression models to predict cognitive scores. RESULTS:Spindle features (amplitude, density, duration, and mean frequency) were associated with the ability to predict raw fluid cognition scores (r=0.503) and age-adjusted fluid cognition scores (r=0.315) with the best spindle parameters. Fast spindle features generally showed better performance relative to slow spindle features. Spindle features weakly predicted total cognition and poorly predicted crystallized cognition regardless of parameter settings. CONCLUSION/CONCLUSIONS:Our exploration of spindle detection parameters identified optimal parameters for studies of fluid cognition and revealed the role of parameter interactions for both slow and fast spindles. Our findings support sleep spindles as a sleep-based biomarker of fluid cognition.