Blake S. Gershon

Background: We have previously reported that a subset of nuclear-encoded mitochondrial genes involved in mitochondrial biogenesis was differentially expressed in Alzheimer's disease (AD) brains. These were associated with compromised biological pathways of mitochondria such as mitochondrial morphology, fragmentation, transmembrane potential and neuronal cell death. Objective: To use an array of energy production genes to determine whether expression changes compromise mitochondrial function and other important biological processes or pathways impacting the development of AD. Methods: RT2-PCR arrays were used to assess expression of mitochondrial energy production genes in AD brains. A subset of genes of interest was identified using Ingenuity Pathway Analysis. Expression values from this filtered group of genes were included in a mathematical model being developed to identify potential therapeutic targets for AD. Results: A majority of these genes was downregulated in AD brains. These AD-related gene expression changes were seen to affect a number of biological functions and pathologic conditions, including synthesis of ATP, generation of reactive oxygen species (ROS), and nerve cell viability. Most importantly, UQCRC1, an essential component of RCIII that is also involved in efficient assembly of the mitochondrial respirasome, was identified by our array analysis and, subsequently implicated by inclusion in our mathematical model to be a potential therapeutic target. Conclusions: There are significant gene expression changes in a small number of nuclear-encoded mitochondrial genes involved in energy production in AD brains. These affect ROS and nucleotide synthesis and pro- and anti-inflammatory pathways and reflect the mitochondrial dysfunction associated with neuronal cell death and AD.

Background Investigations into the effect of previous stroke on thrombectomy outcomes have yielded conflicting results, and are limited by small sample sizes. We present the results of a large single center retrospective study aimed at investigating the effect of chronic stroke laterality on thrombectomy outcomes. Methods A prospectively maintained database was queried for all thrombectomy cases conducted between December 2014 and January 2020, and patient imaging was prospectively reviewed for evidence of prior supratentorial infarction. Procedural, clinical, and demographic characteristics were recorded, and good clinical outcome was defined as a 90 day modified Rankin Scale (mRS) score of 2. Results The final analysis cohort included 555 patients, 79 of whom were found to have radiographic evidence of prior chronic infarcts. On univariate analysis, patients with any chronic supratentorial infarct achieved a lower rate of good clinical outcome than patients with no chronic infarct (22.8% vs 41.0%, p=0.0021). With regard to subgroups, this difference remained only in patients with ipsilateral (14.3%, p=0.0018) and bilateral (11.8%, p=0.015) lesions. Patients with chronic contralateral supratentorial infarcts were no less likely to achieve good outcomes (40.7%, p=0.98). After multivariate regression controlling for age, sex, and baseline mRS, chronic ipsilateral infarcts (OR 0.22, CI 0.07 to 0.67) and chronic bilateral infarcts (OR 0.19, CI 0.04 to 0.85) were the only independent predictors of poor outcome in endovascular thrombectomy patients. Conclusions In this single center retrospective study of thrombectomy patients with chronic supratentorial infarcts, the laterality of the previous stroke significantly affected the likelihood of good clinical outcomes.

BACKGROUND AND PURPOSE: Two-thirds of lymphatic malformations in children are found in the head and neck. Although conventionally managed through surgical resection, percutaneous sclerotherapy has gained popularity. No reproducible grading system has been designed to compare sclerotherapy outcomes on the basis of radiologic findings. We propose an MR imaging–based grading scale to assess the response to sclerotherapy and present an evaluation of its interrater reliability. MATERIALS AND METHODS: A grading system was developed to stratify treatment outcomes on the basis of interval changes observed on MR imaging. By means of this system, 56 consecutive cases from our institution with formally diagnosed head and neck lymphatic malformations treated by sclerotherapy were retrospectively graded. Each patient underwent pre- and posttreatment MR imaging. Each study was evaluated by 3 experienced neuroradiologists. Interrater reliability was assessed using the Krippendorff α statistic, intraclass coefficient, and 2-way Spearman ρ correlation. RESULTS: The overall Krippendorff α statistic was 0.93 (95% CI, 0.89–0.95), denoting excellent agreement among raters. Intraclass coefficients with respect to consistency and absolute agreements were both 0.97 (95% CI, 0.96–0.98), illustrating low variability. Every combination of individual rater pairs demonstrated statistically significant (P < .01) linear Spearman ρ correlations, with values ranging from 0.90 to 0.95. CONCLUSIONS: The proposed radiographic grading scale demonstrates excellent interrater reliability. Adoption of this new scale can standardize reported outcomes following sclerotherapy for head and neck lymphatic malformation and may aid in the investigation of future questions regarding optimal management of these lesions.

This chapter discusses the evolution of devices and techniques in endovascular stroke therapy, beginning with the development of effective intra-arterial thrombolysis in the late 1990s. We discuss the subsequent rise of early mechanical devices such as the Merci Retriever and Penumbra System, which, despite culminating in a series of failed trials in 2013, set the stage for the modern thrombectomy era. These first-generation devices gave way to the stent retriever, which would change the standard of care for acute large vessel occlusion stroke following a series of landmark trials in 2015. Finally, we discuss the more recent establishment of aspiration thrombectomy as an alternative to stent retrievers, as well as current investigations into novel devices and techniques that might further improve patient outcomes. Throughout, attention is paid to the regulatory landscape and evidentiary standards that shaped the field during its development in order to better understand how lessons from this history can guide future studies.

Background Most conventional 0.088 inch guide catheters cannot safely navigate intracranial vasculature. The objective of this study is to evaluate the safety of stroke thrombectomy using a novel 0.088 inch guide catheter designed for intracranial navigation. Methods This is a multicenter retrospective study, which included patients over 18 years old who underwent thrombectomy for anterior circulation large vessel occlusions. Technical outcomes for patients treated using the TracStar Large Distal Platform (TracStar LDP) or earlier generation TRX LDP were compared with a matched cohort of patients treated with other commonly used guide catheters. The primary outcome measure was device-related complications. Secondary outcome measures included guide catheter failure and time between groin puncture and clot engagement. Results Each study arm included 45 patients. The TracStar group was non-inferior to the control group with regard to device-related complications (6.8% vs 8.9%), and the average time to clot engagement was 8.89 min shorter (14.29 vs 23.18 min; p=0.0017). There were no statistically significant differences with regard to other technical outcomes, including time to recanalization (modified Thrombolysis In Cerebral Infarction (mTICI) ≥2B). The TracStar was successfully advanced into the intracranial internal carotid artery in 33 cases (73.33%); in three cases (6.67%), it was swapped for an alternate catheter. Successful reperfusion (mTICI 2B-3) was achieved in 95.56% of cases. Ninety-day follow-up data were available for 86.67% of patients, among whom 46.15% had an modified Rankin Score of 0–2%, and 10.26% were deceased. Conclusions Tracstar LDP is safe for use during stroke thrombectomy and was associated with decreased time to clot engagement. Intracranial access was regularly achieved.

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease that presents with symptoms such as cognitive impairment and a decline in memory. While often characterized by amyloid plaques and neurofibrillary tangles, there are a number of factors that play a role in this chronic disease. Recent studies have shown that mitochondrial function, and particularly, cytochrome oxidase (COX) activity is decreased in AD, disrupting mitochondrial energy production and potentially contributing to neurodegeneration. More recently, studies have indicated that inflammation plays an important role in the development of neurodegenerative diseases such as AD. Here, we analyzed changes in expression of 162 genes involved in mitochondrial energy production and biogenesis from 16 brain samples (11 AD and 5 age‐matched controls) and examined our findings through the lens of correlating any mitochondrial gene changes with inflammation processes.Method: Total RNA was isolated from 80‐180 mg of frozen brain tissue from the 16 samples. Total RNA was quantified and assessed for purity using Nanodrop and Bioanalyzer analysis. cDNA was prepared and applied to the Human Mitochondrial Energy Metabolism and the Mitochondria RT² Profiler™ PCR Arrays. The qPCR data was then analyzed using Qiagen RT² Profiler PCR Array Data Analysis version 3.5. The fold regulation and p‐value data was input into Ingenuity Pathway Analysis software to identify biologically important networks and pathways affected by AD.Result: Three energy metabolism genes – ATP4A, ATP6VIG3, and NDUFA8 – were found to be strongly up‐regulated in AD vs control brains while 6 mitochondrial biogenesis genes – UCP3, TIMM22, SLC25A21, SLC25A23, SLC25A25 and TIMM9 – were found to be strongly downregulated. Furthermore, two transcriptional regulators, RICTOR and KDM5A were activated while upstream regulators PPARGC1A and RB1 were inhibited in the AD vs control samples. The observed changes in mitochondrial gene expression in our data set were associated with neurodegeneration and inflammatory response networks.Conclusion: Gene expression data revealed an overall increase in inflammatory activity in AD brains compared to control brains. Further studies are needed to determine the clinical application of these findings, as an anti‐inflammatory approach to AD directed at mitochondrial genes/proteins could potentially slow the development or onset of the disease

Two patients, separated by 1 year, underwent mechanical thrombectomy using next generation, highly navigable 0.088-inch large bore catheters, which were navigated to and aspirated within the M1 middle cerebral artery segment. Case 1 demonstrates the first reported clinical application of this technique used in conjunction with stent retriever and direct aspiration through an intermediate catheter, resulting in modified thrombolysis in cerebral infarction (mTICI) score 3 recanalisation, and a 90-day modified Rankin Score of 1. In case 2, direct on-clot aspiration was applied through a 0.088-inch guide catheter in the left M1 segment, resulting in mTICI score 3 recanalisation and a National Institutes of Health Stroke Scale score of 1 at discharge. There was no evidence of untoward events in either case. Advancement of a 0.088-inch catheter into the M1 segment offers potential benefits to thrombectomy by improving device-thrombus interaction, inducing local flow arrest and protecting proximal vessels from embolus to new territories.

Two patients, separated by 1 year, underwent mechanical thrombectomy using next generation, highly navigable 0.088-inch large bore catheters, which were navigated to and aspirated within the M1 middle cerebral artery segment. Case 1 demonstrates the first reported clinical application of this technique used in conjunction with stent retriever and direct aspiration through an intermediate catheter, resulting in modified thrombolysis in cerebral infarction (mTICI) score 3 recanalisation, and a 90-day modified Rankin Score of 1. In case 2, direct on-clot aspiration was applied through a 0.088-inch guide catheter in the left M1 segment, resulting in mTICI score 3 recanalisation and a National Institutes of Health Stroke Scale score of 1 at discharge. There was no evidence of untoward events in either case. Advancement of a 0.088-inch catheter into the M1 segment offers potential benefits to thrombectomy by improving device-thrombus interaction, inducing local flow arrest and protecting proximal vessels from embolus to new territories.

Mitochondrial dysfunction is recognized as a critical component in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). Deficits in oxidative capacity and, specifically, cytochrome c oxidase (CO) activity have been repo