Faculty Bibliography

BACKGROUND:Cortical dysfunctioning significantly contributes to the pathogenesis of motor symptoms in Parkinson's disease (PD). OBJECTIVE:We aimed at testing whether an acute levodopa administration has measurable and specific cortical effects possibly related to striatal dopaminergic deficit. METHODS:I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane to identify the more affected and the less affected brain side in each patient, according to the dopaminergic innervation loss of the putamen. Cortical excitability changes before and after an acute intake of levodopa were computed and compared between the more and the less affected brain side at the single-patient as well as at the group level. RESULTS:We found that levodopa intake induces a significant increase (P < 0.01) of cortical excitability nearby the supplementary motor area in the more affected brain side, greater (P < 0.025) than in the less affected brain side. Notably, cortical excitability changes nearby the superior parietal lobule were not statistically significant. CONCLUSIONS:These results strengthen the idea that dysfunction of specific cortico-subcortical circuits may contribute to pathophysiology of PD symptoms. Most important, they support the use of navigated TMS/EEG as a non-invasive tool to better understand the pathophysiology of PD.

BACKGROUND:QT dispersion, maximal interlead difference in QT interval on 12-lead electrocardiogram (ECG), measures cardiac repolarization abnormalities. Data are conflicting whether QT dispersion predicts adverse outcome in acute ischemic stroke (AIS) patients. Our objective is to determine if QT dispersion predicts: (1) short-term clinical outcome in AIS, and (2) stroke location (insular versus noninsular cortex). METHODS:Admission ECGs from 412 consecutive patients with acute stroke symptoms from 2 university-based stroke centers were reviewed. QT dispersion was measured. A neuroradiologist reviewed brain imaging for insular cortex involvement. Favorable clinical outcomes at discharge were modified Rankin Scale (mRS) score of 0-1, discharge National Institutes of Health Stroke Scale (NIHSS) score less than 2, and discharge to home. Multiple logistic regressions were performed for each outcome measure and to determine the association between insular infarct and QT dispersion. RESULTS:Of 145 subjects in the final analysis, median age was 65 years (interquartile range [IQR] 56-75), male patients were 38%, black patients were 68%, median QT dispersion was 78 milliseconds (IQR 59-98), and median admission NIHSS score was 4 (IQR 2-6). QT dispersion did not predict short-term clinical outcome for mRS score (odds ratio [OR] = 1.001, 95% confidence interval [CI] .99-1.01, P = .85), NIHSS at discharge (OR = .994, 95% CI .98-1.01, P = .30), or discharge disposition (OR = 1.001, 95% CI .99-1.01, P = .81). Insular cortex involvement did not correlate with QT dispersion magnitude (OR = 1.009, 95% CI .99-1.02, P = .45). CONCLUSIONS:We could not demonstrate that QT dispersion is useful in predicting short-term clinical outcome at discharge in AIS. Further, the magnitude of QT dispersion did not predict insular cortical stroke location.

Heterozygous mutations in GBA, the gene encoding the lysosomal enzyme glucosylceramidase beta/β-glucocerebrosidase, comprise the most common genetic risk factor for Parkinson disease (PD), but the mechanisms underlying this association remain unclear. Here, we show that in Gba^L444P/WT knockin mice, the L444P heterozygous Gba mutation triggers mitochondrial dysfunction by inhibiting autophagy and mitochondrial priming, two steps critical for the selective removal of dysfunctional mitochondria by autophagy, a process known as mitophagy. In SHSY-5Y neuroblastoma cells, the overexpression of L444P GBA impeded mitochondrial priming and autophagy induction when endogenous lysosomal GBA activity remained intact. By contrast, genetic depletion of GBA inhibited lysosomal clearance of autophagic cargo. The link between heterozygous GBA mutations and impaired mitophagy was corroborated in postmortem brain tissue from PD patients carrying heterozygous GBA mutations, where we found increased mitochondrial content, mitochondria oxidative stress and impaired autophagy. Our findings thus suggest a mechanistic basis for mitochondrial dysfunction associated with GBA heterozygous mutations. Abbreviations: AMBRA1: autophagy/beclin 1 regulator 1; BECN1: beclin 1, autophagy related; BNIP3L/Nix: BCL2/adenovirus E1B interacting protein 3-like; CCCP: carbonyl cyanide 3-chloroyphenylhydrazone; CYCS: cytochrome c, somatic; DNM1L/DRP1: dynamin 1-like; ER: endoplasmic reticulum; GBA: glucosylceramidase beta; GBA-PD: Parkinson disease with heterozygous GBA mutations; GD: Gaucher disease; GFP: green fluorescent protein; LC3B: microtubule-associated protein 1 light chain 3 beta; LC3B-II: lipidated form of microtubule-associated protein 1 light chain 3 beta; MitoGreen: MitoTracker Green; MitoRed: MitoTracker Red; MMP: mitochondrial membrane potential; MTOR: mechanistic target of rapamycin kinase; MYC: MYC proto-oncogene, bHLH transcription factor; NBR1: NBR1, autophagy cargo receptor; Non-GBA-PD: Parkinson disease without GBA mutations; PD: Parkinson disease; PINK1: PTEN induced putative kinase 1; PRKN/PARK2: parkin RBR E3 ubiquitin protein ligase; RFP: red fluorescent protein; ROS: reactive oxygen species; SNCA: synuclein alpha; SQSTM1/p62: sequestosome 1; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; VDAC1/Porin: voltage dependent anion channel 1; WT: wild type.

Although there is an increasing agreement that hypertension is associated with cerebrovascular compromise, relationships between blood pressure (BP) and cerebral blood flow are not fully understood. It is not known what BP level, and consequently what therapeutic goal, is optimal for brain perfusion. Moreover, there is limited data on how BP affects hippocampal perfusion, a structure critically involved in memory. We conducted a cross-sectional (n=445) and longitudinal (n=185) study of adults and elderly without dementia or clinically apparent stroke, who underwent clinical examination and brain perfusion assessment (age 69.2±7.5 years, 62% women, 45% hypertensive). Linear models were used to test baseline BP-blood flow relationship and to examine how changes in BP influence changes in perfusion. In the entire group, systolic BP (SBP) was negatively related to cortical (β=-0.13, P=0.005) and hippocampal blood flow (β=-0.12, P=0.01). Notably, this negative relationship was apparent already in subjects without hypertension. Hypertensive subjects showed a quadratic relationship between SBP and hippocampal blood flow (β=-1.55, P=0.03): Perfusion was the highest in subjects with mid-range SBP around 125 mm Hg. Longitudinally, in hypertensive subjects perfusion increased with increased SBP at low baseline SBP but increased with decreased SBP at high baseline SBP. Cortical and hippocampal perfusion decrease with increasing SBP across the entire BP spectrum. However, in hypertension, there seems to be a window of mid-range SBP which maximizes perfusion.

Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) and poor, intermediate or extensive CYP2D6-metabolizer phenotypes (>90% of patients). We report the final results of a Phase 2 trial and extension (NCT00358150) in previously untreated adult GD1 patients who had splenomegaly with thrombocytopenia and/or anemia and received 50 or 100 mg eliglustat tartrate (equivalent to 42 or 84 mg eliglustat) twice daily for 8 years. Nineteen of 26 patients completed the trial. After 8 years of eliglustat, mean spleen and liver volumes decreased by 69% and 34%, respectively. Mean hemoglobin concentration and platelet count increased by 2.2 g/dL and 113%, respectively. All patients met at least three of four therapeutic goals established for patients on long-term enzyme replacement therapy. Mean final values for patients with severe splenomegaly (n=6), moderate-to-severe anemia (n=6), severe thrombocytopenia (n=8), or osteoporosis (n=6) were similar to patients with milder disease at baseline and within long-term therapeutic goal thresholds. Median chitotriosidase levels decreased by 91%, CCL18 by 87%, glucosylsphingosine by 92%, and plasma glucosylceramide by 80%. Mean lumbar spine T-score increased by 0.96, moving from the osteopenic to the normal range. Mean quality-of-life scores, mostly below normal at baseline, moved into ranges seen in healthy adults. Eliglustat was well-tolerated; 98% of adverse events were mild or moderate and 94% were considered unrelated to treatment. Clinically meaningful improvements in all parameters continued or were maintained over 8 years, with the largest margins of improvement seen in the most severely affected patients.

Introduction/UNASSIGNED:There is practice variability in the treatment of patients with minor ischemic stroke with thrombolysis. We sought to determine which clinical factors physicians prioritize in thrombolysis decision-making for minor stroke using adaptive conjoint analysis. Methods/UNASSIGNED:tests. Statistical significance was set at α = .05. Results/UNASSIGNED:Fifty-four participants completed the survey; 61% were vascular neurologists and 93% worked in academic centers. All neurological deficits were ranked higher than age, premorbid status, or potential contraindications to thrombolysis. Differences between each successive mean preference weight were significant: motor (31.7%, standard deviation [SD]: 9.5), language/speech (24.1%, SD: 9.6), other neurological deficits (16.6%, SD: 6.4), premorbid status (12.9%, SD: 6.6), age (10.1%, SD: 6.3), and potential thrombolysis contraindication (4.7%, SD: 4.4). Conclusion/UNASSIGNED:In a conjoint analysis, surveyed US physicians in academic practice assigned greater weight to motor and speech/language deficits than other neurological deficits, patient age, relative contraindications to thrombolysis, and premorbid disability when deciding to thrombolyse patients with minor stroke.

Background and Purpose/UNASSIGNED:Use of emergency medical services (EMS) is associated with decreased door-to-needle time in acute ischemic stroke (AIS). Whether patient language affects EMS utilization and prenotification in AIS has been understudied. We sought to characterize EMS use and prenotification by patient language among intravenous tissue plasminogen activator (IV-tPA) tissue plasminogen (IV-tPA) treated patients at a single center with a large Spanish-speaking patient population. Methods/UNASSIGNED:We performed a retrospective analysis of all patients who received IV-tPA in our emergency department between July 2011 and June 2016. Baseline characteristics, EMS use, and prenotification were compared between English- and Spanish-speaking patients. Logistic regression was used to measure the association between patient language and EMS use. Results/UNASSIGNED:= .8). In a multivariable model adjusted for age, sex, and NIHSS, Spanish speakers remained more likely to use EMS (odds ratio: 1.8, 95% confidence interval: 1.1-3.0). Conclusion/UNASSIGNED:Emergency medical services usage was higher in Spanish speakers compared to English speakers among AIS patients treated with IV-tPA; however, prenotification rates did not differ. Future studies should evaluate differences in EMS utilization according to primary language and ethnicity.

OBJECTIVE:We aimed to determine the rates and predictors of resection and seizure freedom after bilateral stereo-electroencephalography (SEEG) implantation. METHODS:We reviewed 184 patients who underwent bilateral SEEG implantation (2009-2015). Noninvasive and invasive evaluation findings were collected. Outcomes of interest included subsequent resection and seizure freedom. Statistical analyses employed multivariable logistic regression and proportional hazard modeling. Preoperative and postoperative seizure frequency, severity, and quality of life scales were also compared. RESULTS:Following bilateral SEEG implantation, 106 of 184 patients (58%) underwent resection. Single seizure type (P = 0.007), a family history of epilepsy (P = 0.003), 10 or more seizures per month (P = 0.004), lower number of electrodes (P = 0.02), or sentinel electrode placement (P = 0.04) was predictive of undergoing a resection, as were lack of nonlocalized (P < 0.0001) or bilateral (P < 0.0001) ictal-onset zones on SEEG. Twenty-six of 81 patients (32% with follow-up greater than 1 year) remained seizure-free. Predictors of seizure freedom were single seizure type (P = 0.01), short epilepsy duration (P = 0.008), use of 2 or fewer antiepileptic drugs (AEDs) at the time of surgery (P = 0.0006), primary localization hypothesis involving the frontal lobe (P = 0.002), sentinel electrode placement only (P = 0.02), and lack of overlap between ictal-onset zone and eloquent cortex (P = 0.04), along with epilepsy substrate histopathology (P = 0.007). Complete resection of a suspected focal cortical dysplasia showed a trend to increased likelihood of seizure freedom (P = 0.09). The 44 of 55 patients (80%) who underwent resection and experienced seizure recurrence had >50% seizure reduction, as opposed to 26 of 45 patients (58%) who continued medical therapy alone (P = 0.003). Seventy-two percent of patients had a clinically meaningful quality of life improvement (>10% decrease in the Quality of Life in Epilepsy [QOLIE-10] score) at 1 year. SIGNIFICANCE/CONCLUSIONS:A strong preimplantation hypothesis of a suspected unifocal epilepsy increases the odds of resection and seizure freedom. We discuss a tailored approach, taking into account localization hypothesis and suspected epilepsy etiology in guiding implantation and subsequent surgical strategy.