Browsing by Subject "Central nervous system"
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Item Blood-Based Markers of Neuronal Injury in Adult-Onset Myotonic Dystrophy Type 1(Frontiers Media, 2022-01-20) van der Plas, Ellen; Long, Jeffrey D.; Koscik, Timothy R.; Magnotta, Vincent; Monckton, Darren G.; Cumming, Sarah A.; Gottschalk, Amy C.; Hefti, Marco; Gutmann, Laurie; Nopoulos, Peggy C.; Neurology, School of MedicineIntroduction: The present study had four aims. First, neuronal injury markers, including neurofilament light (NF-L), total tau, glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1), were compared between individuals with and without adult-onset myotonic dystrophy type 1 (DM1). Second, the impact of age and CTG repeat on brain injury markers was evaluated. Third, change in brain injury markers across the study period was quantified. Fourth, associations between brain injury markers and cerebral white matter (WM) fractional anisotropy (FA) were identified. Methods: Yearly assessments, encompassing blood draws and diffusion tensor imaging on a 3T scanner, were conducted on three occasions. Neuronal injury markers were quantified using single molecule array (Simoa). Results: The sample included 53 patients and 70 controls. NF-L was higher in DM1 patients than controls, with individuals in the premanifest phases of DM1 (PreDM1) exhibiting intermediate levels ( χ 2 ( 2 ) = 38.142, P < 0.001). Total tau was lower in DM1 patients than controls (Estimate = -0.62, 95% confidence interval [CI] -0.95: -0.28, P < 0.001), while GFAP was elevated in PreDM1 only (Estimate = 30.37, 95% CI 10.56:50.19, P = 0.003). Plasma concentrations of UCH-L1 did not differ between groups. The age by CTG interaction predicted NF-L: patients with higher estimated progenitor allelege length (ePAL) had higher NF-L at a younger age, relative to patients with lower CTG repeat; however, the latter exhibited faster age-related change (Estimate = -0.0021, 95% CI -0.0042: -0.0001, P = 0.045). None of the markers changed substantially over the study period. Finally, cerebral WM FA was significantly associated with NF-L (Estimate = -42.86, 95% CI -82.70: -3.02, P = 0.035). Interpretation: While NF-L appears sensitive to disease onset and severity, its utility as a marker of progression remains to be determined. The tau assay may have low sensitivity to tau pathology associated with DM1.Item Cadherin-7 function in zebrafish development(Springer, 2008-10) Liu, Qin; Marrs, James A.; Londraville, Richard L.; Wilson, Amy L.; Department of Medicine, IU School of MedicineCadherin cell adhesion molecules play crucial roles in vertebrate development. Most studies have focused on examining the functions of classical type I cadherins (e.g., cadherin-2) in the development of vertebrates. Little information is available concerning the function of classical type II cadherins (e.g., cadherin-7) in vertebrate development. We have previously shown that cadherin-7 mRNA exhibits a dynamic expression pattern in the central nervous system and notochord in embryonic zebrafish. To gain insight into the role of cadherin-7 in the formation of these structures, we analyzed their formation in zebrafish embryos injected with cadherin-7-specific antisense morpholino oligonucleotides (MO). Notochord development was severely disrupted in MO-injected embryos, whereas gross defects in the development of the central nervous system were not detected in MO-injected embryos. Our results thus demonstrate that cadherin-7 plays an important role in the normal development of the zebrafish notochord.Item Central Nervous System Whipple Disease Presenting as Hypersomnolence(Cureus, 2022-03-28) de Oliveira Santana, Marcela A.; Butt, Saira; Nassiri, Mehdi; Medicine, School of MedicineWhipple disease (WD) is a rare systemic infection caused by Tropheryma whipplei (T. whipplei). Its clinical features are broad, and atypical clinical patterns such as the involvement of the heart, lungs, or the central nervous system (CNS) can occur. We report a case of a 58-year-old man who had been previously diagnosed with classic WD; he was evaluated for functional decline, extreme somnolence, and recurrent admissions for hydrocephalus. The patient was diagnosed with a neurologic relapse of WD after a positive T. whipplei polymerase chain reaction (PCR) from a cerebral spinal fluid (CSF) sample. He was successfully treated with IV ceftriaxone followed by oral trimethoprim-sulfamethoxazole (TMP-SMX). In classic WD, the CNS symptoms usually present in the late phase of the disease or in the form of relapse, especially after an inadequate treatment course. This case highlights the importance of considering CNS involvement in WD when a patient with a previous history of classic WD presents with hypersomnolence, hydrocephalus, or other neurologic symptoms.Item Chx10+V2a interneurons in spinal motor regulation and spinal cord injury(Wolters Kluwer, 2023) Li, Wen-Yuan; Deng, Ling-Xiao; Zhai, Feng-Guo; Wang, Xiao-Yu; Li, Zhi-Gang; Wang, Ying; Neurological Surgery, School of MedicineChx10-expressing V2a (Chx10+V2a) spinal interneurons play a large role in the excitatory drive of motoneurons. Chemogenetic ablation studies have demonstrated the essential nature of Chx10+V2a interneurons in the regulation of locomotor initiation, maintenance, alternation, speed, and rhythmicity. The role of Chx10+V2a interneurons in locomotion and autonomic nervous system regulation is thought to be robust, but their precise role in spinal motor regulation and spinal cord injury have not been fully explored. The present paper reviews the origin, characteristics, and functional roles of Chx10+V2a interneurons with an emphasis on their involvement in the pathogenesis of spinal cord injury. The diverse functional properties of these cells have only been substantiated by and are due in large part to their integration in a variety of diverse spinal circuits. Chx10+V2a interneurons play an integral role in conferring locomotion, which integrates various corticospinal, mechanosensory, and interneuron pathways. Moreover, accumulating evidence suggests that Chx10+V2a interneurons also play an important role in rhythmic patterning maintenance, left-right alternation of central pattern generation, and locomotor pattern generation in higher order mammals, likely conferring complex locomotion. Consequently, the latest research has focused on postinjury transplantation and noninvasive stimulation of Chx10+V2a interneurons as a therapeutic strategy, particularly in spinal cord injury. Finally, we review the latest preclinical study advances in laboratory derivation and stimulation/transplantation of these cells as a strategy for the treatment of spinal cord injury. The evidence supports that the Chx10+V2a interneurons act as a new therapeutic target for spinal cord injury. Future optimization strategies should focus on the viability, maturity, and functional integration of Chx10+V2a interneurons transplanted in spinal cord injury foci.Item Compartmentalization of cerebrospinal fluid inflammation across the spectrum of untreated HIV-1 infection, central nervous system injury and viral suppression(Public Library of Science, 2021-05-13) Gisslen, Magnus; Keating, Sheila M.; Spudich, Serena; Arechiga, Victor; Stephenson, Sophie; Zetterberg, Henrik; Di Germanio, Clara; Blennow, Kaj; Fuchs, Dietmar; Hagberg, Lars; Norris, Philip J.; Peterson, Julia; Shacklett, Barbara L.; Yiannoutsos, Constantin T.; Price, Richard W.; Biostatistics, School of Public HealthObjective: To characterize the evolution of central nervous system (CNS) inflammation in HIV-1 infection applying a panel of cerebrospinal fluid (CSF) inflammatory biomarkers to grouped subjects representing a broad spectrum of systemic HIV-1 immune suppression, CNS injury and viral control. Methods: This is a cross-sectional analysis of archived CSF and blood samples, assessing concentrations of 10 functionally diverse soluble inflammatory biomarkers by immunoassays in 143 HIV-1-infected subjects divided into 8 groups: untreated primary HIV-1 infection (PHI); four untreated groups defined by their blood CD4+ T lymphocyte counts; untreated patients presenting with subacute HIV-associated dementia (HAD); antiretroviral-treated subjects with ≥1 years of plasma viral suppression; and untreated elite controllers. Twenty HIV-1-uninfected controls were included for comparison. Background biomarkers included blood CD4+ and CD8+ T lymphocytes, CSF and blood HIV-1 RNA, CSF white blood cell (WBC) count, CSF/blood albumin ratio, CSF neurofilament light chain (NfL), and CSF t-tau. Findings: HIV-1 infection was associated with a broad compartmentalized CSF inflammatory response that developed early in its course and changed with systemic disease progression, development of neurological injury, and viral suppression. CSF inflammation in untreated individuals without overt HAD exhibited at least two overall patterns of inflammation as blood CD4+ T lymphocytes decreased: one that peaked at 200-350 blood CD4+ T cells/μL and associated with lymphocytic CSF inflammation and HIV-1 RNA concentrations; and a second that steadily increased through the full range of CD4+ T cell decline and associated with macrophage responses and increasing CNS injury. Subacute HAD was distinguished by a third inflammatory profile with increased blood-brain barrier permeability and robust combined lymphocytic and macrophage CSF inflammation. Suppression of CSF and blood HIV-1 infections by antiretroviral treatment and elite viral control were associated with reduced CSF inflammation, though not fully to levels found in HIV-1 seronegative controls.Item Development of a three-dimensional organoid model to explore early retinal phenotypes associated with Alzheimer’s disease(Springer Nature, 2023-08-24) Lavekar, Sailee S.; Harkin, Jade; Hernandez, Melody; Gomes, Cátia; Patil, Shruti; Huang, Kang‑Chieh; Puntambekar, Shweta S.; Lamb, Bruce T.; Meyer, Jason S.; Biology, School of ScienceAlzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of Aβ plaques and neurofibrillary tangles, resulting in synaptic loss and neurodegeneration. The retina is an extension of the central nervous system within the eye, sharing many structural similarities with the brain, and previous studies have observed AD-related phenotypes within the retina. Three-dimensional retinal organoids differentiated from human pluripotent stem cells (hPSCs) can effectively model some of the earliest manifestations of disease states, yet early AD-associated phenotypes have not yet been examined. Thus, the current study focused upon the differentiation of hPSCs into retinal organoids for the analysis of early AD-associated alterations. Results demonstrated the robust differentiation of retinal organoids from both familial AD and unaffected control cell lines, with familial AD retinal organoids exhibiting a significant increase in the Aβ42:Aβ40 ratio as well as phosphorylated Tau protein, characteristic of AD pathology. Further, transcriptional analyses demonstrated the differential expression of many genes and cellular pathways, including those associated with synaptic dysfunction. Taken together, the current study demonstrates the ability of retinal organoids to serve as a powerful model for the identification of some of the earliest retinal alterations associated with AD.Item Do Not Lose Your Nerve, Be Callus: Insights Into Neural Regulation of Fracture Healing(Springer, 2024) Nazzal, Murad K.; Morris, Ashlyn J.; Parker, Reginald S.; White, Fletcher A.; Natoli, Roman M.; Kacena, Melissa A.; Fehrenbacher, Jill C.; Orthopaedic Surgery, School of MedicinePurpose of review: Fractures are a prominent form of traumatic injury and shall continue to be for the foreseeable future. While the inflammatory response and the cells of the bone marrow microenvironment play significant roles in fracture healing, the nervous system is also an important player in regulating bone healing. Recent findings: Considerable evidence demonstrates a role for nervous system regulation of fracture healing in a setting of traumatic injury to the brain. Although many of the impacts of the nervous system on fracture healing are positive, pain mediated by the nervous system can have detrimental effects on mobilization and quality of life. Understanding the role the nervous system plays in fracture healing is vital to understanding fracture healing as a whole and improving quality of life post-injury. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.Item Effects of Chronic Voluntary Alcohol Drinking on Thiamine Concentrations, Endoplasmic Reticulum Stress and Oxidative Stress in the Brain of Crossed High Alcohol Preferring Mice(Springer, 2019-11) Xu, Hong; Liu, Dexiang; Chen, Jing; Li, Hui; Xu, Mei; Wen, Wen; Frank, Jacqueline A.; Grahame, Nicholas J.; Zhu, Haining; Luo, Jia; Psychology, School of ScienceChronic alcohol drinking can damage the central nervous system via many mechanisms. One of these may involve a deficiency of an essential nutrient, thiamine, as a result of chronic alcohol exposure. Although thiamine deficiency (TD) has often been linked to the neuropathology of alcohol-related brain damage, the underlying mechanisms remain to be investigated. The crossed High Alcohol Preferring (cHAP) mice prefer alcohol to water when they have free access. In this study, we used cHAP mice to determine the effect of chronic voluntary alcohol exposure on thiamine levels and neuropathological changes in the brain. The male cHAP mice were given free-choice access to 10% ethanol (EtOH) and water for 7 months, sacrificed, and thiamine concentrations in the blood plasma and brain were determined by liquid chromatography–mass spectrometry (LC-MS). The expression of thiamine transporters was examined by immunoblotting. In addition, oxidative stress, endoplasmic reticulum (ER) stress, active caspase-3 dependent apoptosis, and neurogenesis in the brain were evaluated. The results indicated that chronic alcohol exposure decreased thiamine levels and thiamine transporters, and increased oxidative stress, ER stress, and neuronal apoptosis in the brains. Interestingly, alcohol exposure also stimulated neurogenesis in the hippocampus which may serve as a compensatory mechanism in response to alcohol-induced brain damage. Our data have demonstrated that cHAP mice are a useful model to study the interaction between chronic alcohol consumption and TD, as well as TD’s contributions to the neuropathological processes resulting in alcohol-related brain damage.Item Mechanisms of alcohol-induced damage to the developing nervous system(The National Institute on Alcohol Abuse and Alcoholism, 2001) Goodlett, Charles R.; Horn, Kristin H.; Psychology, School of ScienceNumerous mechanisms likely contribute to the damaging effects of prenatal alcohol exposure on the developing fetus and particularly the developing central nervous system (CNS). The coexistence of a multitude of mechanisms that may act simultaneously or consecutively and differ among various cell types poses particular challenges to researchers. To study alcohol’s effects on the fetus more easily, investigators have used animal models and tissue-culture experiments. Such approaches have identified numerous potential mechanisms through which alcohol acts on the fetus, many of which result in cell death by necrosis or apoptosis. Among these mechanisms are increased oxidative stress, damage to the mitochondria, interference with the activity of growth factors, effects on glia cells, impaired development and function of chemical messenger systems involved in neuronal communication, changes in the transport and uptake of the sugar glucose, effects on cell adhesion, and changes in the regulation of gene activity during development.Item Membrane resealing as a promising strategy for early treatment of neurotrauma(Wolters Kluwer, 2014-11) Xiaoming, Jin; Department of Anatomy and Cell Biology, IU School of Medicine