Neurology Commons^™

Parallel Electrophysiological Abnormalities Due To Covid-19 Infection And To Alzheimer’S Disease And Related Dementia, Yang Jiang, Jennifer Neal, Pradoldej Sompol, Görsev Yener, Xianghong Arakaki, Christopher M. Norris, Francesca R. Farina, Agustin Ibanez, Susanna Lopez, Abdulhakim Al-Ezzi, Voyko Kavcic, Bahar Güntekin, Claudio Babiloni, Mihály Hajós

Neurology Faculty Publications

Many coronavirus disease 2019 (COVID-19) positive individuals exhibit abnormal electroencephalographic (EEG) activity reflecting “brain fog” and mild cognitive impairments even months after the acute phase of infection. Resting-state EEG abnormalities include EEG slowing (reduced alpha rhythm; increased slow waves) and epileptiform activity. An expert panel conducted a systematic review to present compelling evidence that cognitive deficits due to COVID-19 and to Alzheimer’s disease and related dementia (ADRD) are driven by overlapping pathologies and neurophysiological abnormalities. EEG abnormalities seen in COVID-19 patients resemble those observed in early stages of neurodegenerative diseases, particularly ADRD. It is proposed that similar EEG abnormalities in …

Cerebrovascular Disease Is Associated With Alzheimer's Plasma Biomarker Concentrations In Adults With Down Syndrome, Andreas Engvig, Karl Trygve Kalleberg, Lars T. Westlye, Esten Høyland Leonardsen, Alzheimer’S Disease Neuroimaging Initiative Consortium

Neurology Faculty Publications

DNA methylation age (MA), brain age (BA), and frailty index (FI) are putative aging biomarkers linked to dementia risk. We investigated their relationship and combined potential for prediction of cognitive impairment and future dementia risk using the ADNI database. Of several MA algorithms, DunedinPACE and GrimAge2, associated with memory, were combined in a composite MA alongside BA and a data-driven FI in predictive analyses. Pairwise correlations between age- and sex-adjusted measures for MA (aMA), aBA, and aFI were low. FI outperformed BA and MA in all diagnostic tasks. A model including age, sex, and aFI achieved an area under the …

Axonal Injury, Sleep Disturbances, And Memory Following Traumatic Brain Injury, Emma M. Tinney, Goretti España-Irla, Aaron E. L. Warren, Lauren N. Whitehurst, Alexandra N. Stillman, Charles H. Hillman, Timothy P. Morris, Alzheimer’S Disease Neuroimaging Initiative

Neurology Faculty Publications

Objectives: Traumatic brain injury (TBI) is associated with sleep deficits, but it is not clear why some report sleep disturbances and others do not. The objective of this study was to assess the associations between axonal injury, sleep, and memory in chronic and acute TBI. Methods: Data were acquired from two independent datasets which included 156 older adult veterans (69.8 years) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with prior moderate- to-severe TBIs and 90 (69.2 years) controls and 374 (39.6 years) from Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) with a recent mild TBI (mTBI) and 87 controls …

Perspectives On The Clinical Use Of Anti-Amyloid Therapy For The Treatment Of Alzheimer's Disease: Insights From The Fields Of Cancer, Rheumatology, And Neurology, Gregory Jicha, Erin Abner, Elif Pinar Coskun, Mark Huffmyer, Thomas Tucker, Peter T. Nelson

Neurology Faculty Publications

Introduction: The advent of disease-modifying therapies for Alzheimer’s disease (AD) has raised many questions and debates in the field as to the clinical benefits, risks, and costs of such therapies. The controversies have resulted in the perception that many clinicians are apprehensive about prescribing these medications to their patient populations. There also remains widespread uncertainty as to the economic impact, cost benefit ratio, and safety oversight for use of these medications in standard clinical care settings.

Methods: To contextualize such issues, the present study compared anti-amyloid biologic therapy (lecanemab) to four commonly used biologic agents in other fields, including trastuzumab …

The Seattle Amyotrophic Lateral Sclerosis (Als) Patient Project Database: Observational, Longitudinal, Dyadic Characterization Of People With Als And Their Partners, Suzanne C. Segerstrom, Edward J. Kasarskis

Neurology Faculty Publications

Introduction: The median survival time in ALS is approximately 3 years, but survival times range from less than a year to more than 10 years and much variance in disease course remains to be explained. As is true for physical outcomes, there is considerable variance in QOL, which is influenced by psychological health, coping, and social support, among other psychosocial factors. The Seattle ALS Patient Project Database (SALSPPD) provides a unique opportunity for researchers to address established and novel hypotheses about disease progression and QOL in ALS.

Methods: The SALSPPD is a longitudinal dataset of people with ALS (n = …

Associations Between Il-1Β, Il-6, And Tnfα Polymorphisms And Longitudinal Trajectories Of Cognitive Function In Non-Demented Older Adults, Karen A. Lawrence, Elana M. Gloger, Cristina N. Pinheiro, Frederick A. Schmitt, Suzanne C. Segerstrom

Neurology Faculty Publications

Inflammation is implicated in Alzheimer’s disease (AD), and specific single nucleotide polymorphisms (SNPs) in inflammatory cytokine genes are associated with increased AD risk. Whether the same polymorphisms also predict domain-specific cognitive change in cognitively healthy older adults is unclear. Specific SNPs in three cytokine genes, IL-1β (rs16944), IL-6 (rs1800795), and TNFα (rs1800629) were assessed for association with longitudinal trajectories spanning up to 16 years of global cognitive function, episodic memory, attention and working memory, and executive function in a sample of 324 non-demented older adults. Only rs1800629 (TNFα) was associated with significant change in global cognitive function over time [γ …

Cerebrovascular Reactivity Mri As A Biomarker For Cerebral Small Vessel Disease–Related Cognitive Decline: Multi-Site Validation In The Markvcid Consortium, Peiying Liu, Zixuan Lin, Kaisha Hazel, George Pottanat, Cuimei Xu, Dengrong Jiang, Jay J. Pillai, Emma Lucke, Christopher E. Bauer, Brian T. Gold, Steven M. Greenburg, Karl G. Helmer, Kay Jann, Gregory Jicha, Joel Kramer, Pauline Maillard, Rachel M. Mulavelil, Pavel Rodriguez, Claudia L. Satizabal, Kristin Schwab, Sudha Seshadri, Herpreet Singh, Ángel G. Velarde Dediós, Danny J. J. Wang, Rita R. Kalyani, Abhay Moghekar, Paul B. Rosenberg, Sevil Yasar, Marilyn Albert, Hanzhang Lu

Neurology Faculty Publications

INTRODUCTION: Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis.

METHODS: We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes.

RESULTS: CVR …

Transcriptomics Analysis Reveals Potential Regulatory Role Of Nsmase2 (Smpd3) In Nervous System Development And Function Of Middle-Aged Mouse Brains, Zhihui Zhu, Timothy S. Mcclintock, Erhard Bieberich

Markey Cancer Center Faculty Publications

Neutral sphingomyelinase-2 (nSMase2), gene name sphingomyelin phosphodiesterase-3 (Smpd3), is a key regulatory enzyme responsible for generating the sphingolipid cer- amide. The function of nSMase2 in the brain is still controversial. To better under- stand the functional roles of nSMase2 in the aging mouse brain, we applied RNA-seq analysis, which identified a total of 1462 differentially abundant mRNAs between +/fro and fro/fro, of which 891 were increased and 571 were decreased in nSMase2-deficient mouse brains. The most strongly enriched GO and KEGG annota- tion terms among transcripts increased in fro/fro mice included synaptogenesis, syn- apse development, synaptic signaling, axon development, and …

Decentralized Clinical Trials For Medications To Reduce The Risk Of Dementia: Consensus Report And Guidance, Leanne Howard, Carla Abdelnour, Erin Abner, Ricardo F. Allegri, Hiroko H. Dodge, Serge Gauthier, Camilla M. Hoyos, Gregory Jicha, Patrick G. Kehoe, Catherine J. Mummery, Adesola Ogunniyi, Nikolaos Scarmeas, Xiaoying Chen, Jodie R. Titiner, Christopher R. Weber, Ruth Peters

Neurology Faculty Publications

INTRODUCTION: Recent growth in the functionality and use of technology has prompted an increased interest in the potential for remote or decentralized clinical trials in dementia. There are many potential benefits associated with decentralized medication trials, but we currently lack specific recommendations for their delivery in the dementia field.

METHODS: A modified Delphi method engaged an expert panel to develop recommendations for the conduct of decentralized medication trials in dementia prevention. A working group of researchers and clinicians with expertise in dementia trials further refined the recommendations.

RESULTS: Overall, the recommendations support the delivery of decentralized trials in dementia prevention …

Type-2 Diabetes, Pancreatic Amylin, And Neuronal Metabolic Remodeling In Alzheimer's Disease, Noah Leibold, James R. Bain, Florin Despa

Neurology Faculty Publications

Type-2 diabetes raises the risk for Alzheimer’s disease (AD)-type dementia and the conversion from mild cognitive impairment to dementia, yet mechanisms connecting type-2 diabetes to AD remain largely unknown. Amylin, a pancreatic 𝜷-cell hormone co-secreted with insulin, participates in the central regulation of satiation, but also forms pancreatic amyloid in persons with type-2 diabetes and synergistically interacts with brain amyloid 𝜷 (A𝜷) pathology, in both sporadic and familial Alzheimer’s disease (AD). Growing evidence from studies of tumor growth, together with early observations in skeletal muscle, indicates amylin as a potential trigger of cellular metabolic reprogramming. Because the blood, cerebrospinal fluid, …

A Pathologic Study Of Perivascular Ptdp-43 Lin Bodies In Late-Nc, Ryan K. Shahidehpour, Peter T. Nelson, Adam D. Bachstetter

Neurology Faculty Publications

Background TAR DNA-Binding Protein 43 (TDP-43) pathological inclusions are a distinctive feature in dozens of neurodegenerative pathologies, including limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Prior investigations identified vascular-associated TDP-43-positive micro-lesions, known as “Lin bodies,” located on or near the brain capillaries of some individuals with LATE-NC. This study aimed to investigate the relationship between the accumulation of Lin bodies and glial cells in LATE-NC and the potential co-localization with ferritin, a protein associated with iron storage. Using multiplexed immunohistochemistry and digital pathology tools, we conducted pathological analyses to investigate the relationship between Lin bodies and glial markers (GFAP for …

Neural Mechanisms Of Respiratory Interoception, Pei-Ying Sarah Chan, Lu-Yuan Lee, Paul W. Davenport

UK CARES Faculty Publications

Respiratory interoception is one of the internal bodily systems that is comprised of different types of somatic and visceral sensations elicited by different patterns of afferent input and respiratory motor drive mediating multiple respiratory modalities. Respiratory interoception is a complex system, having multiple afferents grouped into afferent clusters and projecting into both discriminative and affective centers that are directly related to the behavioral assessment of breathing. The multi-afferent system provides a spectrum of input that result in the ability to interpret the different types of respiratory interceptive sensations. This can result in a response, commonly reported as breathlessness or dyspnea. …

Limbic-Predominant Age-Related Tdp-43 Encephalopathy (Late-Nc): Co-Pathologies And Genetic Risk Factors Provide Clues About Pathogenesis, Peter T. Nelson, David Fardo, Xian Wu, Khine Zin Aung, Matthew D. Cykowski, Yuriko Katsumata

Neurology Faculty Publications

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is detectable at autopsy in more than one- third of people beyond age 85 years and is robustly associated with dementia independent of other pathologies. Although LATE-NC has a large impact on public health, there remain uncertainties about the underlying biologic mechanisms. Here, we review the literature from human studies that may shed light on pathogenetic mechanisms. It is increasingly clear that certain combinations of pathologic changes tend to coexist in aging brains. Although “pure” LATE-NC is not rare, LATE-NC often coexists in the same brains with Alzheimer disease neuropathologic change, brain arteriolosclerosis, …

Comprehensive Assessment Of Tdp‑43 Neuropathology Data In The National Alzheimer’S Coordinating Center Database, Davis C. Woodworth, Katelynn M. Nguyen, Lorena Sordo, Kiana A. Scambray, Elizabeth Head, Claudia H. Kawas, María M. Corrada, Peter T. Nelson, S. Ahmad Sajjadi

Neurology Faculty Publications

TDP-43 proteinopathy is a salient neuropathologic feature in a subset of frontotemporal lobar degeneration (FTLD-TDP), in amyotrophic lateral sclerosis (ALS-TDP), and in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and is associated with hippocampal sclerosis of aging (HS-A). We examined TDP-43-related pathology data in the National Alzheimer’s Coordinating Center (NACC) in two parts: (I) availability of assessments, and (II) associations with clinical diagnoses and other neuropathologies in those with all TDP-43 measures available. Part I: Of 4326 participants with neuropathology data collected using forms that included TDP-43 assessments, data availability was highest for HS-A (97%) and ALS (94%), followed by …

Plant Model Of Α-Synucleinopathy: Expression Of Α-Synuclein A53t Variant In Hairy Root Cultures Leads To Proteostatic Stress And Dysregulation Of Iron Metabolism, Jasmina Kurepa, Kristen A. Bruce, Greg A. Gerhardt, Jan A. Smalle

Neurology Faculty Publications

Synucleinopathies, typified by Parkinson’s disease (PD), entail the accumulation of α- synuclein (αSyn) aggregates in nerve cells. Various αSyn mutants, including the αSyn A53T variant linked to early-onset PD, increase the propensity for αSyn aggregate formation. In addition to disrupting protein homeostasis and inducing proteostatic stress, the aggregation of αSyn in PD is associated with an imbalance in iron metabolism, which increases the generation of reactive oxygen species and causes oxidative stress. This study explored the impact of αSyn A53T expression in transgenic hairy roots of four medicinal plants (Lobelia cardinalis, Artemisia annua, Salvia miltiorrhiza, and Polygonum multiflorum). In all …

Of Hearth And Home: Professional Wellness After Hours, Timothy J. Ainger, Meriem Bensalem-Owen, Joanna Fong-Isariyawongse, Matthew William Luedke

Neurology Faculty Publications

Burnout is a prevalent problem in the contemporary practice of medicine. Defined by the Agency for Healthcare Research and Quality as, “a long-term stress reaction marked by emotional exhaustion, depersonalization, and a lack of sense of personal accomplishment,” this multifactorial condition has significant implications for the clinicians who suffer it, their patients, and families. Neurologists suffer some of the highest rates of burnout. Burnout research on interventions often focus on the work environment. In this article, we will focus on burnout’s effects on home life and features of home life that can impact resiliency, specifically sleep hygiene.

Mnemonic Utilization In Stroke Education: Fast And Befast Adoption By Certified Comprehensive Stroke Centers, Christopher Hogge, Larry B. Goldstein, Sushanth R. Aroor

Neurology Faculty Publications

Introduction: Symptom recognition and timely access to treatment are critical components of acute stroke care systems. Two mnemonics widely used in public educational campaigns for recognizing stroke symptoms include FAST (Face-Arm-Speech-Time) and BEFAST (Balance-Eyes-Face-Arm Speech-Time). The FAST mnemonic can miss up to 14% of strokes. BEFAST includes common posterior circulation stroke symptoms and has been implemented by several Comprehensive Stroke Centers (CSCs).

Methods: We sought to analyze the pattern of public educational materials available on the websites of US CSCs. The Joint Commission (JC) quality check website compiles a list containing the names and locations of the country’s 217 JC-certified …

National Trends Of Vascular Risk Factor Control Among Stroke Survivors: From The National Health And Nutrition Examination Survey 2009 To 2020, Hend Mansoor, Daniel Manion, Kara Jo Swafford, Gregory A. Jicha, Daniela Claudia Moga

Neurology Faculty Publications

BACKGROUND: Contemporary data describing the national trends on vascular risk factor control among stroke survivors are limited.

METHODS AND RESULTS: This is a cross-sectional analysis of the National Health and Nutrition Examination Survey cycles 2009 to 2010 to 2017 to March 2020. Adults (≥18 years of age) with a self-reported diagnosis of stroke were identified. Age- adjusted trends in hypertension, diabetes, and hyperlipidemia control were examined. Sex and racial differences in vascular risk factor control were also investigated. Among 32 497 adult individuals who participated in the National Health and Nutrition Examination Survey, 1354 participants (4.2%) self-reported a prior diagnosis …

Higher Glycemic Index And Glycemic Load Diet Is Associated With Slower Disease Progression In Amyotrophic Lateral Sclerosis, Ikjae Lee, Hiroshi Mitsumoto, Seonjoo Lee, Edward J. Kasarskis, Michael Rosenbaum, Pam Factor-Litvak, Jeri W. Nieves

Neurology Faculty Publications

Objective: High-caloric diets may slow the progression of amyotrophic lateral sclerosis; however, key macronutrients have not been identified. We examined whether dietary macronutrients are associated with the rate of progression and length of survival among the prospective cohort study participants.

Methods: Participants with a confirmed diagnosis of sporadic amyotrophic lateral sclerosis enrolled in the Multicenter Cohort Study of Oxidative Stress were included (n = 304). We evaluated baseline macronutrient intake assessed by food frequency questionnaire in relation to change in revised amyotrophic lateral sclerosis functional rating scale total- score, and tracheostomy-free survival using linear regression and Cox proportional hazard models. …

Alzheimer’S Disease And Inflammatory Biomarkers Positively Correlate In Plasma In The Uk-Adrc Cohort, Kate E. Foley, Zachary Winder, Tiffany L. Sudduth, Barbara J. Martin, Peter T. Nelson, Gregory Jicha, Jordan P. Harp, Erica M. Weekman, Donna M. Wilcock

Neurology Faculty Publications

INTRODUCTION: Protein-based plasma assays provide hope for improving accessibility and specificity of molecular diagnostics to diagnose dementia. METHODS: Plasma was obtained from participants (N = 837) in our community-based University of Kentucky Alzheimer’s Disease Research Center cohort. We evaluated six Alzheimer’s disease (AD)- and neurodegeneration-related (Aβ40, Aβ42, Aβ42/40, p- tau181, total tau, and NfLight) and five inflammatory biomarkers (TNF𝛼, IL6, IL8, IL10, and GFAP) using the SIMOA-based protein assay platform. Statistics were performed to assess correlations. RESULTS: Our large cohort reflects previous plasma biomarker findings. Relationships between biomarkers to understand AD–inflammatory biomarker correlations showed significant associations between AD and inflammatory …

Pathologic Correlates Of Aging-Related Tau Astrogliopathy: Artag Is Associated With Late-Nc And Cerebrovascular Pathologies, But Not With Adnc, Yuriko Katsumata, Xian Wu, Khine Zin Aung, Kathryn Gauthreaux, Charles Mock, Shelley L. Forrest, Gabor G. Kovacs, Peter T. Nelson

Neurology Faculty Publications

Age-related tau astrogliopathy (ARTAG) is detectable in the brains of over one-third of autopsied persons beyond age 80, but the pathoetiology of ARTAG is poorly understood. Insights can be gained by analyzing risk factors and comorbid pathologies. Here we addressed the question of which prevalent co-pathologies are observed with increased frequency in brains with ARTAG. The study sample was the National Alzheimer’s Coordinating Center (NACC) data set, derived from multiple Alzheimer’s disease research centers (ADRCs) in the United States. Data from persons with unusual conditions (e.g. frontotemporal dementia) were excluded leaving 504 individual autopsied research participants, clustering from 20 different …

Azithromycin Reduces Hemoglobin-Induced Innate Neuroimmune Activation, Chirayu D. Pandya, Hemendra J. Vekaria, Miriam Zamorano, Amanda L. Trout, Rodney M. Ritzel, Gary Guzman, Christopher Bolden, Patrick G. Sullivan

Neurology Faculty Publications

Neonatal intraventricular hemorrhage (IVH) releases blood products into the lateral ventricles and brain parenchyma. There are currently no medical treatments for IVH and surgery is used to treat a delayed effect of IVH, post-hemorrhagic hydrocephalus. However, surgery is not a cure for intrinsic brain injury from IVH, and is performed in a subacute time frame. Like many neurological diseases and injuries, innate immune activation is implicated in the pathogenesis of IVH. Innate immune activation is a pharmaceutically targetable mechanism to reduce brain injury and post-hemorrhagic hydrocephalus after IVH. Here, we tested the macrolide antibiotic azithromycin, which has immunomodulatory properties, to …

Amperometric Bio-Sensing Of Lactate And Oxygen Concurrently With Local Field Potentials During Status Epilepticus, Eliana Fernandes, Ana Ledo, Greg A. Gerhardt, Rui M. Barbosa

Neurology Faculty Publications

Epilepsy is a prevalent neurological disorder with a complex pathogenesis and unpredictable nature, presenting limited treatment options in >30 % of affected individuals. Neurometabolic abnormalities have been observed in epilepsy patients, suggesting a disruption in the coupling between neural activity and energy metabolism in the brain. In this study, we employed amperometric biosensors based on a modified carbon fiber microelectrode platform to directly and continuously measure lactate and oxygen dynamics in the brain extracellular space. These biosensors demonstrated high sensitivity, selectivity, and rapid response time, enabling in vivo measurements with high temporal and spatial resolution. In vivo recordings in the …

Hiv-1 Mrna Knockdown With Crispr/Cas9 Enhances Neurocognitive Function, Kristen A. Mclaurin, Hailong Li, Kamel Khalili, Charles F. Mactutus, Rosemarie M. Booze

Neurology Faculty Publications

Mixed glia are infiltrated with HIV-1 virus early in the course of infection leading to the development of a persistent viral reservoir in the central nervous system. Modification of the HIV-1 genome using gene editing techniques, including CRISPR/Cas9, has shown great promise towards eliminating HIV-1 viral reservoirs; whether these techniques are capable of removing HIV-1 viral proteins from mixed glia, however, has not been systematically evaluated. Herein, the efficacy of adeno-associated virus 9 (AAV9)-CRISPR/Cas9 gene editing for eliminating HIV-1 messenger RNA (mRNA) from cortical mixed glia was evaluated in vitro and in vivo. In vitro, a within-subjects experimental design was …

Cancer Research Provides A Model For Advancing Clinical Trials In Dementia In The Era Of Disease-Modifying Alzheimer’S-Type Dementia Therapies, Gregory Jicha, Thomas Tucker, Susanne Arnold, Peter T. Nelson

Neurology Faculty Publications

Dementia and cancer are multifactorial, widely-feared, age-associated clinical syndromes that are increasing in prevalence. There have been major breakthroughs in clinical cancer research leading to some effective treatments, whereas the field of dementia has achieved comparatively limited success in clinical research. The lessons of cancer research may help those in the dementia research field in confronting some of the dilemmas faced when the clinical care regimen is not entirely safe or efficacious. Cancer clinical trials have assumed that untreated individuals with cancer are at high risk for morbidity and mortality after primary diagnoses. Thus, patients deserve a choice of clinical …

Estimating Socio-Economic Status For Alzheimer’S Disease Trials, D. M. Rentz, J. D. Grill, D. P. Molina-Henry, Gregory Jicha, Michael S. Rafii, A. Liu, Reisa A. Sperling, Paul Aisen, R. Raman

Neurology Faculty Publications

INTRODUCTION: Metrics of a participant’s socioeconomic status (SES) are not routinely collected or standardized in clinical trials. This omission limits the ability to evaluate the generalizability of trial results and restricts clinicians from confidently interpreting the efficacy of new treatments across important sub-populations. METHODS: We adapted an SES measure of social disparity; the Hollingshead Two Factor Index of Social Position, which combines education and occupation into a single metric. We modernized the 1965 occupations to reflect the 2017 careers tabulated by the US Bureau of Labor Statistics. We currently use this adapted measure in Alzheimer’s Clinical Trials Consortium studies. RESULTS: …

Clinical Trial Protocol For Beach: A Phase 2a Study Of Mw189 In Patients With Acute Nontraumatic Intracerebral Hemorrhage, Radhika Avadhani, Wendy C. Ziai, Richard E. Thompson, W. Andrew Mould, Karen Lane, Angeline Nanni, Michael Lacobelli, Matthew F. Sharrock, Lauren H. Sansing, Linda J. Van Eldik, Daniel F. Hanley

Neurology Faculty Publications

Patients with acute spontaneous intracerebral hemorrhage (ICH) develop secondary neuroinflammation and cerebral edema that can further damage the brain and lead to increased risk of neurologic complications. Preclinical studies in animal models of acute brain injury have shown that a novel small-molecule drug candidate, MW01-6-189WH (MW189), decreases neuroinflammation and cerebral edema and improves functional outcomes. MW189 was also safe and well tolerated in phase 1 studies in healthy adults. The proof-of-concept phase 2a Biomarker and Edema Attenuation in IntraCerebral Hemorrhage (BEACH) clinical trial is a first-in-patient, multicenter, randomized, double-blind, placebo-controlled trial. It is designed to determine the safety and tolerability …

Multiomics Analysis To Explore Blood Metabolite Biomarkers In An Alzheimer’S Disease Neuroimaging Initiative Cohort, Takaki Oka, Yuki Matsuzawa, Momoka Tsuneyoshi, Yoshitaka Nakamura, Ken Aoshima, Hiroshi Tsugawa, Alzheimer’S Disease Metabolomics Consortium

Neurology Faculty Publications

Alzheimer’s disease (AD) is a neurodegenerative disease that commonly causes dementia. Identifying biomarkers for the early detection of AD is an emerging need, as brain dysfunction begins two decades before the onset of clinical symptoms. To this end, we reanalyzed untargeted metabolomic mass spectrometry data from 905 patients enrolled in the AD Neuroimaging Initiative (ADNI) cohort using MS-DIAL, with 1,304,633 spectra of 39,108 unique biomolecules. Metabolic profiles of 93 hydrophilic metabolites were determined. Additionally, we integrated targeted lipidomic data (4873 samples from 1524 patients) to explore candidate biomarkers for predicting progressive mild cognitive impairment (pMCI) in patients diagnosed with AD …

Nalfurafine Promotes Myelination In Vitro And Facilitates Recovery From Cuprizone + Rapamycin-Induced Demyelination In Mice, Ross Van De Wetering, Rabia Bibi, Andy Biggerstaff, Sheein Hong, Bria Pengelly, Thomas E. Prisinzano, Anne C. La Flamme, Bronwyn M. Kivell

Markey Cancer Center Faculty Publications

The kappa opioid receptor has been identified as a promising therapeutic target for promoting remyelination. In the current study, we evaluated the ability of nalfurafine to promote oligodendrocyte progenitor cell (OPC) differentiation and myelination in vitro, and its efficacy in an extended, cuprizone-induced demyelination model. Primary mouse (C57BL/6J) OPC-containing cultures were treated with nalfurafine (0.6–200 nM), clemastine (0.01–100 μM), T3 (30 ng/mL), or vehicle for 5 days. Using immunocytochemistry and confocal microscopy, we found that nalfurafine treatment increased OPC differentiation, oligodendrocyte (OL) morphological complexity, and myelination of nanofibers in vitro. Adult male mice (C57BL/6J) were given a diet con- taining …

A Brief Report On Juvenile Amyotrophic Lateral Sclerosis Cases In The United States National Als Registry: 2010– 2018, Jaime Raymond, Jasmine Berry, Edward J. Kasarskis, Theodore Larson, D. Kevin Horton, Paul Mehta

Neurology Faculty Publications

Juvenile ALS (jALS) is a rare form of ALS, defined as symptom onset before age 25. This report describes the demographic characteristics of confirmed and likely jALS cases in a large cohort of ALS patients ascertained in the National ALS Registry (Registry) from 2010 to 2018. Patients in the Registry must be at least 18 years of age. Of the 44 identified patients, 37.8% were diagnosed at age 24, were more likely to be nonwhite (54.5%), male (79.5%), and live in the Midwest or Northeast regions (54.5%) of the US. Some 68.9% of the jALS cases were received from federal …