Neurology Commons^™

The Tmem106b T186s Coding Variant Increases Neurite Arborization And Synaptic Density In Primary Hippocampal Neurons, Quynh Nguyen, Caleb A Wood, Peter J Kim, Joanna L Jankowsky

Faculty, Staff and Students Publications

The lysosomal protein TMEM106B was identified as a risk modifier of multiple dementias including frontotemporal dementia and Alzheimer’s disease. The gene comes in two major haplotypes, one associated with disease risk, and by comparison, the other with resilience. Only one coding polymorphism distinguishes the two alleles, a threonine-to-serine substitution at residue 185 (186 in mouse), that is inherited in disequilibrium with multiple non-coding variants. Transcriptional studies suggest synaptic, neuronal, and cognitive preservation in human subjects with the protective haplotype, while murine in vitro studies reveal dramatic effects of TMEM106B deletion on neuronal development. Despite this foundation, the field has not …

Framework For Accurate Classification Of Self-Reported Stress From Multisession Functional Mri Data Of Veterans With Posttraumatic Stress, Rahul Goel, Teresa Tse, Lia J Smith, Andrew Floren, Bruce Naylor, M Wright Williams, Ramiro Salas, Albert S Rizzo, David Ress

Faculty, Staff and Students Publications

Background: Posttraumatic stress disorder (PTSD) is a significant burden among combat Veterans returning from the wars in Iraq and Afghanistan. While empirically supported treatments have demonstrated reductions in PTSD symptomatology, there remains a need to improve treatment effectiveness. Functional magnetic resonance imaging (fMRI) neurofeedback has emerged as a possible treatment to ameliorate PTSD symptom severity. Virtual reality (VR) approaches have also shown promise in increasing treatment compliance and outcomes. To facilitate fMRI neurofeedback-associated therapies, it would be advantageous to accurately classify internal brain stress levels while Veterans are exposed to trauma-associated VR imagery. Methods: Across 2 sessions, we used fMRI …

Postsurgical Morbidity And Mortality Favorably Informs Deep Brain Stimulation For New Indications Including Schizophrenia And Schizoaffective Disorder, Judith M Gault, Patrick Hosokawa, Daniel Kramer, Elyn R Saks, Paul S Appelbaum, John A Thompson, Ann Olincy, Nicola Cascella, Akira Sawa, Wayne Goodman, Nidal Moukaddam, Sameer A Sheth, William S Anderson, Rachel A Davis

Faculty, Staff and Students Publications

BACKGROUND: Deep brain stimulation (DBS) shows promise for new indications like treatment-refractory schizophrenia in early clinical trials. In the first DBS clinical trial for treatment refractory schizophrenia, despite promising results in treating psychosis, one of the eight subjects experienced both a symptomatic hemorrhage and an infection requiring device removal. Now, ethical concerns about higher surgical risk in schizophrenia/schizoaffective disorder (SZ/SAD) are impacting clinical trial progress. However, insufficient cases preclude conclusions regarding DBS risk in SZ/SAD. Therefore, we directly compare adverse surgical outcomes for all surgical procedures between SZ/SAD and Parkinson's disease (PD) cases to infer relative surgical risk relevant to …

Mass Spectrometry Imaging As An Emerging Tool For Studying Metabolism In Human Brain Organoids, Gerarda Cappuccio, Saleh M Khalil, Sivan Osenberg, Feng Li, Mirjana Maletic-Savatic

Faculty, Staff and Students Publications

Human brain organoids are emerging models to study human brain development and pathology as they recapitulate the development and characteristics of major neural cell types, and enable manipulation through an in vitro system. Over the past decade, with the advent of spatial technologies, mass spectrometry imaging (MSI) has become a prominent tool for metabolic microscopy, providing label-free, non-targeted molecular and spatial distribution information of the metabolites within tissue, including lipids. This technology has never been used for studies of brain organoids and here, we set out to develop a standardized protocol for preparation and mass spectrometry imaging of human brain …

Linked-Read Based Analysis Of The Medulloblastoma Genome, Melissa Zwaig, Michael J Johnston, John J Y Lee, Hamza Farooq, Marco Gallo, Nada Jabado, Michael D Taylor, Jiannis Ragoussis

Faculty, Staff and Students Publications

INTRODUCTION: Medulloblastoma is the most common type of malignant pediatric brain tumor with group 4 medulloblastomas (G4 MBs) accounting for 40% of cases. However, the molecular mechanisms that underlie this subgroup are still poorly understood. Point mutations are detected in a large number of genes at low incidence per gene while the detection of complex structural variants in recurrently affected genes typically requires the application of long-read technologies.

METHODS: Here, we applied linked-read sequencing, which combines the long-range genome information of long-read sequencing with the high base pair accuracy of short read sequencing and very low sample input requirements.

RESULTS: …

Cerebral Microdialysis And Glucopenia In Traumatic Brain Injury: A Review, Himanshu Sharma, John P Mcginnis, Katherine E Kabotyanski, Shankar P Gopinath, Jerry C Goodman, Claudia Robertson, Jovany Cruz Navarro

Faculty, Staff and Students Publications

Traditionally, intracranial pressure (ICP) and partial brain tissue oxygenation (PbtO2) have been the primary invasive intracranial measurements used to guide management in patients with severe traumatic brain injury (TBI). After injury however, the brain develops an increased metabolic demand which may require an increment in the oxidative metabolism of glucose. Simultaneously, metabolic, and electrical dysfunction can lead to an inability to meet these demands, even in the absence of ischemia or increased intracranial pressure. Cerebral microdialysis provides the ability to accurately measure local concentrations of various solutes including lactate, pyruvate, glycerol and glucose. Experimental and clinical data demonstrate that such …

Cerebellar Dysfunction In Rodent Models With Dystonia, Tremor, And Ataxia, Meike E Van Der Heijden, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Dystonia is a movement disorder characterized by involuntary co- or over-contractions of the muscles, which results in abnormal postures and movements. These symptoms arise from the pathophysiology of a brain-wide dystonia network. There is mounting evidence suggesting that the cerebellum is a central node in this network. For example, manipulations that target the cerebellum cause dystonic symptoms in mice, and cerebellar neuromodulation reduces these symptoms. Although numerous findings provide insight into dystonia pathophysiology, they also raise further questions. Namely, how does cerebellar pathophysiology cause the diverse motor abnormalities in dystonia, tremor, and ataxia? Here, we describe recent work in rodents …

Focused Ultrasound Thalamotomy: Correlation Of Postoperative Imaging With Neuropathological Findings, Sarah E Blitz, Matthew Torre, Melissa M J Chua, Sarah L Christie, Nathan J Mcdannold, G Rees Cosgrove

Duncan NRI Faculty and Staff Publications

Magnetic resonance-guided high-intensity focused ultrasound (MRgFUS) is a rapidly developing technique used for tremor relief in tremor-predominant Parkinson's disease (PD) and essential tremor that has demonstrated successful results. Here, we describe the neuropathological findings in a woman who died from a fall 10 days after successful MRgFUS for tremor-predominant PD. Histological analysis demonstrates the characteristic early postoperative MRI findings including 3 distinct zones on T2-weighted imaging: (1) a hypointense core, (2) a hyperintense region with hypointense rim, and (3) a slightly hyperintense, poorly marginated surrounding area. Histopathological analyses also demonstrate the suspected cellular processes composing each of these regions including …

Codon-Optimized Tdp-43 Mediates Neurodegeneration In A Drosophila Model Of Als/Ftld, Tanzeen Yusuff, Ya-Chu Chang, Tzu-Kang Sang, George R Jackson, Shreyasi Chatterjee

Faculty, Staff and Students Publications

Transactive response DNA binding protein-43 (TDP-43) is known to mediate neurodegeneration associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The exact mechanism by which TDP-43 exerts toxicity in the brains, spinal cord, and lower motor neurons of affected patients remains unclear. In a novel Drosophila melanogaster model, we report gain-of-function phenotypes due to misexpression of insect codon-optimized version of human wild-type TDP-43 (CO-TDP-43) using both the binary GAL4/UAS system and direct promoter fusion constructs. The CO-TDP-43 model showed robust tissue specific phenotypes in the adult eye, wing, and bristles in the notum. Compared to non-codon optimized …

The Role Of Hyperexcitability In Gliomagenesis, Eric A Goethe, Benjamin Deneen, Jeffrey Noebels, Ganesh Rao

Faculty, Staff and Students Publications

Glioblastoma is the most common malignant primary brain tumor. Recent studies have demonstrated that excitatory or activity-dependent signaling-both synaptic and non-synaptic-contribute to the progression of glioblastoma. Glutamatergic receptors may be stimulated via neuron-tumor synapses or release of glutamate by the tumor itself. Ion currents generated by these receptors directly alter the structure of membrane adhesion molecules and cytoskeletal proteins to promote migratory behavior. Additionally, the hyperexcitable milieu surrounding glioma increases the rate at which tumor cells proliferate and drive recurrent disease. Inhibition of excitatory signaling has shown to effectively reduce its pro-migratory and -proliferative effects.

Editorial: Peripheral Stimulation: Neuromodulation Of The Central Nervous System Through Existing Pathways, Musa Ozturk, Julio Cesar Hernandez-Pavon, Alexander Kent, Jose L Pons, Ilknur Telkes, Arjun Tarakad

Faculty, Staff and Students Publications

No abstract provided.

Association Of Human Leukocyte Antigen Alleles With Carbamazepine-Or Lamotrigine-Induced Stevens-Johnson Syndrome And Toxic Epidermal Necrolysis In An Iranian Population: A Case-Control Study, Ladan Dastgheib, Farima Rostami, Behrouz Gharesi-Fard, Ali Akbar Asadi-Pooya, Saba Namjoo, Foroozan Tahmasebi, Maryam Hadibarhaghtalab

Department of Neurology Faculty Papers

Background: Genetic diversity in human leukocyte antigen (HLA) alleles across populations is a significant risk factor for drug-induced severe cutaneous adverse reactions (SCARs), e.g., carbamazepine (CBZ)- and lamotrigine (LTG)-induced StevensJohnson syndrome (SJS), and toxic epidermal necrolysis (TEN). The present study aimed to investigate the frequency of different HLA alleles in Iranian patients with CBZ- and LTG-induced SJS/TEN.

Methods:A case-control study was conducted from 2011 to 2018 at various hospitals affiliated with Shiraz University of Medical Sciences (Shiraz, Iran). A total of 31 patients receiving anticonvulsant drugs (CZB or LTG) were recruited and divided into two groups. The drug-induced group …

Safety And Tolerability Results Of Atogepant For The Preventive Treatment Of Episodic Migraine From A 40-Week, Open-Label Multicenter Extension Of The Phase 3 Advance Trial, Brad C Klein, Rosa Miceli, Lawrence Severt, Peter Mcallister, Laszlo Mechtler, Jennifer Mcvige, Merle Diamond, Michael J. Marmura, Hua Guo, Michelle Finnegan, Joel M Trugman

Department of Neurology Faculty Papers

Background: Atogepant is a United States Food and Drug Administration-approved oral calcitonin gene-related peptide receptor antagonist for the preventive treatment of episodic migraine. The study objective was to evaluate the long-term safety and tolerability of atogepant in participants who completed the phase 3 ADVANCE trial (NCT03777059).

Methods: This 40-week, open-label extension trial (NCT03939312) monitored safety in participants receiving oral atogepant 60 mg once daily, followed by a four-week safety follow-up period.

Results: Of the 685 participants taking at least one dose of atogepant, the treatment period was completed by 74.6% of participants with a mean (standard …