1
|
Di Muro G, Tessarolo C, Cagnotti G, Favole A, Ferrini S, Ala U, Bellino C, Borriello G, Gallo M, Iamone G, Iulini B, Pezzolato M, Casalone C, Caramelli M, Capucci L, Cavadini P, Corona C, D'Angelo A. Neurofilament light chain (Nf-L) in cerebrospinal fluid and serum as a potential biomarker in the differential diagnosis of neurological diseases in cattle. Vet Res 2025; 56:6. [PMID: 39794836 PMCID: PMC11724550 DOI: 10.1186/s13567-024-01441-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 11/19/2024] [Indexed: 01/13/2025] Open
Abstract
Neurofilament light chain (Nf-L) is a biomarker for axonal damage in human neurology but is understudied in cattle. With this study we wanted to determine Nf-L stability at two different storage temperatures and Nf-L levels in healthy cattle and the relationship with age, evaluate whether Nf-L holds diagnostic potential for neurological disorders, and whether an association exists between Nf-L in serum and in cerebrospinal fluid (CSF). To do this, we measured Nf-L levels in CSF and serum samples from 49 healthy and 75 sick cattle. Storage at -80 °C or -20 °C had no impact on Nf-L concentration. Physiological median Nf-L levels were 6.3 pg/mL (serum) and 414 pg/mL (CSF) in calves and 5.5 pg/mL (serum) and 828 pg/mL (CSF) in adult cattle. There was no association between Nf-L levels in CSF and calf age (r2 0.07, p = 0.13), while a weak association was found for Nf-L in serum (r2 0.26, p = 0.01), and a significant association in adult cattle (CSF, r2 0.69, p = 0.0001; serum, r2 0.68, p = 0.0003). CSF Nf-L levels were higher in samples from animals with degenerative (median Nf-L 49971 pg/mL) and infectious central nervous system (CNS) disorders (median Nf-L, age < 2 months 8863 pg/mL; age 2-12 months 17474 pg/mL; age 1-6 years 3546 pg/mL), CNS anomalies and metabolic/toxic disorders. There was a significant association between CSF Nf-L and serum Nf-L in cattle with neurological disorders (r2 0.2, p = 0.009). Taken together, these findings suggest the potential of Nf-L as a diagnostic tool in cattle neurology.
Collapse
Affiliation(s)
- Giorgia Di Muro
- Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2-5, 10095, Grugliasco, TO, Italy
| | - Carlotta Tessarolo
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, Via Bologna 148, 10154, Turin, TO, Italy
| | - Giulia Cagnotti
- Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2-5, 10095, Grugliasco, TO, Italy.
| | - Alessandra Favole
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, Via Bologna 148, 10154, Turin, TO, Italy
| | - Sara Ferrini
- Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2-5, 10095, Grugliasco, TO, Italy
| | - Ugo Ala
- Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2-5, 10095, Grugliasco, TO, Italy
| | - Claudio Bellino
- Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2-5, 10095, Grugliasco, TO, Italy
| | - Giuliano Borriello
- Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2-5, 10095, Grugliasco, TO, Italy
| | - Marina Gallo
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, Via Bologna 148, 10154, Turin, TO, Italy
| | - Giulia Iamone
- Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2-5, 10095, Grugliasco, TO, Italy
| | - Barbara Iulini
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, Via Bologna 148, 10154, Turin, TO, Italy
| | - Marzia Pezzolato
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, Via Bologna 148, 10154, Turin, TO, Italy
| | - Cristina Casalone
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, Via Bologna 148, 10154, Turin, TO, Italy
| | - Maria Caramelli
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, Via Bologna 148, 10154, Turin, TO, Italy
| | - Lorenzo Capucci
- Istituto Zooprofilattico Sperimentale della Lombardia ed Emilia Romagna, Via Bianchi 9, 25124, Brescia, BS, Italy
| | - Patrizia Cavadini
- Istituto Zooprofilattico Sperimentale della Lombardia ed Emilia Romagna, Via Bianchi 9, 25124, Brescia, BS, Italy
| | - Cristiano Corona
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, Via Bologna 148, 10154, Turin, TO, Italy
| | - Antonio D'Angelo
- Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2-5, 10095, Grugliasco, TO, Italy
| |
Collapse
|
2
|
Yu YM, Jin GH, Zhong C, Qian H, Wang L, Zhan F. Exploring the role of interleukin-6 receptor blockade in epilepsy and associated neuropsychiatric conditions through a mendelian randomization study. World J Psychiatry 2024; 14:1244-1253. [PMID: 39165549 PMCID: PMC11331385 DOI: 10.5498/wjp.v14.i8.1244] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/05/2024] [Accepted: 07/11/2024] [Indexed: 08/12/2024] Open
Abstract
BACKGROUND The interplay between inflammation, immune dysregulation, and the onset of neurological disorders, including epilepsy, has become increasingly recognized. Interleukin (IL)-6, a pro-inflammatory cytokine, is suspected to not only mediate traditional inflammatory pathways but also contribute to neuroinflammatory responses that could underpin neuropsychiatric symptoms and broader psychiatric disorders in epilepsy patients. The role of IL-6 receptor (IL6R) blockade presents an intriguing target for therapeutic intervention due to its potential to attenuate these processes. AIM To explore the potential of IL6R blockade in reducing the risk of epilepsy and investigate whether this pathway might also influence associated psychiatric and neuropsychiatric conditions due to neuroinflammation. METHODS Mendelian randomization (MR) analysis employing single nucleotide polymorphisms (SNPs) in the vicinity of the IL6R gene (total individuals = 408225) was used to evaluate the putative causal relationship between IL6R blockade and epilepsy (total cases/controls = 12891/312803), focal epilepsy (cases/controls = 7526/399290), and generalized epilepsy (cases/controls = 1413/399287). SNP weights were determined by their effect on C-reactive protein (CRP) levels and integrated using inverse variance-weighted meta-analysis as surrogates for IL6R effects. To address potential outlier and pleiotropic influences, sensitivity analyses were conducted employing a variety of MR methods under different modeling assumptions. RESULTS The genetic simulation targeting IL6R blockade revealed a modest but significant reduction in overall epilepsy risk [inverse variance weighting: Odds ratio (OR): 0.827; 95% confidence interval (CI): 0.685-1.000; P = 0.05]. Subtype analysis showed variability, with no significant effect observed in generalized, focal, or specific childhood and juvenile epilepsy forms. Beyond the primary inflammatory marker CRP, the findings also suggested potential non-inflammatory pathways mediated by IL-6 signaling contributing to the neurobiological landscape of epilepsy, hinting at possible links to neuroinflammation, psychiatric symptoms, and associated mental disorders. CONCLUSION The investigation underscored a tentative causal relationship between IL6R blockade and decreased epilepsy incidence, likely mediated via complex neuroinflammatory pathways. These results encouraged further in-depth studies involving larger cohorts and multifaceted psychiatric assessments to corroborate these findings and more thoroughly delineate the neuro-psychiatric implications of IL-6 signaling in epilepsy. The exploration of IL6R blockade could herald a novel therapeutic avenue not just for seizure management but also for addressing the broader psychiatric and cognitive disturbances often associated with epilepsy.
Collapse
Affiliation(s)
- Yan-Mei Yu
- Department of Pediatrics, The First People's Hospital of Chuzhou, Chuzhou 239001, Anhui Province, China
| | - Gui-Hong Jin
- Department of Pediatrics, The First People's Hospital of Chuzhou, Chuzhou 239001, Anhui Province, China
| | - Chong Zhong
- Department of Pediatrics, The First People's Hospital of Chuzhou, Chuzhou 239001, Anhui Province, China
| | - Hao Qian
- Department of Pediatrics, The First People's Hospital of Chuzhou, Chuzhou 239001, Anhui Province, China
| | - Lei Wang
- Department of Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325000, Zhejiang Province, China
| | - Feng Zhan
- Department of Pediatrics, The First People's Hospital of Chuzhou, Chuzhou 239001, Anhui Province, China
| |
Collapse
|
3
|
Damodar T, Dunai C, Prabhu N, Jose M, Akhila L, Kinhal UV, Anusha Raj K, Marate S, Lalitha AV, Dsouza FS, Sajjan SV, Gowda VK, Basavaraja GV, Singh B, Prathyusha PV, Tharmaratnam K, Ravi V, Kolamunnage-Dona R, Solomon T, Turtle L, Yadav R, Michael BD, Mani RS. Diagnostic markers of acute encephalitis syndrome and COVID-associated multisystem inflammatory syndrome in children from Southern India. J Med Virol 2024; 96:e29666. [PMID: 38738569 PMCID: PMC7616670 DOI: 10.1002/jmv.29666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/29/2024] [Accepted: 04/30/2024] [Indexed: 05/14/2024]
Abstract
Acute encephalitis syndrome (AES) in children poses a significant public health challenge in India. This study aims to explore the utility of host inflammatory mediators and neurofilament (NfL) levels in distinguishing etiologies, assessing disease severity, and predicting outcomes in AES. We assessed 12 mediators in serum (n = 58) and 11 in cerebrospinal fluid (CSF) (n = 42) from 62 children with AES due to scrub typhus, viral etiologies, and COVID-associated multisystem inflammatory syndrome (MIS-C) in Southern India. Additionally, NfL levels in serum (n = 20) and CSF (n = 18) were examined. Clinical data, including Glasgow coma scale (GCS) and Liverpool outcome scores, were recorded. Examining serum and CSF markers in the three AES etiology groups revealed notable distinctions, with scrub typhus differing significantly from viral and MIS-C causes. Viral causes had elevated serum CCL11 and CCL2 compared with scrub typhus, while MIS-C cases showed higher HGF levels than scrub typhus. However, CSF analysis showed a distinct pattern with the scrub typhus group exhibiting elevated levels of IL-1RA, IL-1β, and TNF compared with MIS-C, and lower CCL2 levels compared with the viral group. Modeling the characteristic features, we identified that age ≥3 years with serum CCL11 < 180 pg/mL effectively distinguished scrub typhus from other AES causes. Elevated serum CCL11, HGF, and IL-6:IL-10 ratio were associated with poor outcomes (p = 0.038, 0.005, 0.02). Positive CSF and serum NfL correlation, and negative GCS and serum NfL correlation were observed. Median NfL levels were higher in children with abnormal admission GCS and poor outcomes. Measuring immune mediators and brain injury markers in AES provides valuable diagnostic insights, with the potential to facilitate rapid diagnosis and prognosis. The correlation between CSF and serum NfL, along with distinctive serum cytokine profiles across various etiologies, indicates the adequacy of blood samples alone for assessment and monitoring. The association of elevated levels of CCL11, HGF, and an increased IL-6:IL-10 ratio with adverse outcomes suggests promising avenues for therapeutic exploration, warranting further investigation.
Collapse
Affiliation(s)
- Tina Damodar
- Department of Neurovirology, National Institute of Mental Health & Neurosciences, Bangalore, India
| | - Cordelia Dunai
- Department of Clinical Infection, Microbiology & Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
- National Institute for Health and Care Research Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
| | - Namratha Prabhu
- Department of Neurovirology, National Institute of Mental Health & Neurosciences, Bangalore, India
| | - Maria Jose
- Department of Neurovirology, National Institute of Mental Health & Neurosciences, Bangalore, India
| | - L. Akhila
- Department of Neurovirology, National Institute of Mental Health & Neurosciences, Bangalore, India
| | - Uddhava V. Kinhal
- Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India
| | - K. Anusha Raj
- Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India
| | - Srilatha Marate
- Department of Neurovirology, National Institute of Mental Health & Neurosciences, Bangalore, India
| | - A. V. Lalitha
- Department of Pediatric Critical Care, St John’s Medical College and Hospital, Bangalore, India
| | | | - Sushma Veeranna Sajjan
- Department of Pediatrics, Bangalore Medical College and Research Institute, Bangalore, India
| | - Vykuntaraju K. Gowda
- Department of Pediatrics, Indira Gandhi Institute of Child Health, Bangalore, India
| | - G. V. Basavaraja
- Department of Pediatrics, Indira Gandhi Institute of Child Health, Bangalore, India
| | - Bhagteshwar Singh
- Tropical & Infectious Diseases Unit, Royal Liverpool University Hospital, Liverpool, UK
- Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
- Department of Infectious Diseases, Christian Medical College, Vellore, India
| | - P. V. Prathyusha
- Department of Biostatistics, National Institute of Mental Health & Neurosciences, Bangalore, India
| | | | - Vasanthapuram Ravi
- Department of Neurovirology, National Institute of Mental Health & Neurosciences, Bangalore, India
| | | | - Tom Solomon
- National Institute for Health and Care Research Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
- The Pandemic Institute, Liverpool, UK
- Department of Neurology, Walton Centre NHS Foundation Trust, Liverpool, UK
| | - Lance Turtle
- Department of Clinical Infection, Microbiology & Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
- National Institute for Health and Care Research Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
- Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
| | - Ravi Yadav
- Department of Neurology, National Institute of Mental Health & Neurosciences, Bangalore, India
| | - Benedict D. Michael
- Department of Clinical Infection, Microbiology & Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
- National Institute for Health and Care Research Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
- The Pandemic Institute, Liverpool, UK
- Department of Neurology, Walton Centre NHS Foundation Trust, Liverpool, UK
| | - Reeta S. Mani
- Department of Neurovirology, National Institute of Mental Health & Neurosciences, Bangalore, India
| |
Collapse
|
4
|
Elmers J, Colzato LS, Akgün K, Ziemssen T, Beste C. Neurofilaments - Small proteins of physiological significance and predictive power for future neurodegeneration and cognitive decline across the life span. Ageing Res Rev 2023; 90:102037. [PMID: 37619618 DOI: 10.1016/j.arr.2023.102037] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 05/15/2023] [Accepted: 08/17/2023] [Indexed: 08/26/2023]
Abstract
Neurofilaments (NFs) are not only important for axonal integrity and nerve conduction in large myelinated axons but they are also thought to be crucial for receptor and synaptic functioning. Therefore, NFs may play a critical role in cognitive functions, as cognitive processes are known to depend on synaptic integrity and are modulated by dopaminergic signaling. Here, we present a theory-driven interdisciplinary approach that NFs may link inflammation, neurodegeneration, and cognitive functions. We base our hypothesis on a wealth of evidence suggesting a causal link between inflammation and neurodegeneration and between these two and cognitive decline (see Fig. 1), also taking dopaminergic signaling into account. We conclude that NFs may not only serve as biomarkers for inflammatory, neurodegenerative, and cognitive processes but also represent a potential mechanical hinge between them, moreover, they may even have predictive power regarding future cognitive decline. In addition, we advocate the use of both NFs and MRI parameters, as their synthesis offers the opportunity to individualize medical treatment by providing a comprehensive view of underlying disease activity in neurological diseases. Since our society will become significantly older in the upcoming years and decades, maintaining cognitive functions and healthy aging will play an important role. Thanks to technological advances in recent decades, NFs could serve as a rapid, noninvasive, and relatively inexpensive early warning system to identify individuals at increased risk for cognitive decline and could facilitate the management of cognitive dysfunctions across the lifespan.
Collapse
Affiliation(s)
- Julia Elmers
- Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Germany; Center of Clinical Neuroscience, Department of Neurology, University Hospital Carl Gustav Carus, TU Dresden, Germany
| | - Lorenza S Colzato
- Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Germany; Cognitive Psychology, Faculty of Psychology, Shandong Normal University, Jinan, China.
| | - Katja Akgün
- Center of Clinical Neuroscience, Department of Neurology, University Hospital Carl Gustav Carus, TU Dresden, Germany
| | - Tjalf Ziemssen
- Center of Clinical Neuroscience, Department of Neurology, University Hospital Carl Gustav Carus, TU Dresden, Germany
| | - Christian Beste
- Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Germany; Cognitive Psychology, Faculty of Psychology, Shandong Normal University, Jinan, China.
| |
Collapse
|
5
|
He X, Zhong Q, Yan K, Li G, Yang J. Oral exposure to an acceptable daily intake dose of aspartame induced a delayed proinflammatory cytokine response in the cerebrospinal fluid of rats. Food Chem Toxicol 2023; 178:113931. [PMID: 37437708 DOI: 10.1016/j.fct.2023.113931] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 06/10/2023] [Accepted: 07/02/2023] [Indexed: 07/14/2023]
Abstract
This study aimed to investigate the effect of exposure to aspartame (ASP) at safe levels on proinflammatory cytokines in the cerebrospinal fluid (CSF) of rats. Sprague Dawley rats were sacrificed after 1, 2, 4 or 8 week(s) of continuous exposure to ASP (40 mg/kg body weight). Serum, CSF and brain tissue samples were prepared, and the levels of the IL-1β, IL-6 and TNF-α were analyzed by ELISA. In serum, the levels of all three cytokines showed a two-phase alteration, a decrease followed by an increase in the ASP group. In the brain, their levels increased from the second or fourth week compared with the control group. In CSF, the levels of these cytokines showed a similar change to that in brain tissue, but the increase appeared at a later time point. For each cytokine, there was a significant positive correlation between its levels in serum, brain tissue and CSF. This is the first discovery that ASP exposure increased the levels of proinflammatory cytokines in CSF in rats, which emerged later than in blood and brain tissue. This study suggests the necessity of conducting related clinical studies to evaluate potential neuroinflammatory effects induced by chronic ASP exposure through CSF analysis.
Collapse
Affiliation(s)
- Xiaoyi He
- Department of Anatomy, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Qianyi Zhong
- School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Kai Yan
- Department of Anatomy, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Guoying Li
- Guangdong Medical Association, Guangzhou, Guangdong, 510180, China.
| | - Junhua Yang
- Department of Anatomy, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, China; Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
| |
Collapse
|
6
|
Kruckow KL, Zhao K, Bowdish DME, Orihuela CJ. Acute organ injury and long-term sequelae of severe pneumococcal infections. Pneumonia (Nathan) 2023; 15:5. [PMID: 36870980 PMCID: PMC9985869 DOI: 10.1186/s41479-023-00110-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 01/31/2023] [Indexed: 03/06/2023] Open
Abstract
Streptococcus pneumoniae (Spn) is a major public health problem, as it is a main cause of otitis media, community-acquired pneumonia, bacteremia, sepsis, and meningitis. Acute episodes of pneumococcal disease have been demonstrated to cause organ damage with lingering negative consequences. Cytotoxic products released by the bacterium, biomechanical and physiological stress resulting from infection, and the corresponding inflammatory response together contribute to organ damage accrued during infection. The collective result of this damage can be acutely life-threatening, but among survivors, it also contributes to the long-lasting sequelae of pneumococcal disease. These include the development of new morbidities or exacerbation of pre-existing conditions such as COPD, heart disease, and neurological impairments. Currently, pneumonia is ranked as the 9th leading cause of death, but this estimate only considers short-term mortality and likely underestimates the true long-term impact of disease. Herein, we review the data that indicates damage incurred during acute pneumococcal infection can result in long-term sequelae which reduces quality of life and life expectancy among pneumococcal disease survivors.
Collapse
Affiliation(s)
- Katherine L Kruckow
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Kevin Zhao
- McMaster Immunology Research Centre and the Firestone Institute for Respiratory Health, McMaster University, Hamilton, Canada
| | - Dawn M E Bowdish
- McMaster Immunology Research Centre and the Firestone Institute for Respiratory Health, McMaster University, Hamilton, Canada
| | - Carlos J Orihuela
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA.
| |
Collapse
|
7
|
Müller A, Lekhuleni C, Hupp S, du Plessis M, Holivololona L, Babiychuk E, Leib SL, Grandgirard D, Iliev AI, von Gottberg A, Hathaway LJ. Meningitis-associated pneumococcal serotype 8, ST 53, strain is hypervirulent in a rat model and has non-haemolytic pneumolysin which can be attenuated by liposomes. Front Cell Infect Microbiol 2023; 12:1106063. [PMID: 36683678 PMCID: PMC9852819 DOI: 10.3389/fcimb.2022.1106063] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 12/19/2022] [Indexed: 01/09/2023] Open
Abstract
Introduction Streptococcus pneumoniae bacteria cause life-threatening invasive pneumococcal disease (IPD), including meningitis. Pneumococci are classified into serotypes, determined by differences in capsular polysaccharide and both serotype and pneumolysin toxin are associated with disease severity. Strains of serotype 8, ST 53, are increasing in prevalence in IPD in several countries. Methods Here we tested the virulence of such an isolate in a rat model of meningitis in comparison with a serotype 15B and a serotype 14 isolate. All three were isolated from meningitis patients in South Africa in 2019, where serotype 8 is currently the most common serotype in IPD. Results and Discussion Only the serotype 8 isolate was hypervirulent causing brain injury and a high mortality rate. It induced a greater inflammatory cytokine response than either the serotype 15B or 14 strain in the rat model and from primary mixed-glia cells isolated from mouse brains. It had the thickest capsule of the three strains and produced non-haemolytic pneumolysin. Pneumolysin-sequestering liposomes reduced the neuroinflammatory cytokine response in vitro indicating that liposomes have the potential to be an effective adjuvant therapy even for hypervirulent pneumococcal strains with non-haemolytic pneumolysin.
Collapse
Affiliation(s)
- Annelies Müller
- Institute for Infectious Diseases, Faculty of Medicine, University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, Faculty of Medicine, University of Bern, Bern, Switzerland
| | - Cebile Lekhuleni
- Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases, Division of the National Health Laboratory Service, Johannesburg, South Africa
- School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Sabrina Hupp
- Institute of Anatomy, University of Bern, Bern, Switzerland
| | - Mignon du Plessis
- Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases, Division of the National Health Laboratory Service, Johannesburg, South Africa
- School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Lalaina Holivololona
- Institute for Infectious Diseases, Faculty of Medicine, University of Bern, Bern, Switzerland
| | | | - Stephen L. Leib
- Institute for Infectious Diseases, Faculty of Medicine, University of Bern, Bern, Switzerland
| | - Denis Grandgirard
- Institute for Infectious Diseases, Faculty of Medicine, University of Bern, Bern, Switzerland
| | | | - Anne von Gottberg
- Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases, Division of the National Health Laboratory Service, Johannesburg, South Africa
- School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Lucy J. Hathaway
- Institute for Infectious Diseases, Faculty of Medicine, University of Bern, Bern, Switzerland
| |
Collapse
|
8
|
Chiffi G, Grandgirard D, Stöckli S, Valente LG, Adamantidis A, Leib SL. Tick-borne encephalitis affects sleep–wake behavior and locomotion in infant rats. Cell Biosci 2022; 12:121. [PMID: 35918749 PMCID: PMC9344439 DOI: 10.1186/s13578-022-00859-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 07/21/2022] [Indexed: 03/05/2025] Open
Abstract
Background/Aims Tick-borne encephalitis (TBE) is a disease affecting the central nervous system. Over the last decade, the incidence of TBE has steadily increased in Europe and Asia despite the availably of effective vaccines. Up to 50% of patients after TBE suffer from post-encephalitic syndrome that may develop into long-lasting morbidity. Altered sleep–wake functions have been reported by patients after TBE. The mechanisms causing these disorders in TBE are largely unknown to date. As a first step toward a better understanding of the pathology of TBEV-inducing sleep dysfunctions, we assessed parameters of sleep structure in an established infant rat model of TBE. Methods 13-day old Wistar rats were infected with 1 × 106 FFU Langat virus (LGTV). On day 4, 9, and 21 post infection, Rotarod (balance and motor coordination) and open field tests (general locomotor activity) were performed and brains from representative animals were collected in each subgroup. On day 28 the animals were implanted with a telemetric EEG/EMG system. Sleep recording was continuously performed for 24 consecutive hours starting at day 38 post infection and visually scored for Wake, NREM, and REM in 4 s epochs. Results As a novelty of this study, infected animals showed a significant larger percentage of time spend awake during the dark phase and less NREM and REM compared to the control animals (p < 0.01 for all comparisons). Furthermore, it was seen, that during the dark phase the wake bout length in infected animals was prolonged (p = 0.043) and the fragmentation index decreased (p = 0.0085) in comparison to the control animals. LGTV-infected animals additionally showed a reduced rotarod performance ability at day 4 (p = 0.0011) and day 9 (p = 0.0055) and day 21 (p = 0.0037). A lower locomotor activity was also seen at day 4 (p = 0.0196) and day 9 (p = 0.0473). Conclusion Our data show that experimental TBE in infant rats affects sleep–wake behavior, leads to decreased spontaneous locomotor activity, and impaired moto-coordinative function. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-022-00859-7.
Collapse
|
9
|
Mudra Rakshasa-Loots A, Whalley HC, Vera JH, Cox SR. Neuroinflammation in HIV-associated depression: evidence and future perspectives. Mol Psychiatry 2022; 27:3619-3632. [PMID: 35618889 PMCID: PMC9708589 DOI: 10.1038/s41380-022-01619-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 05/04/2022] [Accepted: 05/10/2022] [Indexed: 02/08/2023]
Abstract
People living with HIV face a high risk of mental illness, especially depression. We do not yet know the precise neurobiological mechanisms underlying HIV-associated depression. Depression severity in the general population has been linked to acute and chronic markers of systemic inflammation. Given the associations between depression and peripheral inflammation, and since HIV infection in the brain elicits a neuroinflammatory response, it is possible that neuroinflammation contributes to the high prevalence of depression amongst people living with HIV. The purpose of this review was to synthesise existing evidence for associations between inflammation, depression, and HIV. While there is strong evidence for independent associations between these three conditions, few preclinical or clinical studies have attempted to characterise their interrelationship, representing a major gap in the literature. This review identifies key areas of debate in the field and offers perspectives for future investigations of the pathophysiology of HIV-associated depression. Reproducing findings across diverse populations will be crucial in obtaining robust and generalisable results to elucidate the precise role of neuroinflammation in this pathophysiology.
Collapse
Affiliation(s)
- Arish Mudra Rakshasa-Loots
- Edinburgh Neuroscience, School of Biomedical Sciences, The University of Edinburgh, Edinburgh, UK.
- Lothian Birth Cohorts Group, Department of Psychology, The University of Edinburgh, Edinburgh, UK.
| | - Heather C Whalley
- Division of Psychiatry, Centre for Clinical Brain Sciences, Royal Edinburgh Hospital, The University of Edinburgh, Edinburgh, UK
| | - Jaime H Vera
- Department of Global Health and Infection, Brighton and Sussex Medical School, University of Sussex, Brighton, UK
| | - Simon R Cox
- Lothian Birth Cohorts Group, Department of Psychology, The University of Edinburgh, Edinburgh, UK
| |
Collapse
|
10
|
Hcp Proteins of the Type VI Secretion System Promote Avian Pathogenic E. coli DE205B (O2:K1) to Induce Meningitis in Rats. Life (Basel) 2022; 12:life12091353. [PMID: 36143390 PMCID: PMC9503490 DOI: 10.3390/life12091353] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/09/2022] [Accepted: 08/21/2022] [Indexed: 11/16/2022] Open
Abstract
Avian pathogenic Escherichia coli (APEC) is an important extra-intestinal pathogenic E. coli (ExPEC), which often causes systemic infection in poultry and causes great economic loss to the breeding industry. In addition, as a major source of human ExPEC infection, the potential zoonotic risk of APEC has been an ongoing concern. Previous studies have pointed out that APEC is a potential zoonotic pathogen, which has high homology with human pathogenic E. coli such as uro-pathogenic E. coli (UPEC) and neonatal meningitis E. coli (NMEC), shares multiple virulence factors and can cause mammalian diseases. Previous studies have reported that O18 and O78 could cause different degrees of meningitis in neonatal rats, and different serotypes had different degrees of zoonotic risk. Here, we compared APEC DE205B (O2:K1) with NMEC RS218 (O18:K1:H7) by phylogenetic analysis and virulence gene identification to analyze the potential risk of DE205B in zoonotic diseases. We found that DE205B possessed a variety of virulence factors associated with meningitis and, through phylogenetic analysis, had high homology with RS218. DE205B could colonize the cerebrospinal fluid (CSF) of rats, and cause meningitis and nerve damage. Symptoms and pathological changes in the brain were similar to RS218. In addition, we found that DE205B had a complete T6SS, of which Hcp protein was its important structural protein. Hcp1 induced cytoskeleton rearrangement in human brain microvascular endothelial cells (HBMECs), and Hcp2 was mainly involved in the invasion of DE205B in vitro. In the meningitis model of rats, deletion of hcp2 gene reduced survival in the blood and the brain invasiveness of DE205B. Compared with WT group, Δhcp2 group induced lower inflammation and neutrophils infiltration in brain tissue, alleviating the process of meningitis. Together, these results suggested that APEC DE205B had close genetic similarities to NMEC RS218, and a similar mechanism in causing meningitis and being a risk for zoonosis. This APEC serotype provided a basis for zoonotic research.
Collapse
|
11
|
van Zeggeren IE, ter Horst L, Heijst H, Teunissen CE, van de Beek D, Brouwer MC. Neurofilament light chain in central nervous system infections: a prospective study of diagnostic accuracy. Sci Rep 2022; 12:14140. [PMID: 35986031 PMCID: PMC9391449 DOI: 10.1038/s41598-022-17643-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 07/28/2022] [Indexed: 11/30/2022] Open
Abstract
Diagnosing central nervous system (CNS) infections quickly is often difficult. Neurofilament light chain (NfL) is a component of the axonal cytoskeleton and identified as marker of neuronal damage in several CNS diseases. We evaluated the diagnostic accuracy of NfL for diagnosing CNS infections. We included patients from a prospective cohort of consecutive patients in whom a lumbar puncture was performed for suspected CNS infection in an academic hospital in The Netherlands. The index test was NfL in cerebrospinal fluid (CSF) and reference standard the final clinical diagnosis. Diagnostic accuracy was determined using the area-under-the-curve (AUC) with 95% confidence intervals (CI). The association of CSF NfL with clinical characteristics, diagnosis and outcome was evaluated. Between 2012 and 2015, 273 episodes in adults of which sufficient CSF was available were included. CNS infection was diagnosed in 26%(n = 70), CNS inflammatory disease in 7%(n = 20), systemic infection in 32%(n = 87), and other neurological disorders in 33%(n = 90). Median CSF NfL level was 593 pg/ml (IQR 249–1569) and did not discriminate between diagnostic categories or CNS infection subcategories. AUC for diagnosing any CNS infection compared to patients without CNS infections was 0.50 (95% CI 0.42–0.59). Patients presenting with an altered mental status had higher NfL levels compared to other patients. We concluded that NfL cannot discriminate between causes in patients suspected of CNS infections. High concentrations of NfL are associated with severe neurological disease and the prognostic value of NfL in patients with CNS infections should be investigated in future research.
Collapse
|
12
|
Neuro-Axonal Damage and Alteration of Blood–Brain Barrier Integrity in COVID-19 Patients. Cells 2022; 11:cells11162480. [PMID: 36010557 PMCID: PMC9406414 DOI: 10.3390/cells11162480] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/04/2022] [Accepted: 08/07/2022] [Indexed: 01/08/2023] Open
Abstract
Neurofilament light chain (NfL) is a specific biomarker of neuro-axonal damage. Matrix metalloproteinases (MMPs) are zinc-dependent enzymes involved in blood–brain barrier (BBB) integrity. We explored neuro-axonal damage, alteration of BBB integrity and SARS-CoV-2 RNA presence in COVID-19 patients with severe neurological symptoms (neuro-COVID) as well as neuro-axonal damage in COVID-19 patients without severe neurological symptoms according to disease severity and after recovery, comparing the obtained findings with healthy donors (HD). Overall, COVID-19 patients (n = 55) showed higher plasma NfL levels compared to HD (n = 31) (p < 0.0001), especially those who developed ARDS (n = 28) (p = 0.0005). After recovery, plasma NfL levels were still higher in ARDS patients compared to HD (p = 0.0037). In neuro-COVID patients (n = 12), higher CSF and plasma NfL, and CSF MMP-2 levels in ARDS than non-ARDS group were observed (p = 0.0357, p = 0.0346 and p = 0.0303, respectively). SARS-CoV-2 RNA was detected in four CSF and two plasma samples. SARS-CoV-2 RNA detection was not associated to increased CSF NfL and MMP levels. During COVID-19, ARDS could be associated to CNS damage and alteration of BBB integrity in the absence of SARS-CoV-2 RNA detection in CSF or blood. CNS damage was still detectable after discharge in blood of COVID-19 patients who developed ARDS during hospitalization.
Collapse
|
13
|
Le ND, Steinfort M, Grandgirard D, Maleska A, Leppert D, Kuhle J, Leib SL. The CCR5 antagonist maraviroc exerts limited neuroprotection without improving neurofunctional outcome in experimental pneumococcal meningitis. Sci Rep 2022; 12:12945. [PMID: 35902720 PMCID: PMC9334283 DOI: 10.1038/s41598-022-17282-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 07/22/2022] [Indexed: 11/10/2022] Open
Abstract
One-third of pneumococcal meningitis (PM) survivors suffer from neurological sequelae including learning disabilities and hearing loss due to excessive neuroinflammation. There is a lack of efficacious compounds for adjuvant therapy to control this long-term consequence of PM. One hallmark is the recruitment of leukocytes to the brain to combat the bacterial spread. However, this process induces excessive inflammation, causing neuronal injury. Maraviroc (MVC)-a CCR5 antagonist-was demonstrated to inhibit leukocyte recruitment and attenuate neuroinflammation in several inflammatory diseases. Here, we show that in vitro, MVC decreased nitric oxide production in astroglial cells upon pneumococcal stimulation. In vivo, infant Wistar rats were infected with 1 × 104 CFU/ml S. pneumoniae and randomized for treatment with ceftriaxone plus MVC (100 mg/kg) or ceftriaxone monotherapy. During the acute phase, neuroinflammation in the CSF was measured and histopathological analyses were performed to determine neuronal injury. Long-term neurofunctional outcome (learning/memory and hearing capacity) after PM was assessed. MVC treatment reduced hippocampal cell apoptosis but did not affect CSF neuroinflammation and the neurofunctional outcome after PM. We conclude that MVC treatment only exerted limited effect on the pathophysiology of PM and is, therefore, not sufficiently beneficial in this experimental paradigm of PM.
Collapse
Affiliation(s)
- Ngoc Dung Le
- Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences (GCB), University of Bern, Bern, Switzerland
| | - Marel Steinfort
- Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland
| | - Denis Grandgirard
- Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland
| | - Aleksandra Maleska
- Multiple Sclerosis Centre, Neurology, Departments of Head, Spine and Neuromedicine, Biomedicine and Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland
- Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), University Hospital and University of Basel, Basel, Switzerland
| | - David Leppert
- Multiple Sclerosis Centre, Neurology, Departments of Head, Spine and Neuromedicine, Biomedicine and Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland
- Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), University Hospital and University of Basel, Basel, Switzerland
| | - Jens Kuhle
- Multiple Sclerosis Centre, Neurology, Departments of Head, Spine and Neuromedicine, Biomedicine and Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland
- Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), University Hospital and University of Basel, Basel, Switzerland
| | - Stephen L Leib
- Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
| |
Collapse
|
14
|
Wai CH, Jin J, Cyrklaff M, Genoud C, Funaya C, Sattler J, Maceski A, Meier S, Heiland S, Lanzer M, Frischknecht F, Kuhle J, Bendszus M, Hoffmann A. Neurofilament light chain plasma levels are associated with area of brain damage in experimental cerebral malaria. Sci Rep 2022; 12:10726. [PMID: 35750882 PMCID: PMC9232608 DOI: 10.1038/s41598-022-14291-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 06/03/2022] [Indexed: 11/23/2022] Open
Abstract
Neurofilament light chain (NfL), released during central nervous injury, has evolved as a powerful serum marker of disease severity in many neurological disorders, including infectious diseases. So far NfL has not been assessed in cerebral malaria in human or its rodent model experimental cerebral malaria (ECM), a disease that can lead to fatal brain edema or reversible brain edema. In this study we assessed if NfL serum levels can also grade disease severity in an ECM mouse model with reversible (n = 11) and irreversible edema (n = 10). Blood–brain-barrier disruption and brain volume were determined by magnetic resonance imaging. Neurofilament density volume as well as structural integrity were examined by electron microscopy in regions of most severe brain damage (olfactory bulb (OB), cortex and brainstem). NfL plasma levels in mice with irreversible edema (317.0 ± 45.01 pg/ml) or reversible edema (528.3 ± 125.4 pg/ml) were significantly increased compared to controls (103.4 ± 25.78 pg/ml) by three to five fold, but did not differ significantly in mice with reversible or irreversible edema. In both reversible and irreversible edema, the brain region most affected was the OB with highest level of blood–brain-barrier disruption and most pronounced decrease in neurofilament density volume, which correlated with NfL plasma levels (r = − 0.68, p = 0.045). In cortical and brainstem regions neurofilament density was only decreased in mice with irreversible edema and strongest in the brainstem. In reversible edema NfL plasma levels, MRI findings and neurofilament volume density normalized at 3 months’ follow-up. In conclusion, NfL plasma levels are elevated during ECM confirming brain damage. However, NfL plasma levels fail short on reliably indicating on the final outcomes in the acute disease stage that could be either fatal or reversible. Increased levels of plasma NfL during the acute disease stage are thus likely driven by the anatomical location of brain damage, the olfactory bulb, a region that serves as cerebral draining pathway into the nasal lymphatics.
Collapse
Affiliation(s)
- Chi Ho Wai
- Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.,Centre for Infectious Diseases, Parasitology Unit, Heidelberg University Hospital, Heidelberg, Germany
| | - Jessica Jin
- Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.,Centre for Infectious Diseases, Parasitology Unit, Heidelberg University Hospital, Heidelberg, Germany
| | - Marek Cyrklaff
- Centre for Infectious Diseases, Parasitology Unit, Heidelberg University Hospital, Heidelberg, Germany
| | - Christel Genoud
- Electron Microscopy Facility, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Charlotta Funaya
- Electron Microscopy Core Facility, Heidelberg University, Heidelberg, Germany
| | - Julia Sattler
- Centre for Infectious Diseases, Parasitology Unit, Heidelberg University Hospital, Heidelberg, Germany
| | - Aleksandra Maceski
- Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Basel, Switzerland
| | - Stephanie Meier
- Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Basel, Switzerland
| | - Sabine Heiland
- Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Michael Lanzer
- Centre for Infectious Diseases, Parasitology Unit, Heidelberg University Hospital, Heidelberg, Germany
| | - Friedrich Frischknecht
- Centre for Infectious Diseases, Parasitology Unit, Heidelberg University Hospital, Heidelberg, Germany.,German Center for Infection Research (DZIF), Heidelberg, Germany
| | - Jens Kuhle
- Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Basel, Switzerland
| | - Martin Bendszus
- Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Angelika Hoffmann
- Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany. .,Department of Neuroradiology, University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Bern, Inselspital, University of Bern, Freiburgstrasse, 3010, Bern, Switzerland.
| |
Collapse
|
15
|
Fader KA, Pardo ID, Kovi RC, Somps CJ, Wang HH, Vaidya VS, Ramaiah SK, Sirivelu MP. Circulating neurofilament light chain as a promising biomarker of AAV-induced dorsal root ganglia toxicity in nonclinical toxicology species. Mol Ther Methods Clin Dev 2022; 25:264-277. [PMID: 35505662 PMCID: PMC9024379 DOI: 10.1016/j.omtm.2022.03.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 03/27/2022] [Indexed: 12/14/2022]
Abstract
Adeno-associated virus (AAV)-induced dorsal root ganglia (DRG) toxicity has been observed in several nonclinical species, where lesions are characterized by neuronal degeneration/necrosis, nerve fiber degeneration, and mononuclear cell infiltration. As AAV vectors become an increasingly common platform for novel therapeutics, non-invasive biomarkers are needed to better characterize and manage the risk of DRG neurotoxicity in both nonclinical and clinical studies. Based on biological relevance, reagent availability, antibody cross-reactivity, DRG protein expression, and assay performance, neurofilament light chain (NF-L) emerged as a promising biomarker candidate. Dose- and time-dependent changes in NF-L were evaluated in male Wistar Han rats and cynomolgus monkeys following intravenous or intrathecal AAV injection, respectively. NF-L profiles were then compared against microscopic DRG lesions on day 29 post-dosing. In animals exhibiting DRG toxicity, plasma/serum NF-L was strongly associated with the severity of neuronal degeneration/necrosis and nerve fiber degeneration, with elevations beginning as early as day 8 in rats (≥5 × 1013 vg/kg) and day 14 in monkeys (≥3.3 × 1013 vg/dose). Consistent with the unique positioning of DRGs outside the blood-brain barrier, NF-L in cerebrospinal fluid was only weakly associated with DRG findings. In summary, circulating NF-L is a promising biomarker of AAV-induced DRG toxicity in nonclinical species.
Collapse
Affiliation(s)
- Kelly A Fader
- Pfizer Worldwide Research, Development and Medical, Drug Safety Research and Development, Groton, CT 06340, USA
| | | | - Ramesh C Kovi
- Pfizer Worldwide Research, Development and Medical, Drug Safety Research and Development, Pfizer Inc., 300 Technology Square, Cambridge, MA 02139, USA
| | - Christopher J Somps
- Pfizer Worldwide Research, Development and Medical, Drug Safety Research and Development, Groton, CT 06340, USA
| | - Helen Hong Wang
- Pfizer Worldwide Research, Development and Medical, Drug Safety Research and Development, Pfizer Inc., 300 Technology Square, Cambridge, MA 02139, USA
| | - Vishal S Vaidya
- Pfizer Worldwide Research, Development and Medical, Drug Safety Research and Development, Pfizer Inc., 300 Technology Square, Cambridge, MA 02139, USA
| | - Shashi K Ramaiah
- Pfizer Worldwide Research, Development and Medical, Drug Safety Research and Development, Pfizer Inc., 300 Technology Square, Cambridge, MA 02139, USA
| | - Madhu P Sirivelu
- Pfizer Worldwide Research, Development and Medical, Drug Safety Research and Development, Pfizer Inc., 300 Technology Square, Cambridge, MA 02139, USA
| |
Collapse
|
16
|
West Nile Virus Neuroinfection in Humans: Peripheral Biomarkers of Neuroinflammation and Neuronal Damage. Viruses 2022; 14:v14040756. [PMID: 35458486 PMCID: PMC9027124 DOI: 10.3390/v14040756] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 01/27/2023] Open
Abstract
Among emerging arthropod-borne viruses (arbovirus), West Nile virus (WNV) is a flavivirus that can be associated with severe neuroinvasive infections in humans. In 2018, the European WNV epidemic resulted in over 2000 cases, representing the most important arboviral epidemic in the European continent. Characterization of inflammation and neuronal biomarkers released during WNV infection, especially in the context of neuronal impairments, could provide insight into the development of predictive tools that could be beneficial for patient outcomes. We first analyzed the inflammatory signature in the serum of WNV-infected mice and found increased concentrations of several inflammatory cytokines. We next analyzed serum and cerebrospinal-fluid (CSF) samples from a cohort of patients infected by WNV between 2018 and 2019 in Hungary to quantify a large panel of inflammatory cytokines and neurological factors. We found higher levels of inflammatory cytokines (e.g., IL4, IL6, and IL10) and neuronal factors (e.g., BDNF, GFAP, MIF, TDP-43) in the sera of WNV-infected patients with neuroinvasive disease. Furthermore, the serum inflammatory profile of these patients persisted for several weeks after initial infection, potentially leading to long-term sequelae and having a deleterious effect on brain neurovasculature. This work suggests that early signs of increased serum concentrations of inflammatory cytokines and neuronal factors could be a signature underlying the development of severe neurological impairments. Biomarkers could play an important role in patient monitoring to improve care and prevent undesirable outcomes.
Collapse
|
17
|
Chekrouni N, van Soest TM, Brouwer MC, Willemse EAJ, Teunissen CE, van de Beek D. CSF Neurofilament Light Chain Concentrations Predict Outcome in Bacterial Meningitis. NEUROLOGY(R) NEUROIMMUNOLOGY & NEUROINFLAMMATION 2022; 9:9/1/e1123. [PMID: 34903639 PMCID: PMC8669658 DOI: 10.1212/nxi.0000000000001123] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 11/01/2021] [Indexed: 12/12/2022]
Abstract
Background and Objectives Neurofilament light chain (NfL) is a biomarker for neuroaxonal damage and has been found to be elevated proportionally to the degree of neuronal damage in neurologic diseases. The objective of this study was to determine the prognostic accuracy of NfL concentrations on unfavorable outcome in adults with community-acquired bacterial meningitis. Methods We measured NfL concentration CSF samples from a prospective cohort study of adults with community-acquired bacterial meningitis in The Netherlands and determined associations between NfL CSF concentrations, clinical characteristics, and outcome in multivariate analyses. We identified independent predictors of an unfavorable outcome (Glasgow Outcome Scale scores 1–4) by logistic regression. Results CSF NfL concentrations were evaluated in 429 episodes of 425 patients with community-acquired bacterial meningitis. The median age of 429 episodes was 62 years (interquartile range, 50–69 years). Of note, 290 of 422 (68%) episodes presented with an altered mental status (Glasgow Coma Scale score < 14). Most common causative pathogens were Streptococcus pneumoniae (73%), Neisseria meningitidis (7%), and Listeria monocytogenes (5%). The overall case fatality rate was 62 of 429 (15%), and unfavorable outcome occurred in 57 (37%) of 429 episodes. In multivariate analysis, predictors of unfavorable outcome were older age (OR 1.03, 95% CI 1.01–1.05), cranial nerve palsy (OR 4, 95% CI 1.6–10.3), high serum C-reactive protein concentration (OR 1.3, 95% CI 1.01–1.05), and high CSF NfL concentration (OR 1.5, 95% CI 1.07–2.00). CSF NfL concentrations were higher in patients presenting with focal cerebral deficits (717 pg/mL [416–1,401] vs 412 pg/mL [278–731]; p < 0.001). The area under the curve (AUC) for predicting unfavorable outcome in bacterial meningitis of CSF NfL concentration was 0.69 (95% CI, 0.64–0.74). Discussion CSF NfL concentration is independently associated with unfavorable outcome in adults with community-acquired bacterial meningitis, suggesting that CSF NfL concentration may be a useful biomarker for prognostic assessment in bacterial meningitis. Classification of Evidence Can the level of NfL in CSF (the index test) predict unfavorable outcome in patients with bacterial meningitis, in a cohort of bacterial meningitis patients with a favorable and unfavorable outcome? This study provides Class II evidence that NfL level in CSF is a moderate predictor, with the AUC for predicting unfavorable outcome in bacterial meningitis being 0.69 (95% CI, 0.64–0.74).
Collapse
Affiliation(s)
- Nora Chekrouni
- From the Department of Neurology (N.C., T.M.S., M.C.B., D.B.), University of Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Meibergdreef; and Department of Clinical Chemistry (E.A.J.W., C.E.T.), Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Neurochemistry Laboratory, Amsterdam UMC, De Boelelaan 1117, Amsterdam, The Netherlands
| | - Thijs M van Soest
- From the Department of Neurology (N.C., T.M.S., M.C.B., D.B.), University of Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Meibergdreef; and Department of Clinical Chemistry (E.A.J.W., C.E.T.), Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Neurochemistry Laboratory, Amsterdam UMC, De Boelelaan 1117, Amsterdam, The Netherlands
| | - Matthijs C Brouwer
- From the Department of Neurology (N.C., T.M.S., M.C.B., D.B.), University of Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Meibergdreef; and Department of Clinical Chemistry (E.A.J.W., C.E.T.), Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Neurochemistry Laboratory, Amsterdam UMC, De Boelelaan 1117, Amsterdam, The Netherlands
| | - Eline A J Willemse
- From the Department of Neurology (N.C., T.M.S., M.C.B., D.B.), University of Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Meibergdreef; and Department of Clinical Chemistry (E.A.J.W., C.E.T.), Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Neurochemistry Laboratory, Amsterdam UMC, De Boelelaan 1117, Amsterdam, The Netherlands
| | - Charlotte E Teunissen
- From the Department of Neurology (N.C., T.M.S., M.C.B., D.B.), University of Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Meibergdreef; and Department of Clinical Chemistry (E.A.J.W., C.E.T.), Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Neurochemistry Laboratory, Amsterdam UMC, De Boelelaan 1117, Amsterdam, The Netherlands
| | - Diederik van de Beek
- From the Department of Neurology (N.C., T.M.S., M.C.B., D.B.), University of Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Meibergdreef; and Department of Clinical Chemistry (E.A.J.W., C.E.T.), Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Neurochemistry Laboratory, Amsterdam UMC, De Boelelaan 1117, Amsterdam, The Netherlands.
| |
Collapse
|
18
|
Sano T, Masuda Y, Yasuno H, Shinozawa T, Watanabe T, Kakehi M. Blood Neurofilament Light Chain as a Potential Biomarker for Central and Peripheral Nervous Toxicity in Rats. Toxicol Sci 2021; 185:10-18. [PMID: 34677616 PMCID: PMC8714368 DOI: 10.1093/toxsci/kfab122] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Neurotoxicity is a principal concern in nonclinical drug development. However, standardized and universally accepted fluid biomarkers for evaluating neurotoxicity are lacking. Increasing clinical evidence supports the potential use of neurofilament light (NfL) chain as a biomarker of several neurodegenerative diseases; therefore, we investigated changes in the cerebrospinal fluid (CSF) and serum levels of NfL in Sprague Dawley rats treated with central nervous system (CNS) toxicants (trimethyltin [TMT, 10 mg/kg po, single dose], kainic acid [KA, 12 mg/kg sc, single dose], MK-801 [1 mg/kg sc, single dose]), and a peripheral nervous system (PNS) toxicant (pyridoxine, 1200 mg/kg/day for 3 days). Animals were euthanized 1 (day 2), 3 (day 4), or 7 days after administration (day 8). Increased serum NfL was observed in TMT- and KA-treated animals, which indicated neuronal cell death in the brain on days 2, 4, and/or 8. MK-801-treated animals exhibited no changes in the serum and CSF levels of NfL and no histopathological changes in the brain at any time point. Pyridoxine-induced chromatolysis of the dorsal root ganglion on day 2 and degeneration of peripheral nerve fiber on day 4; additionally, serum NfL was increased. A strong correlation was observed between the serum and CSF levels of NfL and brain lesions caused by TMT and KA, indicating that NfL could be a useful biomarker for detecting CNS toxicity. Additionally, PNS changes were correlated with serum NfL levels. Therefore, serum NfL could serve as a useful peripheral biomarker for detecting both CNS and PNS toxicity in rats.
Collapse
Affiliation(s)
- Tomoya Sano
- Drug Safety Research and Evaluation, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan
| | - Yasushi Masuda
- Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan
| | - Hironobu Yasuno
- Drug Safety Research and Evaluation, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan
| | - Tadahiro Shinozawa
- Drug Safety Research and Evaluation, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan
| | - Takeshi Watanabe
- Drug Safety Research and Evaluation, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan
| | - Masaaki Kakehi
- Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan
| |
Collapse
|
19
|
Elevated Levels of Serum Neurofilament Light Chain Associated with Cognitive Impairment in Vascular Dementia. DISEASE MARKERS 2020; 2020:6612871. [PMID: 33204362 PMCID: PMC7652600 DOI: 10.1155/2020/6612871] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 10/20/2020] [Accepted: 10/22/2020] [Indexed: 12/12/2022]
Abstract
Objective Vascular dementia (VaD) is a progressive neurodegenerative disease with cognitive decline caused by cerebrovascular factors. Despite the great progress made in the past decade, VaD still lacks effective treatments and peripheral blood biomarkers. In this study, we tested the level of peripheral blood neurofilament light chain (NfL) in VaD patients and explored its relationship with cognitive impairment. Method A total of 176 study subjects including 80 normal controls (NC) and 96 VaD patients were included in our study. Upon admission, we collected clinical and biochemical characteristics of all research subjects. We also evaluate the Montreal cognitive assessment scale (MoCA) scores of all subjects. The serum NfL level was measured by the single-molecule array (Simoa) method. Results The years of education in the NC group and VaD group were (11.65 ± 3.04) years and (10.53 ± 3.87) years, respectively. Compared with VaD patients, the NC group has a higher level of education (p = 0.037). Furthermore, the results of Simoa indicated that VaD subjects had higher serum NfL levels compared with the NC group [(8.49 ± 2.37) pg/ml vs. (19.26 ± 4.71) pg/ml, p < 0.001]. In terms of other clinical and biochemical characteristics, there was no significant difference between VaD and NC. The Spearman correlation analysis indicated that educational years have a significant positive correlation with MoCA scores (r = 0.238, p = 0.041), while age and serum NfL levels have a significantly negative correlation with MoCA scores (age: r = -0.213, p = 0.040; NfL: r = -0.395, p = 0.027). However, further multiple regression analysis showed that only serum NfL level might serve as an independent risk factor for cognitive decline in VaD (β = 0.317, p = 0.021). Conclusion The serum NfL levels in VaD subjects are significantly elevated, which may be used as a potential peripheral blood marker for predicting cognitive impairment in patients with VaD.
Collapse
|