Nervous System Diseases Commons^™

Neuronal Activity-Dependent Gene Dysregulation In C9orf72 I3neuronal Models Of Als/Ftd Pathogenesis, Layla T. Ghaffari, Emily A. Welebob, Sarah E. Bond Newton, Ashley V. Boehringer, Kelly L. Cyliax, Piera Pasinelli, Davide Trotti, Aaron R. Haeusler

Farber Institute for Neuroscience Faculty Papers

The GGGGCC nucleotide repeat expansion (NRE) mutation in the C9ORF72 (C9) gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuronal activity plays an essential role in shaping biological processes within both healthy and neurodegenerative disease scenarios. Here, we show that at baseline conditions, C9-NRE-induced pluripotent stem cell-cortical neurons display aberrations in several pathways, including synaptic signaling and transcriptional machinery, potentially priming diseased neurons for an altered response to neuronal stimulation. Indeed, exposure to two pathophysiologically relevant stimulation modes, prolonged membrane depolarization or a blockade of K⁺ channels, followed by RNA sequencing, induces …

Migraine-Related Disability According To Headache Frequency Subclassifications: A Systematic Review And Meta-Analysis, Manjit Singh Matharu, Stephen Silberstein, Hsiangkuo Yuan, Deborah Edgar, Roos Colman, Todd Schwedt, Michel Lanteri-Minet, Mark Obermann

Department of Jefferson Headache Center Papers and Presentations

BackgroundThis systematic review and meta-analysis synthesized migraine-related disability outcomes according to headache frequency subclassifications, including low-frequency episodic migraine (LFEM), high-frequency episodic migraine (HFEM) and chronic migraine (CM).MethodsWe searched the PubMed and Cochrane Library (CENTRAL) up to 16 October 2024 for peer-reviewed non-interventional studies reporting migraine-related disability outcomes in CM and subclassifications of episodic migraine (e.g. LFEM and HFEM). Eligible studies with an HFEM subgroup were grouped by headache frequency measure (monthly migraine days [MMD] or monthly headache days [MHD]), HFEM subgroup, disability parameter and study setting. Random-effects meta-analyses were conducted on groups with three or more studies, with the results …

Predictive Gene Expression Signatures For Alzheimer's Disease Using Post-Mortem Brain Tissue, Ashley Duche, Oliver Tan, Andrius Baskys, Rachita K. Sumbria, Moom R. Roosan

Pharmacy Faculty Articles and Research

Background: Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques and tau protein aggregates in the brain. These pathological features manifest in specific regions, but mechanisms rendering some areas more susceptible to early AD-related changes remain poorly understood. To address this, we developed predictive gene expression signatures to explore molecular mechanisms underlying regional vulnerability to AD pathology.

Methods: Post-mortem brain tissues from participants of the Religious Orders Study and Memory and Aging Project (ROSMAP), Mayo Clinic, and Mount Sinai Brain Bank (MSBB) were used to derive gene expression signatures from six brain regions affected at varying …

Neurofilament Light (Nfl) Chain Levels Predict Clinical Decline In Alzheimer’S Disease: A Systematic Review And Meta-Analysis, Kim Thomas, Paul Spin, Nikita Sir, Kevin Hou, Nicholas J. Ashton, Henrik Zetterberg, Sonya Miller, Carol Pringle, Richard G. Stefanacci, Claude M. Wischik, Serge Gauthier

College of Population Health Faculty Papers

BACKGROUND: Regulatory approval of new investigational Alzheimer's disease (AD) therapies could be accelerated if reasonably likely surrogate endpoints could be used. Neurofilament light chain (NfL) has potential utility as a prognostic biomarker of neurodegeneration in AD.

OBJECTIVE: To synthesize available evidence on the relationship between baseline NfL levels and longitudinal clinical decline.

METHODS: A systematic literature review identified 19 eligible studies, contributing 37 longitudinal statistical models evaluating the association between baseline NfL (plasma or cerebrospinal fluid [CSF]) with subsequent clinical decline based on validated clinical scales including Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale, and Clinical Dementia Rating. …

Ocular Blood Flow And Retinal Vascular Reactivity In Alzheimer’S Disease: A Systematic Review Of Retinal Images, Tori Sayers, Alexa Nichols, Amin Ibrahim, Igor Zwir, Andrew Tsin, Lorena Flores-Hernandez, Gladys E. Maestre, Jesus D. Melgarejo

Research Colloquium

Background: Alzheimer’s disease (AD) is the most common form of dementia and one of the leading causes of disability and death in the United States¹. Research efforts aim to identify pathological changes that may help support earlier detection of AD and lead to more accessible tools for monitoring disease progression². The retina is being explored as a potential non-invasive marker of AD, reflecting the shared embryology and microvasculature features between the retina and the brain. Although research has focused on structural changes in retinal vessel diameters and density, few studies have evaluated functional markers of retinal …

Ischemic Stroke In A Patient With Atrial Fibrillation Despite Therapeutic Anticoagulation With Rivaroxaban: A Clinical Reminder, Ridwan Ademola Lawal, Angelica Lan Pham

Research Colloquium

Background: Atrial fibrillation is a well-established risk factor for cardioembolic stroke, with anticoagulation significantly reducing this risk. However, breakthrough ischemic strokes can still occur in anti-coagulated patients, with an estimated annual incidence of 1-2% despite appropriate direct oral anticoagulant (DOAC) therapy. These rare but consequential events challenge clinicians to maintain high diagnostic vigilance, especially in patients presenting with atypical or subtle neurological symptoms. Here, we present a case of an embolus in a patient on long-term rivaroxaban therapy, underscoring a vital clinical teaching point: therapeutic anticoagulation does not eliminate stroke risk, and homonymous hemianopsia may be the only presenting feature. …

A Unique Case Of Limbic Encephalitis In The Rio Grande Valley, A Case Report, Osiris Fernandez-Betances, Kevin A. Garcia Valdez

Research Colloquium

Background: Limbic encephalitis (LE) is a rare but increasingly recognized autoimmune subtype of encephalitis that primarily affects the limbic system, which includes the medial temporal lobe, hippocampus, frontobasal, and cingulate cortex. LE was initially believed to cause inflammation restricted to the limbic region; however, subsequent studies have shown that the disease process can extend to other brain areas, resulting in a wide range of neurological and psychiatric manifestations.

Case Presentation: We present the case of a 64-year-old Hispanic male with multiple emergency department visits due to progressive neurologic symptoms. From late November of 2023 to January of 2024, the patient …

Wernicke’S Encephalopathy With Classic Triad And Normal Mri In A Young Woman Following Rapid-Sequence Bariatric And Biliary Surgery, Hugo Zamarron, Nina Mourao, Roberto A. Cruz Saldana

Research Colloquium

Background: Wernicke’s encephalopathy is a life-threatening neurological disorder caused by thiamine deficiency, most commonly associated with alcoholism. However, postoperative nutritional deficiencies in young patients undergoing bariatric procedures are increasingly recognized. This case is unique due to the rapid succession of bariatric and cholecystectomy surgeries, development of classic Wernicke’s symptoms with a normal MRI, and diagnostic delay due to overlapping differential diagnoses including intracranial hypotension and myelopathy.

Case Presentation: A 22-year-old woman with class III obesity underwent sleeve gastrectomy in July 2022, followed by significant weight loss and persistent intractable vomiting. Due to suspected gallbladder disease, she underwent a cholecystectomy in …

Corticobasal Syndrome With Mixed Pathology In The Absence Of Grn Mutation: A Clinico-Pathological Case Of Ftld-Tdp With Coexisting Alzheimer’S And Lewy Body Pathology, Hugo Zamarron, David Irwin, Jeffery Phillips, Edward Lee, Matthew Tisdall, Corey Mcmillan

Research Colloquium

Background: Corticobasal syndrome (CBS) is a neurodegenerative disorder characterized by often asymmetric fronto-pariteal and extra-pyramidal features that is traditionally associated with tauopathy, but pathological findings are heterogenous, including other forms of frontotemporal lobar degeneration (FTLD) and mixed pathologies of aging. We present clinical, radiographic, and histopathologic features of asymmetry in a unique patient with CBS and underlying FTLD with TDP-43 pathology (FTLD-TDP), co-occurring with other age-related pathologies.

Case Presentation: A 76-year-old man presented with progressive cognitive and motor dysfunction including asymmetric parkinsonism, left-sided dystonia and rigidity, apraxia, visuospatial impairment, and a subtle social disorder including apathy and social withdrawal. The …

Bilateral Small Vessel Strokes In A Young Male With Coccidioidal Meningitis And Suspected Cns Vasculitis, Hugo Zamarron, Ahsan Ali

Research Colloquium

Background: Cerebral small vessel strokes in young, otherwise healthy adults without traditional vascular risk factors are rare and warrant further investigation. Central nervous system (CNS) vasculitis is an uncommon etiology that may be triggered by infections, including fungal pathogens. This case is notable for a suspected primary CNS vasculitis manifesting as bilateral deep infarcts in the setting of Coccidioidal meningitis. It highlights the importance of considering fungal infections and vasculitis in the differential diagnosis of stroke in younger patients.

Case Presentation: A 32-year-old previously healthy male presented with fever, headache, and was diagnosed with aseptic meningitis. He was later readmitted …

Rapid Mapping Of Spinal And Supraspinal Connectome Via Self-Targeting Glucose-Based Carbon Dots, Yasin B. Seven, Elif S. Seven, Emel Kirbas Cilingir, Komal Parikh, Mehmet Aydin, Edward K. Luca, Jayakrishnan Nair, Roger M. Leblanc

Department of Physical Therapy Faculty Papers

The spinal cord is a highly dynamic network, playing significant roles in the vital functions of the brain. Disorders of the spinal cord, such as spinal cord injury and amyotrophic lateral sclerosis (ALS), are associated with neurodegeneration, often resulting in morbidity and mortality. The blood-brain barrier (BBB) poses a major challenge to imaging and therapeutic agents because less than 2% of small-molecule drugs and almost no large-molecule drugs can cross the BBB. Furthermore, spatial spectroscopy studies have shown highly heterogeneous BBB crossing with significant accumulation at the unintended brain regions. Thus, targeting systems that can cross the BBB at the …

Early Blood Pressure Targets In Acute Spinal Cord Injury: A Randomized Clinical Trial, Ruba Sajdeya, N. David Yanez, Michael Kampp, Michael D. Goodman, David Zonies, Brandon Togioka, Andrew Nunn, Robert D. Winfield, Niels D. Martin, Anirudh Kohli, Toan T. Huynh, David O. Okonkwo, Roy A. Poblete, Emily J. Gilmore, Randall M. Chesnut, Aaron E. Bunnell, Tetsu Ohnuma, Mona Hashemaghaie, Miriam M. Treggiari

Department of Surgery Faculty Papers

IMPORTANCE: Early blood pressure management is central to neurologic resuscitation of spinal cord injury; however, the role of augmented blood pressure is unclear.

OBJECTIVE: To compare the efficacy and safety of augmented vs conventional blood pressure on 6-month neurologic outcomes after acute spinal cord injury.

DESIGN, SETTING, AND PARTICIPANTS: This multicenter randomized clinical trial took place from October 3, 2017, to July 26, 2023, and assessed patients 18 years or older with spinal cord injury followed up for 6 months at 13 large US trauma centers.

INTERVENTIONS: Patients were equally randomized to augmented (>85-90 mm Hg) or conventional ( …

A Single Center Study Of The Symbol Digit Modalities Test As A Screening Tool For Cognitive Impairment In Parkinson’S Disease, Daniyell Thomason, Morganne Manuel, Shannin Moody, Jesus Lovera, Brain Copeland, Deidre Devier

School of Medicine Faculty Publications

Background: Parkinson’s Disease (PD) can include physical signs and possibly cognitive impairment, resulting from the convergence of pathologicalprocesses involving dopaminergic dysfunction, accumulation ofalpha-synuclein, cholinergic deficits, and disruption of otherneurotransmitter systems. We used screening tests to evaluate thecharacteristics of cognitive performance in patients with PD and to assess their validity compared tothe Montreal Cognitive Assessment (MoCA). Methods: This is a natural history study of participants with PD and controls screened for possible cognitive impairment using the MoCA, Symbol Digit Modalities Test (SDMT), and King-Devick (KD). The groups were compared on performance and then factors associated with cognitive performance (age, diagnosis, and …

Reaching International Consensus On The Definition Of Refractory Migraine Using The Delphi Method, Jennifer Robblee, Fawad A. Khan, Michael J. Marmura, Hope L. O'Brien, Lawrence D. Robbins, Marielle K. Samaha, Morris Levin, Simona Sacco, Raffaele Ornello, Stephanie J. Nahas, Heike Hesse, Annika Ehrlich, Adam S. Sprouse-Blum, Christina Sun-Edelstein, Bronwyn Jenkins, Elizabeth K, Seng, Shivang Joshi, Meredith J. Barad, Mi Ji Lee, Sheena K. Aurora, Mario Fernando Prieto Peres

Department of Neurology Faculty Papers

Aim: Despite its frequency in tertiary headache centers, the International Classification of Headache Disorders, 3rd edition (ICHD-3) does not include refractory migraine. Multiple definitions have been proposed with a recent 2020 proposal for both refractory migraine and resistant migraine by the European Headache Federation (EHF). The aim is to reach an international consensus on the definition of refractory migraine.

Methods: This study is a Delphi consensus carried out by a group of international experts in headache medicine. Following a focus group, a panel of 20 experts and one facilitator reviewed the EHF proposed criteria to build upon their definitions. The …

High Energy Consumption Characterizes Abnormal Brain State Transitions In Temporal Lobe Epilepsy, Sam S. Javidi, Qirui Zhang, Ankeeta Ankeeta, Michael R. Sperling, Joseph I. Tracy

Farber Institute for Neuroscience Faculty Papers

Temporal lobe epilepsy (TLE) patients experience shifts between non-seizing and seizing brain states, but the structural networks underlying these transitions remain undefined and poorly characterized. We detected dynamic brain states in resting-state fMRI and constructed linked structural networks utilizing multi-shell diffusion-weighted MR data. Leveraging network control theory, we interrogated the structural data for all possible brain state transitions, identifying those requiring abnormal levels of transition energy (low or high) in TLE compared to matched healthy participants (n's = 25). Results revealed three transitions requiring significantly higher energy in TLE; no abnormally low-energy transitions were observed. In HPs, transitions relied on …

Emerging Clinical Role Of Tavapadon, A Novel Dopamine Partial Agonist, In The Treatment Of Parkinson’S Disease, Alan D. Kaye, Bennett M. Ford, Brennan M. Abbott, Kalob M. Broocks, Sofia Novacic, Sahar Shekoohi

School of Medicine Faculty Publications

Tavapadon, a novel oral dopamine-D1R/D5R partial agonist, has been studied in recent years for the treatment of late-stage development Parkinson’s disease (PD). Levodopa, a dopamine precursor that currently remains the gold-standard first-line therapy for PD motor symptoms, serves as a benchmark against emerging dopaminergic agents. By selectively activating D1-family receptors on direct-pathway medium neurons, Tavapadon differs in that it delivers levodopa-level motor benefit while avoiding its many D2R/D3R-mediated adverse effects. In placebo-controlled trials, Tavapadon produced clear, clinically meaningful gains in motor function and day-to-day activities, as captured by the Unified Parkinson’s Disease Rating Scale (UPDRS). Recent late-stage results have revealed …

Biofluid Biomarkers Aid In Diagnosing And Developing Improved Treatments For People With Alzheimer's Disease, Jonatan A. Lopez

University Honors Theses

Dementia is a disease in which daily life is disrupted by a loss of cognitive function. Late-onset Alzheimer's disease (AD) is the most common dementia that largely begins to affect individuals in their mid 60s or older. AD was selected as the focus of this paper because it is the most common form of dementia, accounting for 50-70% of dementia cases. A typical diagnostic approach used by physicians starts with a simple clinical test, the Mini-Mental State Examination (MMSE), when cognitive decline is suspected in a patient. Then if there is enough evidence to suggest AD, a physician would order …

The 9th Annual Lafora Science Symposium: A Rare Epilepsy Community Makes Progress Towards Clinical Readiness, Meredith I. Williams, Katherine J. Donahue, Pascual Sanz, Souad Messahel, Jose M. Serratosa, Jordi Duran, Roberto Michelucci, Lorenzo Muccioli, Antonio Delgado-Escueta, Viet-Hong Nguyen, Berge A. Minassian, Matthew S. Gentry

Pharmacy Faculty Articles and Research

Lafora disease (LD) is a fatal childhood progressive myoclonus epilepsy and glycogen storage disease that is caused by recessive mutations in either EPM2A or EPM2B. The hallmarks of LD are cytoplasmic, aberrant glycogen-like aggregates, called Lafora bodies (LBs), that drive disease progression. The 9th Annual Lafora Science Symposium was held in San Diego, California and brought together over 70 researchers, clinicians, academic trainees, and friends and family members of patients with LD and 80 attendees joined virtually. This symposium focused primarily on international collaborations for therapeutic development and biomarker identification and strategies for preparing the Lafora community for upcoming …

Efficacy Of Submuscular Transposition For Revision Cubital Tunnel Release: Comparative Outcomes Analysis, Joshua Riklan, Alexzandra Mattia, Markos Mardourian, Harvey Chim

School of Medicine Faculty Publications

Purpose: To assess outcomes after revision cubital tunnel release and submuscular transposition and compare these to a cohort of patients undergoing primary release with in situ decompression. Methods: Patients who underwent revision cubital tunnel release and submuscular transposition (n = 16) were enrolled. Mean follow-up was 21.4 months (range 12.8–55.6). Patients were evaluated in person using the Michigan Hand Outcomes Questionnaire (MHQ) and Disabilities of the Arm, Shoulder and Hand (DASH). Dellon stage, McGowan grade, visual analog scale for pain, and improvement of symptoms using the Messina's criteria and Modified Bishop score were assessed. Comparative analysis was performed with a …

Adaptive Deep Brain Stimulation Targeting The Subthalamic Nucleus In A Patient With Parkinson's Disease: A Care Compliant Case Report, Tirath Patel, Christopher Hanani, Anaya Noor, Shamikha Cheema, Muhammad Farhan, Rohab Sohail, Abhishek Goyal, Jabez David John, Adekunle E. Omole, Richard M. Millis

School of Nursing Faculty Publications

RATIONALE: Adaptive deep brain stimulation (aDBS) represents a notable advancement in treating Parkinson's disease (PD), as it offers enhanced therapeutic outcomes and personalized management by adjusting stimulation parameters in real-time according to individual neural signals. This approach minimizes adverse effects commonly associated with standard continuous deep brain stimulation (cDBS). This case report describes the progress of a 62-year-old man with severe PD who demonstrated notable enhancement in motor symptoms and quality of life throughout a 3-month trial period using aDBS. PATIENT CONCERNS: A 62-year-old man who has been suffering from Parkinson's disease. DIAGNOSES: The patient had been diagnosed with PD …