Faculty Bibliography

Importance:Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated. Objective:To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel. Design, Setting, and Participants:This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019. Main Outcomes and Measures:Diagnosis of Alzheimer disease. Results:A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration. Conclusions and Relevance:While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.

BACKGROUND AND IMPORTANCE/BACKGROUND:Spinal cord infarction is rare but can be extremely disabling. Prompt diagnosis and treatment of these infarcts is important for patient outcomes. While intravenous thrombolytic therapy is a well-established form of treatment in circumstances of cerebral stroke, it has only recently been successfully used in a few incidents of spinal cord ischemia. We present a case of anterior spinal artery (ASA) territory ischemia treated with ASA intra-arterial thrombolytic therapy. CLINICAL PRESENTATION/METHODS:A 52-year-old male presented with acute onset of severe lumbar pain, rapidly progressing paraplegia and loss of pain and temperature sensation, with preservation of proprioception and vibratory sensation at the L1 level and below on the right and at the L3 level and below on the left. MRI showed restricted diffusion involving the cord at and below L1 level, with normal cord T2 signal. Digital subtraction spinal angiography showed ASA cutoff in the descending limb at the level of L1. Intra-arterial tissue plasminogen activator (t-PA) combined with verapamil and eptifibatide was administered within the ASA and the patient had significant neurological improvement immediately postoperatively and at 8-month clinical follow-up. CONCLUSION/CONCLUSIONS:Direct ASA intra-arterial thrombolysis is feasible, and this drug combination might be an effective therapy for spinal stroke.

OBJECTIVE:Treatment of ruptured cerebral aneurysms by endovascular coiling is associated with better neurologic outcome when compared to neurosurgical clipping but has a higher risk for target aneurysm rebleeding after treatment. We hypothesize that aggressive retreatment of coiled aneurysms will lead to fewer recurrent hemorrhages as compared to historical values of 2.3-3.0%. METHODS:All first time GDC embolized cerebral aneurysms were retrospectively reviewed at a single institution from 2004 to 2015. Aneurysm retreatment after first time embolization was recorded as well as time to retreatment. Retreatment at our institution is routinely performed for incomplete coiling with etiologies including incomplete initial coiling, coil compaction, aneurysmal dilatation. Aneurysm re-rupture was treated with additional coiling. Kaplan-Meier survival analysis was performed to evaluate embolization durability. RESULTS:There were 214 aneurysms which met inclusion criteria. Mean (SD) follow-up was 2.74 (2.24) years. Aneurysms that were patent or recanalized were retreated. Mean (SD) time to retreatment was 9 (9) months. Overall, 46 (21.5%) aneurysms required retreatment. Retreatment was performed for coil compaction/remnant growth, recanalization, persistent remnant, and re-bleed. Two (0.9%) patients had recurrent aneurysm hemorrhage and both were treated with additional coil embolization. There were no new long-term neurologic deficits caused by aneurysm retreatment. CONCLUSIONS:Aggressive retreatment of previously ruptured, coiled cerebral aneurysms for persistent aneurysm patency reduces the recurrent hemorrhage risk to that historically seen in neurosurgically clipped aneurysms with minimal additional morbidity. This study validates a large body of literature demonstrating the significance of post-treatment aneurysm remnants and their association with recurrent hemorrhage.

BACKGROUND:Little is known about the effects of eradication of HCV on bone mineral density (BMD) and biomarkers of bone remodeling in HIV/HCV coinfected patients. METHODS:We prospectively assessed standardized BMD (sBMD) at the lumbar spine and femoral neck, World Health Organization (WHO) BMD categories at both sites, and plasma concentrations of soluble receptor activator of nuclear factor-kappaβ ligand (sRANKL), and osteoprotegerin (OPG) at baseline (the date of initiation of anti-HCV therapy) and at 96 weeks. RESULTS:A total of 238 patients were included, median age 49.5 years, 76.5% males, 48.3% with cirrhosis, 98.3% on antiretroviral therapy, median CD4+ cell count 527 cells/mm 3, 86.6% with HIV-1 RNA < 50 copies/mL. The prevalence of osteoporosis at baseline at the lumbar spine (LS) and femoral neck (FN) was 17.6% and 7.2%, respectively. Anti-HCV therapy comprised pegylated interferon and ribavirin (PegIFN-RBV) plus one direct-acting antiviral in 53.4%, PegIFN-RBV in 34.5%, and sofosbuvir/RBV in 12.2%. A total of 145 (60.9%) patients achieved sustained viral response (SVR). No significant effect of SVR was observed on sBMD for the interaction between time and SVR either in the LS (P=0.801) or the FN (P=0.911). Likewise, no significant effect of SVR was observed in plasma levels of sRANKL (P=0.205), OPG (P=0.249), and sRANKL/OPG ratio (P=0.123) for the interaction between time and SVR. No significant correlation was found between fibrosis by transient elastography, and LS and FN sBMD, at baseline, and week 96. CONCLUSIONS:SVR was not associated with significant changes in BMD nor biomarkers of bone remodeling in HIV/HCV-coinfected persons.

Recently the coronavirus disease (COVID-19) outbreak has been declared a pandemic. Despite its aggressive extension and significant morbidity and mortality, risk factors are poorly characterized outside China. We designed a registry, HOPE COVID-19 (NCT04334291), assessing data of 1021 patients discharged (dead or alive) after COVID-19, from 23 hospitals in 4 countries, between 8 February and 1 April. The primary end-point was all-cause mortality aiming to produce a mortality risk score calculator. The median age was 68 years (IQR 52-79), and 59.5% were male. Most frequent comorbidities were hypertension (46.8%) and dyslipidemia (35.8%). A relevant heart or lung disease were depicted in 20%. And renal, neurological, or oncological disease, respectively, were detected in nearly 10%. Most common symptoms were fever, cough, and dyspnea at admission. 311 patients died and 710 were discharged alive. In the death-multivariate analysis, raised as most relevant: age, hypertension, obesity, renal insufficiency, any immunosuppressive disease, 02 saturation < 92% and an elevated C reactive protein (AUC = 0.87; Hosmer-Lemeshow test, p > 0.999; bootstrap-optimist: 0.0018). We provide a simple clinical score to estimate probability of death, dividing patients in four grades (I-IV) of increasing probability. Hydroxychloroquine (79.2%) and antivirals (67.6%) were the specific drugs most commonly used. After a propensity score adjustment, the results suggested a slight improvement in mortality rates (adjusted-OR_{hydroxychloroquine} 0.88; 95% CI 0.81-0.91, p = 0.005; adjusted-OR_antiviral 0.94; 95% CI 0.87-1.01; p = 0.115). COVID-19 produces important mortality, mostly in patients with comorbidities with respiratory symptoms. Hydroxychloroquine could be associated with survival benefit, but this data need to be confirmed with further trials. Trial Registration: NCT04334291/EUPAS34399.

The ESM was updated in the original article to replace an incorrect version that was published with tracked changes notes.

BACKGROUND:Resection of large nerve sheath tumors in the lumbar spine using minimally invasive approaches is challenging, as approaches to tumors in this region may require facetectomy or partial resection of adjacent ribs for access to the involved neuroforamen and instrumentation across the involved joint to prevent subsequent kyphotic deformity. OBJECTIVE:To describe a robot-assisted retroperitoneal approach for resection of a lumbar nerve sheath tumor, obviating the need for facetectomy and instrumentation. The operation is described, together with intraoperative images and an annotated video, in the context of a schwannoma arising from the right L1 root. METHODS:The operation was performed by a urologic surgeon and a neurosurgeon. The patient was placed in lateral position, and the da Vinci Xi robot was used for retroperitoneal access via 5 ports along the right flank. Ultrasound was used to localize the tumor within the psoas. The tumor capsule was defined and released. Encountered nerves were stimulated, allowing small sensory nerves to be identified and safely divided. The tumor was traced into the right L1-L2 neuroforamen and removed. RESULTS:Complete en bloc resection of the tumor was achieved, including the paraspinal and foraminal components, without any removal of bone and without violation of the dura. CONCLUSION/CONCLUSIONS:In selected patients, a robot-assisted retroperitoneal approach represents a minimally invasive alternative to traditional approaches for resection of lumbar nerve sheath tumors. This approach obviates the need for bone removal and instrumented spinal fusion. Interdisciplinary collaboration, as well as use of adjunctive technologies, including intraoperative ultrasound and neurophysiologic monitoring, is advised.

Background: We assessed cost-effectiveness of insertable cardiac monitors (ICMs) in a US cryptogenic stroke population. Materials & methods: We modelled lifetime costs and quality-adjusted life years for three monitoring strategies post cryptogenic stroke: ICM starting immediately, ICM starting after Holter monitoring (delayed ICM) and standard of care involving intermittent ECG and Holter monitoring. Patient characteristics and detection efficacy were based on the CRYSTAL-AF trial. AF detection altered the modelled anticoagulation therapy and subsequent stroke and bleed risks. Results & conclusion: Immediate ICM was found to be cost-effective versus standard of care and cost-saving versus delayed ICM. Results were robust to sensitivity analyses. ICMs are a cost-effective diagnostic tool for the prevention of recurrent stroke in a US cryptogenic stroke population.

OBJECTIVE:1) to describe the clinical manifestations of functional motor disorders (FMDs) coexisting with other neurological diseases ("comorbid-FMDs"); 2) to compare comorbid-FMDs to FMDs not overlapping with other neurological diseases ("pure FMDs"). METHODS:For this multicenter observational study, we enrolled outpatients with a definite diagnosis of FMDs attending 25 tertiary movement disorders centers in Italy. Each subject with FMDs underwent a detailed clinical assessment including screening for other associated neurological conditions. Groups comparisons (comorbid-FMDs versus pure-FMDs) were performed in order to compare demographical and clinical variables. Logistic regression models were created to estimate adjusted odds ratio (OR; 95% confidence interval) of comorbid-FMDs (dependent variable) in relation to sociodemographic and clinical characteristics (independent variables). RESULTS:Out of 410 FMDs, 21.7% (n=89) of patients had comorbid-FMDs. The most frequent coexisting neurological diseases were migraine, cerebrovascular disease and parkinsonism. In the majority of cases (86.5%) FMDs appeared after the diagnosis of neurological disease. Patients with comorbid-FMDs were older, had more frequent tremor, non-neurological comorbidities, paroxysmal non-epileptic seizures, major depressive disorders, and benzodiazepine intake. Multivariate regression analysis showed that diagnosis of comorbid-FMDs was more likely associated with longer time lag to reach the final diagnosis of FMDs, presence of tremor and non-neurological comorbidities. CONCLUSIONS:Our findings highlight the need of a prompt diagnosis of FMDs, given their relatively high frequency of associated neurological and non-neurological diseases.