Faculty Bibliography

BACKGROUND AND PURPOSE/OBJECTIVE:Studies have shown an association between infarct patterns and recurrent stroke in patients with symptomatic intracranial stenosis (sICAS) but there are limited data on associations with perfusion imaging mismatch profile. We aim to determine the association between infarct pattern, optimal mismatch profile definition, and recurrent cerebrovascular events (RCVE) in patients with anterior circulation sICAS. METHODS:This is a retrospective study of consecutive patients with acutely sICAS admitted to a comprehensive stroke center over 18 month's period. Patients with sICAS underwent magnetic resonance perfusion (MRP) imaging within 24 hours from admission. Infarct patterns (internal BZ [IBZ], cortical BZ [CBZ], and core/perforator [C/P]) and RCVE within 90 days, were independently adjudicated by two reviewers. We compared mismatch profiles and recurrent event rates across infarct patterns. RESULTS:> 6 seconds (60% vs. 6.7%, P = .007) and RCVE (62.5% vs. 11.8%, P = .01). There were no associations between CBZ and C/P infarcts and target mismatch profiles and RCVE. CONCLUSION/CONCLUSIONS:IBZ infarcts may be a surrogate marker of distal perfusion status and RCVE risk. Larger multicenter, prospective, core-lab blindly adjudicated studies are needed to confirm our findings.

Background: Natalizumab (NTZ) is a highly efficacious therapy for relapsing forms of multiple sclerosis (MS), but is associated with risk of progressive multifocal leukoencephalopathy (PML). A previous study demonstrated that extending NTZ dosing to every 35-43 days (EID) was associated with lower PML risk than the standard (every 28 days) dosing (SID). This finding raises the important question of whether NTZ should be administered as EID.
Method(s): MS patients receiving NTZ prior to May 31, 2018 at NYU (New York, NY) or Rocky Mountain (Salt Lake City, UT) MS centers were retrospectively identified. EID cohorts were defined similarly to definitions used for the previous PML risk study. For definition 1 (DEF 1), the last 18 months of treatment was considered (<=15 infusions in the last 18 months) while definition 3 (DEF 3) considered the entire infusion history (mean of <=10 infusions/year). Eligible patients were required to have >=24 months of treatment; >=1 MRI available for review; no gaps > 3 months on treatment; no infusions <= 21 days apart; and had no PML. Disease activity was identified by review of MRI radiology reports evaluating for presence of gadolinium (Gd) and new T2 lesions. Generalized Estimating Equation (GEE) logistic models and SAS 3.4 were used in the data analyses.
Result(s): 690 patients met the criteria. For DEF 1, no difference was observed between EID and SID in the odds of presence of Gd lesions (n=500) (OR/month increse 1.1; 95% CI 0.93, 1.31; p=0.27) or new T2 lesions (n=450) (OR/month increase 1.11; 95%CI 0.99, 1.24; p=0.07). Similarly, for DEF 3 no difference was observed between EID and SID in the odds of presence of Gd lesions (n =401) (OR/month increase1.00; 95%CI0.983, 1.025; p=0.75). There is a small increase in the odds of presence of new T2 lesions in EID group (n =437) (OR/month increase1.05; 95% CI 1.01, 1.10; p=0.02). GEE models included adjustments for the frequencies of MRIs for Gd lesions.
Conclusion(s): The study helps address a currently unmet need for evaluating EID NTZ efficacy. These findings suggest that EID of NTZ does not result in significant increased radiological MS disease activity compared to SID, providing further evidence that NTZ efficacy is comparable with EID

Sensory neurons of the peripheral nervous system are critical in health and disease. Sensory neurons derived from induced pluripotent stem (iPS) cells are now being used increasingly for in vitro models of neuropathy, pain, and neurotoxicity. DNA methylation is critical for neurodevelopment and has been implicated in many neuronal diseases, but has not been examined in iPS-derived sensory neurons. In order to better characterize the iPS-derived sensory neuron model, we have undertaken a genome-wide DNA methylation study on the cells from human iPS to iPS-derived sensory neurons during differentiation through reduced representation and bisulfite sequencing. We report decreasing DNA methylation with iPS-derived sensory neuronal differentiation that is reflected in increasing numbers and proportions of hypomethylated individual CpGs and regions, as well as lowered DNMT3b expression. Furthermore, genes with changes in DNA methylation near their TSS suggest key pathways that may be involved in iPS-derived sensory neuronal differentiation. These findings provide insights into sensory neuronal differentiation and can be used for further in vitro modelling of disease states.

INTRODUCTION/BACKGROUND:The GREENFIELD observational study assessed the effect of levodopa/carbidopa intestinal gel (LCIG) on motor and non-motor symptoms, and the related impact on patient quality of life and caregiver burden up to 8 years. METHODS:Final results of a large Italian cohort of patients who started LCIG in routine care between 2007 and 2014 are presented. Comparison between baseline (before LCIG) and follow-up visits on yearly basis (visit 2/3) is reported. Primary endpoint was Unified Parkinson's Disease Rating Scale (UPDRS-IV) Item 39; secondary endpoints were UPDRS I and II, dyskinesia items, PD Quality of Life Questionnaire-39, Parkinson's Disease Sleep Scale-2, Gait and Falls Questionnaire, Questionnaire on Impulsive Disorders, and Relative Stress Scale. RESULTS:Overall, 145 patients from 14 centers were assessed with a mean time since LCIG start of 2.8 ± 1.7 years at visit 2. The mean UPDRS-IV item 39 score showed significant reductions compared to baseline (mean score 2.0 ± 0.81) at visit 2 (mean score 0.9 ± 0.69; - 55%; p < 0.001) and at visit 3 (mean score 1.0 ± 0.75; - 50%; p < 0.001). At visit 3, significant reductions were observed for dyskinesia duration score (- 28%; p < 0.001), dyskinesia disability (- 40%; p < 0.001), and painful dyskinesia (- 50%; p < 0.001). Overall, 40 (27.6%) patients experienced 49 serious adverse events which were considered related to PEG/J procedure or to device in 16.3% of the cases. CONCLUSIONS:The results of this study support the long-term efficacy of LCIG on PD symptoms as well as on activities of daily living. The adverse events were consistent with the established LCIG safety profile.

BACKGROUND:Migraine is a chronic disabling neurologic condition that can be treated with a combination of both pharmacologic and complementary and integrative health options. EVIDENCE ACQUISITION/METHODS:With the growing interest in the US population in the use of nonpharmacologic treatments, we reviewed the evidence for supplements and behavioral interventions used for migraine prevention. RESULTS:Supplements reviewed included vitamins, minerals, and certain herbal preparations. Behavioral interventions reviewed included cognitive behavioral therapy, biofeedback, relaxation, the third-wave therapies, acupuncture, hypnosis, and aerobic exercise. CONCLUSIONS:This article should provide an appreciation for the wide range of nonpharmacologic therapies that might be offered to patients in place of or in addition to migraine-preventive medications.

Introduction: Natalizumab treatment in patients with early relapsing-remitting multiple sclerosis (RRMS) may improve clinical outcomes. STRIVE is a completed, 4-year, multicentre, observational, open-label, single-arm study of anti-JC virus antibody negative patients starting natalizumab < 3 years after RRMS diagnosis.
Objective(s): To examine 4-year, end-of-study no evidence of disease activity (NEDA) status, disability worsening and improvement, and cognitive performance of natalizumab-treated patients with early RRMS.
Method(s): Clinical NEDA, the primary endpoint, was defined as no relapses or Expanded Disability Status Scale (EDSS) worsening (score increase of >=1.5 from a baseline [BL] of 0.0, >=1.0 from a BL of 1.0-5.5, or >=0.5 from a BL >=6.0, confirmed over 24 weeks). MRI NEDA was defined as no gadolinium-enhancing or new/enlarging T2-hyperintense lesions. Overall NEDA encompassed both clinical and MRI NEDA. Annualised relapse rates (ARRs) were analysed with a negative binomial regression model. The Kaplan-Meier method estimated time to 24-week-confirmed EDSS worsening or improvement (score decrease of >=1.0 from a BL >=2.0). The Symbol Digit Modalities Test (SDMT) change from BL to year 4 was analysed via a Wilcoxon signed-rank test.
Result(s): At BL (N=222), patients had active disease, a mean (standard deviation [SD]) of 1.4 (1.2) relapses in the prior year, and a mean (SD) EDSS score of 2.04 (1.13). At study end, 100 of 169 patients (59.2%) achieved cumulative clinical NEDA, and 72 of 143 (50.4%) and 45 of 163 (27.6%) had MRI and overall NEDA, respectively. In year 4, 101 of 134 patients (75.4%) had overall NEDA. ARRs decreased by 90.2%, from 1.43 in the year before natalizumab to 0.14 on natalizumab (P< 0.0001). Cumulative probabilities of EDSS worsening and improvement over 4 years were 19.3% and 43.9%, respectively. At study end, the mean (SD) EDSS score was 1.77 (1.55). From BL to year 4, patients had significant improvement in SDMT score (n=174; mean change from BL: 4.6 [95% confidence interval: 2.9-6.2]; P< 0.0001). Serious adverse events were reported in 25 of 222 patients (11.3%), with no cases of progressive multifocal leukoencephalopathy.
Conclusion(s): Natalizumab treatment over 4 years was associated with NEDA achievement, a 43.9% probability of disability improvement, a 19.3% probability of disability worsening, and significantly improved cognitive performance. These results support natalizumab's long-term effectiveness in early RRMS patients

PURPOSE/OBJECTIVE:There is variability in survival within IDH mutant gliomas determined by chromosomal events. Copy number variation (CNV) abundance associated with survival in low-grade and IDH mutant astrocytoma has been reported. Our purpose was to correlate the extent of genome-wide CNV abundance in IDH mutant astrocytomas with MRI features. METHODS:Presurgical MRI and CNV plots derived from Illumina 850k EPIC DNA methylation arrays of 18 cases of WHO grade II-IV IDH mutant astrocytomas were reviewed. IDH mutant astrocytomas were divided into CNV stable group (CNV-S) with ≤ 3 chromosomal gains or losses and lack of focal gene amplifications and CNV unstable group (CNV-U) with > 3 large chromosomal gains/losses and/or focal amplifications. The associations between MR features, relative cerebral blood volume (rCBV), CNV abundance, and time to progression were assessed. Tumor rCBV estimates were obtained using DSC T2* perfusion analysis. RESULTS:There were nine (50%) CNV-S and nine (50%) CNV-U IDH mutant astrocytomas. CNV-U tumors showed larger mean tumor size (P = 0.004) and maximum diameter on FLAIR (P = 0.004) and also demonstrated significantly higher median rCBV than CNV-S tumors (2.62 vs 0.78, P = 0.019). CNV-U tumors tended to have shorter time to progression although without statistical significance (P = 0.393). CONCLUSIONS:Larger size/diameter and higher rCBVs were seen associated CNV-U astrocytomas, suggesting a correlation of aggressive imaging phenotype with unstable and aggressive genotype in IDH mutant astrocytomas.

Objective: To investigate cognitive deficits in African Americans (AA) with MS.
Background(s): Cognitive impairment is one of the most frequent and burdensome symptoms of MS. Although a more severe disease course has been descibed in AA in comparison with Caucasians (CA) patients, an objective assessment of the cognitive profile of AA and potential differences with CA patients has not been investigated yet.
Method(s): Fifty-one AA patients (40F, mean age 38.45 +/- 11.13 yrs, mean disease duration 7.88 +/- 5.39 yrs), 37 AA healthy controls (HC) (25F, mean age 35.97 +/- 12.44 yrs), 43 CA patients (32F, mean age 39.00 +/- 10.56 yrs, mean disease duration 6.67 +/- 7.00 yrs) and 18 CA HC (12F, mean age 30.72 +/- 6.94 yrs) were prospectively enrolled as part of an ongoing longitudinal study. In all subjects, an extensive neuropsychological evaluation was performed, including: Symbol Digit Modalities Test (SDMT), California Verbal Learning Test-II (CVLT), Brief Visuospatial Memory Test-Revised (BVMT), Stroop Color and Word Test (SCVT), Controlled Oral Word Association Test (COWAT), Pattern Comparison Processing Speed Test (PCPST) and a multitasking attention-memory test (MAMT). Each patient's group was compared with a race-matched HC group via ANCOVA analysis, accounting for age, gender, years of education, premorbid intelligence estimated with the Wechsler Test of Adult Reading (WTAR) and socioeconomic status expressed as yearly income.
Result(s): AA patients and HC did not differ in gender, age, years of education, WTAR score or socioeconomic status. CA patients and HC did not differ in gender, years of education and socioeconomic status, while significantly differ in age and WTAR scores (p=0.001 for both). Significant differences in SDMT (p=0.002), BVMT (p=0.012), COWAT (p=0.006), PCPST (p=0.008) and MAMT (p=0.018) scores were identified between AA patients and AA HC. Significant differences in SDMT (p=0.003), CVLT (p=0.009), BVMT (p=0.021), COWAT (p=0.003) and PCPST (p< 0.0001) scores were identified between CA patients and CA HC.
Conclusion(s): AA and CA patients showed similar deficits in information processing speed, attention, visuospatial memory and verbal fluency. CA patients showed additional impairment in the verbal memory domain, while AA patients showed deficits in multitasking capability. These results suggest that the cognitive profile of MS patients mostly overlaps across different races, although it seem to show group-specific deficits in specific domains

Introduction: Neuroaxonal loss and demyelination are the main substrate of disability in multiple sclerosis (MS). In this study, we assessed the potential of sodium and

Objective: Network analysis is the utilization of mathematical techniques to analyze the relationships of information within a network. We conducted a network analysis of the International Classification of Headache Disorders, 3rd Edition (ICHD3). Our goal is to better understand individual disease entity based on the interconnectedness inherent in the ICHD hierarchy.
Method(s): A network is defined by a set of objects, called "nodes", and the connections between them. If two nodes are connected, an "edge" exists between them. We define a node as a headache diagnosis identified by at least one ICHD3 diagnosis criterium. An edge between two headache disorders exists if one disorder is mentioned explicitly by the other in the "notes" or "comments" section of the ICHD3. We identify key nodes in a network by measuring mathematically a node's interconnectedness in three ways: degree centrality, between-ness centrality, and closeness centrality. To examine how hierarchy affects classification, we developed two models for the ICHD3, a non-hierarchical model and a hierarchical model. In the non-hierarchical model, only cross-references in the subsections qualify as edges. In the hierarchical model, the structure of the ICHD3 is taken into account by establishing additional edges between sections and their subsections.
Result(s): There are 396 nodes in both of our models. In the non-hierarchical model, there are 718 edges with average degree of separation of 3.63. In the hierarchical model, there are 1385 edges with average degree of 6.99. In both models, migraine and medication-overuse headache (MOH) are in the top 10 diagnoses according to the three centrality measurements. The choice of nonhierarchical or hierarchical model affects which diagnoses occupy the top 10 centrality nodes; specifically, there are more secondary headache diagnoses in the top 10 position in the hierarchy model compared to the non-hierarchical model.
Conclusion(s): Migraine and MOH are the most well connected nodes in ICHD3. Diagnostic hierarchy allows for unification of secondary headaches that would otherwise be considered isolated diagnoses. Once connected in a hierarchical fashion, secondary headache diagnoses form a majority of the most well-connected nodes in our field