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Pini S, Raia A, Carpita B, Nardi B, Benvenuti M, Scatena A, Di Paolo M. Unexplained Coma and Sudden Death in Psychiatric Patients Due to Self-Induced Water Intoxication: Clinical Insights and Autopsy Findings From Two Fatal Cases. Cureus 2025; 17:e79813. [PMID: 40161073 PMCID: PMC11955096 DOI: 10.7759/cureus.79813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/25/2025] [Indexed: 04/02/2025] Open
Abstract
Self-induced water intoxication is a life-threatening condition caused by excessive water intake that surpasses renal excretion capacity, resulting in hypotonic hyponatremia. This acute imbalance leads to cerebral and pulmonary edema, neurological deterioration, and potentially fatal outcomes. Psychiatric disorders such as schizophrenia and postpartum psychosis are significant contributors, often driving these behaviors through unique psychopathological mechanisms exacerbated by inadequate patient supervision. This study presents two fatal cases. The first involves a 42-year-old woman with chronic schizophrenia and psychogenic polydipsia, whose condition progressed gradually, allowing partial therapeutic intervention. The second describes a 28-year-old woman with postpartum psychosis and compulsive water drinking linked to religious delusions, whose condition deteriorated rapidly, leading to cardiopulmonary arrest shortly after admission. Both cases highlight the connection between psychiatric disorders and severe hyponatremia (<120 mmol/L), resulting in irreversible brain damage and sudden death. Autopsy findings revealed diffuse cerebral edema, pulmonary congestion, and diffuse axonal injury with reactive astrogliosis, demonstrating the severe impact of electrolyte imbalances on neuronal damage. Neuropathological findings, such as ubiquitin-positive axonal swellings and astrocytic activation, underscore the critical role of ionic homeostasis disruption in bridging clinical and autopsy observations. These cases highlight the importance of early recognition of psychogenic polydipsia and compulsive water-drinking behaviors, particularly in high-risk psychiatric patients. Preventative strategies should include routine electrolyte monitoring, caregiver education, and proactive management of psychiatric disorders. Critically, water intoxication must always be considered among the possible causes of unexplained coma or sudden death in psychiatric patients, stressing the need for clinical vigilance and accurate postmortem assessment to improve prevention.
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Affiliation(s)
- Stefano Pini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, ITA
| | - Accursio Raia
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, ITA
| | - Barbara Carpita
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, ITA
| | - Bendetta Nardi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, ITA
| | - Matteo Benvenuti
- Department of Medicine, Surgery, Neuroscience, and Forensic Medicine, University of Siena, Siena, ITA
| | - Andrea Scatena
- Department of Legal Medicine, University of Pisa, Pisa, ITA
| | - Marco Di Paolo
- Department of Legal Medicine, University of Pisa, Pisa, ITA
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2
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Nabizadeh F. Brain white matter damage biomarkers. Adv Clin Chem 2024; 125:55-91. [PMID: 39988408 DOI: 10.1016/bs.acc.2024.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2025]
Abstract
White matter (WM), constituting nearly half of the human brain's mass, is pivotal for the rapid transmission of neural signals across different brain regions, significantly influencing cognitive processes like learning, memory, and problem-solving. The integrity of WM is essential for brain function, and its damage, which can occur due to conditions such as multiple sclerosis (MS), stroke, and traumatic brain injury, results in severe neurological deficits and cognitive decline. The primary objective of this book chapter is to discuss the clinical significance of fluid biomarkers in assessing WM damage within the central nervous system (CNS). It explores the biological underpinnings and pathological changes in WM due to various neurological conditions and details how alterations can be detected and quantified through fluid biomarkers. By examining biomarkers like Myelin Basic Protein (MBP), Neurofilament light chain (NFL), and others, the chapter highlights their role in enhancing diagnostic precision, monitoring disease progression, and guiding therapeutic interventions, thus providing crucial insights into maintaining WM integrity and preventing cognitive and physical disabilities.
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Affiliation(s)
- Fardin Nabizadeh
- School of Medicine, Iran University of Medical Sciences, and Alzheimer's Disease Institute, Tehran, Iran.
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3
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O'Connor EE, Salerno-Goncalves R, Rednam N, O'Brien R, Rock P, Levine AR, Zeffiro TA. Macro- and Microstructural White Matter Differences in Neurologic Postacute Sequelae of SARS-CoV-2 Infection. AJNR Am J Neuroradiol 2024; 45:1910-1918. [PMID: 39389778 PMCID: PMC11630878 DOI: 10.3174/ajnr.a8481] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 07/11/2024] [Indexed: 10/12/2024]
Abstract
BACKGROUND AND PURPOSE Neuropsychiatric complications of SARS-CoV-2 infection, also known as neurologic postacute sequelae of SARS-CoV-2 infection (NeuroPASC), affect 10%-60% of infected individuals. There is growing evidence that NeuroPASC is a multi system immune dysregulation disease affecting the brain. The behavioral manifestations of NeuroPASC, such as impaired processing speed, executive function, memory retrieval, and sustained attention, suggest widespread WM involvement. Although previous work has documented WM damage following acute SARS-CoV-2 infection, its involvement in NeuroPASC is less clear. We hypothesized that macrostructural and microstructural WM differences in NeuroPASC participants would accompany cognitive and immune system differences. MATERIALS AND METHODS In a cross-sectional study, we screened a total of 159 potential participants and enrolled 72 participants, with 41 asymptomatic controls (NoCOVID) and 31 NeuroPASC participants matched for age, sex, and education. Exclusion criteria included neurologic disorders unrelated to SARS-CoV-2 infection. Assessments included clinical symptom questionnaires, psychometric tests, brain MRI measures, and peripheral cytokine levels. Statistical modeling included separate multivariable regression analyses of GM/WM/CSF volume, WM microstructure, cognitive, and cytokine concentration between-group differences. RESULTS NeuroPASC participants had larger cerebral WM volume than NoCOVID controls (β = 0.229; 95% CI: 0.017-0.441; t = 2.16; P = .035). The most pronounced effects were in the prefrontal and anterior temporal WM. NeuroPASC participants also exhibited higher WM mean kurtosis, consistent with ongoing neuroinflammation. NeuroPASC participants had more self-reported symptoms, including headache, and lower performance on measures of attention, concentration, verbal learning, and processing speed. A multivariate profile analysis of the cytokine panel showed different group cytokine profiles (Wald-type-statistic = 44.6, P = .046), with interferon (IFN)-λ1 and IFN-λ2/3 levels higher in the NeuroPASC group. CONCLUSIONS NeuroPASC participants reported symptoms of lower concentration, higher fatigue, and impaired cognition compatible with WM syndrome. Psychometric testing confirmed these findings. NeuroPASC participants exhibited larger cerebral WM volume and higher WM mean kurtosis than NoCOVID controls. These findings suggest that immune dysregulation could influence WM properties to produce WM volume increases and consequent cognitive effects and headaches. Further work will be needed to establish mechanistic links among these variables.
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Affiliation(s)
- Erin E O'Connor
- From the Department of Diagnostic Radiology & Nuclear Medicine (E.E.O., N.R., T.A.Z.), University of Maryland School of Medicine, Baltimore, Maryland
| | | | - Nikita Rednam
- From the Department of Diagnostic Radiology & Nuclear Medicine (E.E.O., N.R., T.A.Z.), University of Maryland School of Medicine, Baltimore, Maryland
| | | | - Peter Rock
- Department of Anesthesiology (P.R.), University of Maryland School of Medicine, Baltimore, Maryland
| | - Andrea R Levine
- Department of Medicine (A.R.L.), Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Thomas A Zeffiro
- From the Department of Diagnostic Radiology & Nuclear Medicine (E.E.O., N.R., T.A.Z.), University of Maryland School of Medicine, Baltimore, Maryland
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4
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Yilmaz SN, Steiner K, Marksteiner J, Faserl K, Villunger M, Sarg B, Humpel C. From Organotypic Mouse Brain Slices to Human Alzheimer's Plasma Biomarkers: A Focus on Nerve Fiber Outgrowth. Biomolecules 2024; 14:1326. [PMID: 39456259 PMCID: PMC11506054 DOI: 10.3390/biom14101326] [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: 09/26/2024] [Revised: 10/08/2024] [Accepted: 10/14/2024] [Indexed: 10/28/2024] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory loss and progressive deterioration of cognitive functions. Being able to identify reliable biomarkers in easily available body fluids such as blood plasma is vital for the disease. To achieve this, we used a technique that applied human plasma to organotypic brain slice culture via microcontact printing. After a 2-week culture period, we performed immunolabeling for neurofilament and myelin oligodendrocyte glycoprotein (MOG) to visualize newly formed nerve fibers and oligodendrocytes. There was no significant change in the number of new nerve fibers in the AD plasma group compared to the healthy control group, while the length of the produced fibers significantly decreased. A significant increase in the number of MOG+ dots around these new fibers was detected in the patient group. According to our hypothesis, there are factors in the plasma of AD patients that affect the growth of new nerve fibers, which also affect the oligodendrocytes. Based on these findings, we selected the most promising plasma samples and conducted mass spectrometry using a differential approach and we identified three putative biomarkers: aldehyde-dehydrogenase 1A1, alpha-synuclein and protein S100-A4. Our method represents a novel and innovative approach for translating research findings from mouse models to human applications.
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Affiliation(s)
- Sakir Necat Yilmaz
- Laboratory of Psychiatry and Experimental Alzheimer’s Research, Medical University of Innsbruck, 6020 Innsbruck, Austria; (S.N.Y.); (K.S.)
- Department of Histology and Embryology, Faculty of Medicine, Mersin University, Mersin 33130, Turkey
| | - Katharina Steiner
- Laboratory of Psychiatry and Experimental Alzheimer’s Research, Medical University of Innsbruck, 6020 Innsbruck, Austria; (S.N.Y.); (K.S.)
| | - Josef Marksteiner
- Department of Psychiatry and Psychotherapy A, Hall State Hospital, 6060 Hall in Tirol, Austria;
| | - Klaus Faserl
- Protein Core Facility, Institute of Medical Biochemistry, CCB-Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria; (K.F.); (M.V.); (B.S.)
| | - Mathias Villunger
- Protein Core Facility, Institute of Medical Biochemistry, CCB-Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria; (K.F.); (M.V.); (B.S.)
| | - Bettina Sarg
- Protein Core Facility, Institute of Medical Biochemistry, CCB-Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria; (K.F.); (M.V.); (B.S.)
| | - Christian Humpel
- Laboratory of Psychiatry and Experimental Alzheimer’s Research, Medical University of Innsbruck, 6020 Innsbruck, Austria; (S.N.Y.); (K.S.)
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5
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Mohamadiyeh AM, Allami SJ, Thomas L, Sabahat U. Central Pontine Myelinolysis Induced by Rapid Correction of Hyponatremia in a Patient With Chronic Alcohol Use Disorder: A Case Report. Cureus 2024; 16:e72521. [PMID: 39606533 PMCID: PMC11600095 DOI: 10.7759/cureus.72521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/28/2024] [Indexed: 11/29/2024] Open
Abstract
Central pontine myelinolysis (CPM) is a demyelinating disorder often associated with the rapid correction of hyponatremia. Elevated creatine phosphokinase (CPK) levels have been observed in some cases of CPM but are not well studied. A 38-year-old patient with chronic alcohol use disorder presented with jerky movements, confusion, and disorientation following severe hyponatremia. Initial lab results revealed severe hyponatremia (113 mmol/L) (reference range: 136-145 mmol/L), elevated liver enzymes, and extremely high CPK levels (up to 92,763 U/L) (reference range: <190 U/L). Imaging showed bilateral thalamic and pontine hypodensities, with MRI confirming CPM in the central pons. This case highlights the risk of CPM due to rapid sodium correction in patients with chronic alcohol use disorder and suggests that elevated CPK levels may be associated with CPM. The patient's condition improved with gradual sodium correction and alcohol withdrawal management. This underscores the importance of careful electrolyte management to prevent CPM and suggests further investigation into the role of highly elevated CPK in CPM. The occurrence of CPM in a patient with chronic alcohol use disorder and elevated CPK levels emphasizes the need for cautious sodium correction, with the association between elevated CPK and CPM warranting further study.
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Affiliation(s)
- Amjad M Mohamadiyeh
- Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, ARE
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6
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Bradfield C, Voo L, Bhaduri A, Ramesh KT. Validation of a computational biomechanical mouse brain model for rotational head acceleration. Biomech Model Mechanobiol 2024; 23:1347-1367. [PMID: 38662175 DOI: 10.1007/s10237-024-01843-5] [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: 11/03/2023] [Accepted: 03/17/2024] [Indexed: 04/26/2024]
Abstract
Recent mouse brain injury experiments examine diffuse axonal injury resulting from accelerative head rotations. Evaluating brain deformation during these events would provide valuable information on tissue level thresholds for brain injury, but there are many challenges to imaging the brain's mechanical response during dynamic loading events, such as a blunt head impact. To address this shortcoming, we present an experimentally validated computational biomechanics model of the mouse brain that predicts tissue deformation, given the motion of the mouse head during laboratory experiments. First, we developed a finite element model of the mouse brain that computes tissue strains, given the same head rotations as previously conducted in situ hemicephalic mouse brain experiments. Second, we calibrated the model using a single brain segment, and then validated the model based on the spatial and temporal strain responses of other regions. The result is a computational tool that will provide researchers with the ability to predict brain tissue strains that occur during mouse laboratory experiments, and to link the experiments to the resulting neuropathology, such as diffuse axonal injury.
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Affiliation(s)
- Connor Bradfield
- Applied Physics Laboratory, Johns Hopkins University, Laurel, MD, 20723, USA, 11100 Johns Hopkins Road.
- Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA, 3400 North Charles Street.
| | - Liming Voo
- Applied Physics Laboratory, Johns Hopkins University, Laurel, MD, 20723, USA, 11100 Johns Hopkins Road
- Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA, 3400 North Charles Street
| | - Anindya Bhaduri
- Department of Civil Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA, 3400 North Charles Street
| | - K T Ramesh
- Applied Physics Laboratory, Johns Hopkins University, Laurel, MD, 20723, USA, 11100 Johns Hopkins Road
- Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA, 3400 North Charles Street
- Hopkins Extreme Materials Institute, Johns Hopkins University, Baltimore, MD, 21218, USA, 3400 North Charles Street
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7
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Affrald R J, Narayan S. A review: oligodendrocytes in neuronal axonal conduction and methods for enhancing their performance. Int J Neurosci 2024:1-22. [PMID: 38850232 DOI: 10.1080/00207454.2024.2362200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 05/08/2024] [Accepted: 05/27/2024] [Indexed: 06/10/2024]
Abstract
OBJECTIVES This review explores the vital role of oligodendrocytes in axon myelination and efficient neuronal transmission and the impact of dysfunction resulting from neurotransmitter deficiencies related disorders. Furthermore, the review also provides insight into the potential of bionanotechnology for addressing neurodegenerative diseases by targeting oligodendrocytes. METHODS A review of literature in the field was conducted using Google scholar. Systematic searches were performed to identify relevant studies and reviews addressing the role of oligodendrocytes in neural function, the influence of neurotransmitters on oligodendrocyte differentiation, and the potential of nanotechnology-based strategies for targeted therapy of oligodendrocytes. RESULTS This review indicates the mechanisms underlying oligodendrocyte differentiation and the influence of neurotransmitters on this process. The importance of action potentials and neurotransmission in neural function and the susceptibility of damaged nerve axons to ischemic or toxic damage is provided in detail. The potential of bionanotechnology for targeting neurodegenerative diseases using nanotechnology-based strategies, including polymeric, lipid-based, inorganic, organic, and biomimetic nanoparticles, suggests better management of neurodegenerative disorders. CONCLUSION While nanotechnology-based biomaterials show promise for targeted oligodendrocyte therapy in addressing neurodegenerative disorders linked to oligodendrocyte dysfunction, encapsulating neuroprotective agents within nanoparticles offers additional advantages. Nano-based delivery systems effectively protect drugs from degradation and prolong their therapeutic effects, holding promise in overcoming the blood-brain barrier by facilitating drug transport. However, a multifaceted approach is essential to enhance oligodendrocyte differentiation, promote myelin repair, and facilitate myelin dynamics with reduced toxicity. Further research is needed to elucidate the optimal therapeutic approaches and enhance patient outcomes.
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Affiliation(s)
- Jino Affrald R
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Tamilnadu, India
| | - Shoba Narayan
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Tamilnadu, India
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8
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Qiu C, Li Z, Leigh DA, Duan B, Stucky JE, Kim N, Xie G, Lu KP, Zhou XZ. The role of the Pin1- cis P-tau axis in the development and treatment of vascular contribution to cognitive impairment and dementia and preeclampsia. Front Cell Dev Biol 2024; 12:1343962. [PMID: 38628595 PMCID: PMC11019028 DOI: 10.3389/fcell.2024.1343962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 03/14/2024] [Indexed: 04/19/2024] Open
Abstract
Tauopathies are neurodegenerative diseases characterized by deposits of abnormal Tau protein in the brain. Conventional tauopathies are often defined by a limited number of Tau epitopes, notably neurofibrillary tangles, but emerging evidence suggests structural heterogeneity among tauopathies. The prolyl isomerase Pin1 isomerizes cis P-tau to inhibit the development of oligomers, tangles and neurodegeneration in multiple neurodegenerative diseases such as Alzheimer's disease, traumatic brain injury, vascular contribution to cognitive impairment and dementia (VCID) and preeclampsia (PE). Thus, cis P-tau has emerged as an early etiological driver, blood marker and therapeutic target for multiple neurodegenerative diseases, with clinical trials ongoing. The discovery of cis P-tau and other tau pathologies in VCID and PE calls attention for simplistic classification of tauopathy in neurodegenerative diseases. These recent advances have revealed the exciting novel role of the Pin1-cis P-tau axis in the development and treatment of vascular contribution to cognitive impairment and dementia and preeclampsia.
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Affiliation(s)
- Chenxi Qiu
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Zhixiong Li
- Departments of Biochemistry and Oncology, Schulich School of Medicine and Dentistry and Robarts Research Institute, Western University, London, ON, Canada
| | - David A. Leigh
- Department of Genetics, Harvard Medical School, Boston, MA, United States
| | - Bingbing Duan
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, United States
| | - Joseph E. Stucky
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Nami Kim
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - George Xie
- Departments of Biochemistry and Oncology, Schulich School of Medicine and Dentistry and Robarts Research Institute, Western University, London, ON, Canada
| | - Kun Ping Lu
- Departments of Biochemistry and Oncology, Schulich School of Medicine and Dentistry and Robarts Research Institute, Western University, London, ON, Canada
| | - Xiao Zhen Zhou
- Departments of Biochemistry and Oncology, Schulich School of Medicine and Dentistry and Robarts Research Institute, Western University, London, ON, Canada
- Departments of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, and Lawson Health Research Institute, Western University, London, ON, Canada
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9
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Looser ZJ, Faik Z, Ravotto L, Zanker HS, Jung RB, Werner HB, Ruhwedel T, Möbius W, Bergles DE, Barros LF, Nave KA, Weber B, Saab AS. Oligodendrocyte-axon metabolic coupling is mediated by extracellular K + and maintains axonal health. Nat Neurosci 2024; 27:433-448. [PMID: 38267524 PMCID: PMC10917689 DOI: 10.1038/s41593-023-01558-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 12/13/2023] [Indexed: 01/26/2024]
Abstract
The integrity of myelinated axons relies on homeostatic support from oligodendrocytes (OLs). To determine how OLs detect axonal spiking and how rapid axon-OL metabolic coupling is regulated in the white matter, we studied activity-dependent calcium (Ca2+) and metabolite fluxes in the mouse optic nerve. We show that fast axonal spiking triggers Ca2+ signaling and glycolysis in OLs. OLs detect axonal activity through increases in extracellular potassium (K+) concentrations and activation of Kir4.1 channels, thereby regulating metabolite supply to axons. Both pharmacological inhibition and OL-specific inactivation of Kir4.1 reduce the activity-induced axonal lactate surge. Mice lacking oligodendroglial Kir4.1 exhibit lower resting lactate levels and altered glucose metabolism in axons. These early deficits in axonal energy metabolism are associated with late-onset axonopathy. Our findings reveal that OLs detect fast axonal spiking through K+ signaling, making acute metabolic coupling possible and adjusting the axon-OL metabolic unit to promote axonal health.
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Affiliation(s)
- Zoe J Looser
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
- Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland
| | - Zainab Faik
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
- Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland
| | - Luca Ravotto
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
- Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland
| | - Henri S Zanker
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
- Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland
| | - Ramona B Jung
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Hauke B Werner
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Torben Ruhwedel
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Wiebke Möbius
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Dwight E Bergles
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, USA
| | - L Felipe Barros
- Centro de Estudios Científicos (CECs), Valdivia, Chile
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Valdivia, Chile
| | - Klaus-Armin Nave
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Bruno Weber
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
- Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland
| | - Aiman S Saab
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
- Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland.
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10
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Aydın MŞ, Bay S, Yiğit EN, Özgül C, Oğuz EK, Konuk EY, Ayşit N, Cengiz N, Erdoğan E, Him A, Koçak M, Eroglu E, Öztürk G. Active shrinkage protects neurons following axonal transection. iScience 2023; 26:107715. [PMID: 37701578 PMCID: PMC10493506 DOI: 10.1016/j.isci.2023.107715] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 07/31/2023] [Accepted: 08/22/2023] [Indexed: 09/14/2023] Open
Abstract
Trauma, vascular events, or neurodegenerative processes can lead to axonal injury and eventual transection (axotomy). Neurons can survive axotomy, yet the underlying mechanisms are not fully understood. Excessive water entry into injured neurons poses a particular risk due to swelling and subsequent death. Using in vitro and in vivo neurotrauma model systems based on laser transection and surgical nerve cut, we demonstrated that axotomy triggers actomyosin contraction coupled with calpain activity. As a consequence, neurons shrink acutely to force water out through aquaporin channels preventing swelling and bursting. Inhibiting shrinkage increased the probability of neuronal cell death by about 3-fold. These studies reveal a previously unrecognized cytoprotective response mechanism to neurotrauma and offer a fresh perspective on pathophysiological processes in the nervous system.
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Affiliation(s)
- Mehmet Şerif Aydın
- Regenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul 34810, Türkiye
| | - Sadık Bay
- Regenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul 34810, Türkiye
| | - Esra Nur Yiğit
- Regenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul 34810, Türkiye
| | - Cemil Özgül
- Regenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul 34810, Türkiye
| | - Elif Kaval Oğuz
- Department of Science Education, Faculty of Education, Yüzüncü Yıl University, Van 65080, Türkiye
| | - Elçin Yenidünya Konuk
- Department of Medical Biology, School of Medicine, Bakırçay University, İzmir 35665, Türkiye
| | - Neşe Ayşit
- Regenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul 34810, Türkiye
- Department of Medical Biology and Genetics, School of Medicine, Istanbul Medipol University, Istanbul 34810, Türkiye
| | - Nureddin Cengiz
- Department of Histology and Embryology, School of Medicine, Bandırma Onyedi Eylül University, Bandırma, Balıkesir 10200, Türkiye
| | - Ender Erdoğan
- Department of Histology and Embryology, School of Medicine, Selçuk University, Konya 42130, Türkiye
| | - Aydın Him
- Department of Physiology, School of Medicine, Bolu Abant İzzet Baysal University, Bolu 14030, Türkiye
| | - Mehmet Koçak
- Biostatistics and Bioinformatics Analysis Unit, Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul 34810, Türkiye
- Department of Biostatistics and Medical Informatics, International School of Medicine, Istanbul Medipol University, Istanbul 34810, Türkiye
| | - Emrah Eroglu
- Regenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul 34810, Türkiye
| | - Gürkan Öztürk
- Regenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul 34810, Türkiye
- Department of Physiology, International School of Medicine, Istanbul Medipol University, Istanbul 34810, Türkiye
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11
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Ali DG, Bahrani AA, El Khouli RH, Gold BT, Jiang Y, Zachariou V, Wilcock DM, Jicha GA. White matter hyperintensities influence distal cortical β-amyloid accumulation in default mode network pathways. Brain Behav 2023; 13:e3209. [PMID: 37534614 PMCID: PMC10570488 DOI: 10.1002/brb3.3209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 07/19/2023] [Accepted: 07/22/2023] [Indexed: 08/04/2023] Open
Abstract
BACKGROUND AND PURPOSE Cerebral small vessel disease (SVD) has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). Yet, the role of SVD in potentially contributing to AD pathology is unclear. The main objective of this study was to test the hypothesis that WMHs influence amyloid β (Aβ) levels within connected default mode network (DMN) tracts and cortical regions in cognitively unimpaired older adults. METHODS Regional standard uptake value ratios (SUVr) from Aβ-PET and white matter hyperintensity (WMH) volumes from three-dimensional magnetic resonance imaging FLAIR images were analyzed across a sample of 72 clinically unimpaired (mini-mental state examination ≥26), older adults (mean age 74.96 and standard deviation 8.13) from the Alzheimer's Disease Neuroimaging Initiative (ADNI3). The association of WMH volumes in major fiber tracts projecting from cortical DMN regions and Aβ-PET SUVr in the connected cortical DMN regions was analyzed using linear regression models adjusted for age, sex, ApoE, and total brain volumes. RESULTS The regression analyses demonstrate that increased WMH volumes in the superior longitudinal fasciculus were associated with increased regional SUVr in the inferior parietal lobule (p = .011). CONCLUSION The findings suggest that the relation between Aβ in parietal cortex is associated with SVD in downstream white matter (WM) pathways in preclinical AD. The biological relationships and interplay between Aβ and WM microstructure alterations that precede overt WMH development across the continuum of AD progression warrant further study.
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Affiliation(s)
- Doaa G. Ali
- Sanders‐Brown Center on Aging, College of MedicineUniversity of KentuckyLexingtonKentuckyUSA
- Department of Behavioral Science, College of MedicineUniversity of KentuckyLexingtonKentuckyUSA
| | - Ahmed A. Bahrani
- Sanders‐Brown Center on Aging, College of MedicineUniversity of KentuckyLexingtonKentuckyUSA
- Department of Neurology, College of MedicineUniversity of KentuckyLexingtonKentuckyUSA
| | - Riham H. El Khouli
- Department of Radiology, College of MedicineUniversity of KentuckyLexingtonKentuckyUSA
| | - Brian T. Gold
- Sanders‐Brown Center on Aging, College of MedicineUniversity of KentuckyLexingtonKentuckyUSA
- Department of Neuroscience, College of MedicineUniversity of KentuckyLexingtonKentuckyUSA
| | - Yang Jiang
- Sanders‐Brown Center on Aging, College of MedicineUniversity of KentuckyLexingtonKentuckyUSA
- Department of Behavioral Science, College of MedicineUniversity of KentuckyLexingtonKentuckyUSA
| | - Valentinos Zachariou
- Department of Neuroscience, College of MedicineUniversity of KentuckyLexingtonKentuckyUSA
| | - Donna M. Wilcock
- Sanders‐Brown Center on Aging, College of MedicineUniversity of KentuckyLexingtonKentuckyUSA
- Department of Physiology, College of MedicineUniversity of KentuckyLexingtonKentuckyUSA
| | - Gregory A. Jicha
- Sanders‐Brown Center on Aging, College of MedicineUniversity of KentuckyLexingtonKentuckyUSA
- Department of Behavioral Science, College of MedicineUniversity of KentuckyLexingtonKentuckyUSA
- Department of Neurology, College of MedicineUniversity of KentuckyLexingtonKentuckyUSA
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Alsameen MH, Gong Z, Qian W, Kiely M, Triebswetter C, Bergeron CM, Cortina LE, Faulkner ME, Laporte JP, Bouhrara M. C-NODDI: a constrained NODDI model for axonal density and orientation determinations in cerebral white matter. Front Neurol 2023; 14:1205426. [PMID: 37602266 PMCID: PMC10435293 DOI: 10.3389/fneur.2023.1205426] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 07/14/2023] [Indexed: 08/22/2023] Open
Abstract
Purpose Neurite orientation dispersion and density imaging (NODDI) provides measures of neurite density and dispersion through computation of the neurite density index (NDI) and the orientation dispersion index (ODI). However, NODDI overestimates the cerebrospinal fluid water fraction in white matter (WM) and provides physiologically unrealistic high NDI values. Furthermore, derived NDI values are echo-time (TE)-dependent. In this work, we propose a modification of NODDI, named constrained NODDI (C-NODDI), for NDI and ODI mapping in WM. Methods Using NODDI and C-NODDI, we investigated age-related alterations in WM in a cohort of 58 cognitively unimpaired adults. Further, NDI values derived using NODDI or C-NODDI were correlated with the neurofilament light chain (NfL) concentration levels, a plasma biomarker of axonal degeneration. Finally, we investigated the TE dependence of NODDI or C-NODDI derived NDI and ODI. Results ODI derived values using both approaches were virtually identical, exhibiting constant trends with age. Further, our results indicated a quadratic relationship between NDI and age suggesting that axonal maturation continues until middle age followed by a decrease. This quadratic association was notably significant in several WM regions using C-NODDI, while limited to a few regions using NODDI. Further, C-NODDI-NDI values exhibited a stronger correlation with NfL concentration levels as compared to NODDI-NDI, with lower NDI values corresponding to higher levels of NfL. Finally, we confirmed the previous finding that NDI estimation using NODDI was dependent on TE, while NDI derived values using C-NODDI exhibited lower sensitivity to TE in WM. Conclusion C-NODDI provides a complementary method to NODDI for determination of NDI in white matter.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Mustapha Bouhrara
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
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Luo J, Ma Y, Agboola FJ, Grant E, Morris JC, McDade E, Fagan AM, Benzinger TLS, Hassenstab J, Bateman RJ, Perrin RJ, Gordon BA, Goyal M, Strain JF, Yakushev I, Day GS, Xiong C. Longitudinal Relationships of White Matter Hyperintensities and Alzheimer Disease Biomarkers Across the Adult Life Span. Neurology 2023; 101:e164-e177. [PMID: 37202169 PMCID: PMC10351551 DOI: 10.1212/wnl.0000000000207378] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 03/20/2023] [Indexed: 05/20/2023] Open
Abstract
BACKGROUND AND OBJECTIVES White matter hyperintensities (WMH) correlate with Alzheimer disease (AD) biomarkers cross-sectionally and modulate AD pathogenesis. Longitudinal changes have been reported for AD biomarkers, including concentrations of CSF β-amyloid (Aβ) 42, Aβ40, total tau and phosphorylated tau181, standardized uptake value ratio from the molecular imaging of cerebral fibrillar Aβ with PET using [11C] Pittsburgh Compound-B, MRI-based hippocampal volume, and cortical thickness. Correlations between established AD biomarkers and the longitudinal change for WMH have not been fully evaluated, especially among cognitively normal individuals across the adult life span. METHODS We jointly analyzed the longitudinal data of WMH volume and each of the established AD biomarkers and cognition from 371 cognitively normal individuals whose baseline age spanned from 19.6 to 88.20 years from 4 longitudinal studies of aging and AD. A 2-stage algorithm was applied to identify the inflection point of baseline age whereby older participants had an accelerated longitudinal change in WMH volume, in comparison with the younger participants. The longitudinal correlations between WMH volume and AD biomarkers were estimated from the bivariate linear mixed-effects models. RESULTS A longitudinal increase in WMH volume was associated with a longitudinal increase in PET amyloid uptake and a decrease in MRI hippocampal volume, cortical thickness, and cognition. The inflection point of baseline age in WMH volume was identified at 60.46 (95% CI 56.43-64.49) years, with the annual increase for the older participants (83.12 [SE = 10.19] mm3 per year) more than 13 times faster (p < 0.0001) than that for the younger participants (6.35 [SE = 5.63] mm3 per year). Accelerated rates of change among the older participants were similarly observed in almost all the AD biomarkers. Longitudinal correlations of WMH volume with MRI, PET amyloid biomarkers, and cognition seemed to be numerically stronger for the younger participants, but not significantly different from those for the older participants. Carrying APOE ε4 alleles did not alter the longitudinal correlations between WMH and AD biomarkers. DISCUSSION Longitudinal increases in WMH volume started to accelerate around a baseline age of 60.46 years and correlated with the longitudinal change in PET amyloid uptake, MRI structural outcomes, and cognition.
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Affiliation(s)
- Jingqin Luo
- From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., Y.M., F.J.A., E.G., C.X.), Knight Alzheimer Disease Research Center (Y.M., F.J.A., E.G., J.C.M., A.M.F., T.L.S.B., J.H., R.J.B., R.J.P., B.A.G., C.X.), Department of Neurology (J.C.M., E.M., A.M.F., J.H., R.J.B., R.J.P., M.G., J.F.S.), Department of Pathology and Immunology (J.C.M., R.J.P.), and Department of Radiology (T.L.S.B., B.A.G., M.G.), Washington University School of Medicine, St. Louis, MO; Department of Nuclear Medicine (I.Y.), and Klinikum rechts der Isar (I.Y.), School of Medicine, Neuroimaging Center (TUM-NIC), Technical University of Munich, Germany; and Department of Neurology (G.S.D.), Mayo Clinic, Jacksonville, FL
| | - Yinjiao Ma
- From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., Y.M., F.J.A., E.G., C.X.), Knight Alzheimer Disease Research Center (Y.M., F.J.A., E.G., J.C.M., A.M.F., T.L.S.B., J.H., R.J.B., R.J.P., B.A.G., C.X.), Department of Neurology (J.C.M., E.M., A.M.F., J.H., R.J.B., R.J.P., M.G., J.F.S.), Department of Pathology and Immunology (J.C.M., R.J.P.), and Department of Radiology (T.L.S.B., B.A.G., M.G.), Washington University School of Medicine, St. Louis, MO; Department of Nuclear Medicine (I.Y.), and Klinikum rechts der Isar (I.Y.), School of Medicine, Neuroimaging Center (TUM-NIC), Technical University of Munich, Germany; and Department of Neurology (G.S.D.), Mayo Clinic, Jacksonville, FL
| | - Folasade Jane Agboola
- From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., Y.M., F.J.A., E.G., C.X.), Knight Alzheimer Disease Research Center (Y.M., F.J.A., E.G., J.C.M., A.M.F., T.L.S.B., J.H., R.J.B., R.J.P., B.A.G., C.X.), Department of Neurology (J.C.M., E.M., A.M.F., J.H., R.J.B., R.J.P., M.G., J.F.S.), Department of Pathology and Immunology (J.C.M., R.J.P.), and Department of Radiology (T.L.S.B., B.A.G., M.G.), Washington University School of Medicine, St. Louis, MO; Department of Nuclear Medicine (I.Y.), and Klinikum rechts der Isar (I.Y.), School of Medicine, Neuroimaging Center (TUM-NIC), Technical University of Munich, Germany; and Department of Neurology (G.S.D.), Mayo Clinic, Jacksonville, FL
| | - Elizabeth Grant
- From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., Y.M., F.J.A., E.G., C.X.), Knight Alzheimer Disease Research Center (Y.M., F.J.A., E.G., J.C.M., A.M.F., T.L.S.B., J.H., R.J.B., R.J.P., B.A.G., C.X.), Department of Neurology (J.C.M., E.M., A.M.F., J.H., R.J.B., R.J.P., M.G., J.F.S.), Department of Pathology and Immunology (J.C.M., R.J.P.), and Department of Radiology (T.L.S.B., B.A.G., M.G.), Washington University School of Medicine, St. Louis, MO; Department of Nuclear Medicine (I.Y.), and Klinikum rechts der Isar (I.Y.), School of Medicine, Neuroimaging Center (TUM-NIC), Technical University of Munich, Germany; and Department of Neurology (G.S.D.), Mayo Clinic, Jacksonville, FL
| | - John C Morris
- From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., Y.M., F.J.A., E.G., C.X.), Knight Alzheimer Disease Research Center (Y.M., F.J.A., E.G., J.C.M., A.M.F., T.L.S.B., J.H., R.J.B., R.J.P., B.A.G., C.X.), Department of Neurology (J.C.M., E.M., A.M.F., J.H., R.J.B., R.J.P., M.G., J.F.S.), Department of Pathology and Immunology (J.C.M., R.J.P.), and Department of Radiology (T.L.S.B., B.A.G., M.G.), Washington University School of Medicine, St. Louis, MO; Department of Nuclear Medicine (I.Y.), and Klinikum rechts der Isar (I.Y.), School of Medicine, Neuroimaging Center (TUM-NIC), Technical University of Munich, Germany; and Department of Neurology (G.S.D.), Mayo Clinic, Jacksonville, FL
| | - Eric McDade
- From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., Y.M., F.J.A., E.G., C.X.), Knight Alzheimer Disease Research Center (Y.M., F.J.A., E.G., J.C.M., A.M.F., T.L.S.B., J.H., R.J.B., R.J.P., B.A.G., C.X.), Department of Neurology (J.C.M., E.M., A.M.F., J.H., R.J.B., R.J.P., M.G., J.F.S.), Department of Pathology and Immunology (J.C.M., R.J.P.), and Department of Radiology (T.L.S.B., B.A.G., M.G.), Washington University School of Medicine, St. Louis, MO; Department of Nuclear Medicine (I.Y.), and Klinikum rechts der Isar (I.Y.), School of Medicine, Neuroimaging Center (TUM-NIC), Technical University of Munich, Germany; and Department of Neurology (G.S.D.), Mayo Clinic, Jacksonville, FL
| | - Anne M Fagan
- From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., Y.M., F.J.A., E.G., C.X.), Knight Alzheimer Disease Research Center (Y.M., F.J.A., E.G., J.C.M., A.M.F., T.L.S.B., J.H., R.J.B., R.J.P., B.A.G., C.X.), Department of Neurology (J.C.M., E.M., A.M.F., J.H., R.J.B., R.J.P., M.G., J.F.S.), Department of Pathology and Immunology (J.C.M., R.J.P.), and Department of Radiology (T.L.S.B., B.A.G., M.G.), Washington University School of Medicine, St. Louis, MO; Department of Nuclear Medicine (I.Y.), and Klinikum rechts der Isar (I.Y.), School of Medicine, Neuroimaging Center (TUM-NIC), Technical University of Munich, Germany; and Department of Neurology (G.S.D.), Mayo Clinic, Jacksonville, FL
| | - Tammie L S Benzinger
- From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., Y.M., F.J.A., E.G., C.X.), Knight Alzheimer Disease Research Center (Y.M., F.J.A., E.G., J.C.M., A.M.F., T.L.S.B., J.H., R.J.B., R.J.P., B.A.G., C.X.), Department of Neurology (J.C.M., E.M., A.M.F., J.H., R.J.B., R.J.P., M.G., J.F.S.), Department of Pathology and Immunology (J.C.M., R.J.P.), and Department of Radiology (T.L.S.B., B.A.G., M.G.), Washington University School of Medicine, St. Louis, MO; Department of Nuclear Medicine (I.Y.), and Klinikum rechts der Isar (I.Y.), School of Medicine, Neuroimaging Center (TUM-NIC), Technical University of Munich, Germany; and Department of Neurology (G.S.D.), Mayo Clinic, Jacksonville, FL
| | - Jason Hassenstab
- From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., Y.M., F.J.A., E.G., C.X.), Knight Alzheimer Disease Research Center (Y.M., F.J.A., E.G., J.C.M., A.M.F., T.L.S.B., J.H., R.J.B., R.J.P., B.A.G., C.X.), Department of Neurology (J.C.M., E.M., A.M.F., J.H., R.J.B., R.J.P., M.G., J.F.S.), Department of Pathology and Immunology (J.C.M., R.J.P.), and Department of Radiology (T.L.S.B., B.A.G., M.G.), Washington University School of Medicine, St. Louis, MO; Department of Nuclear Medicine (I.Y.), and Klinikum rechts der Isar (I.Y.), School of Medicine, Neuroimaging Center (TUM-NIC), Technical University of Munich, Germany; and Department of Neurology (G.S.D.), Mayo Clinic, Jacksonville, FL
| | - Randall J Bateman
- From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., Y.M., F.J.A., E.G., C.X.), Knight Alzheimer Disease Research Center (Y.M., F.J.A., E.G., J.C.M., A.M.F., T.L.S.B., J.H., R.J.B., R.J.P., B.A.G., C.X.), Department of Neurology (J.C.M., E.M., A.M.F., J.H., R.J.B., R.J.P., M.G., J.F.S.), Department of Pathology and Immunology (J.C.M., R.J.P.), and Department of Radiology (T.L.S.B., B.A.G., M.G.), Washington University School of Medicine, St. Louis, MO; Department of Nuclear Medicine (I.Y.), and Klinikum rechts der Isar (I.Y.), School of Medicine, Neuroimaging Center (TUM-NIC), Technical University of Munich, Germany; and Department of Neurology (G.S.D.), Mayo Clinic, Jacksonville, FL
| | - Richard J Perrin
- From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., Y.M., F.J.A., E.G., C.X.), Knight Alzheimer Disease Research Center (Y.M., F.J.A., E.G., J.C.M., A.M.F., T.L.S.B., J.H., R.J.B., R.J.P., B.A.G., C.X.), Department of Neurology (J.C.M., E.M., A.M.F., J.H., R.J.B., R.J.P., M.G., J.F.S.), Department of Pathology and Immunology (J.C.M., R.J.P.), and Department of Radiology (T.L.S.B., B.A.G., M.G.), Washington University School of Medicine, St. Louis, MO; Department of Nuclear Medicine (I.Y.), and Klinikum rechts der Isar (I.Y.), School of Medicine, Neuroimaging Center (TUM-NIC), Technical University of Munich, Germany; and Department of Neurology (G.S.D.), Mayo Clinic, Jacksonville, FL
| | - Brian A Gordon
- From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., Y.M., F.J.A., E.G., C.X.), Knight Alzheimer Disease Research Center (Y.M., F.J.A., E.G., J.C.M., A.M.F., T.L.S.B., J.H., R.J.B., R.J.P., B.A.G., C.X.), Department of Neurology (J.C.M., E.M., A.M.F., J.H., R.J.B., R.J.P., M.G., J.F.S.), Department of Pathology and Immunology (J.C.M., R.J.P.), and Department of Radiology (T.L.S.B., B.A.G., M.G.), Washington University School of Medicine, St. Louis, MO; Department of Nuclear Medicine (I.Y.), and Klinikum rechts der Isar (I.Y.), School of Medicine, Neuroimaging Center (TUM-NIC), Technical University of Munich, Germany; and Department of Neurology (G.S.D.), Mayo Clinic, Jacksonville, FL
| | - Manu Goyal
- From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., Y.M., F.J.A., E.G., C.X.), Knight Alzheimer Disease Research Center (Y.M., F.J.A., E.G., J.C.M., A.M.F., T.L.S.B., J.H., R.J.B., R.J.P., B.A.G., C.X.), Department of Neurology (J.C.M., E.M., A.M.F., J.H., R.J.B., R.J.P., M.G., J.F.S.), Department of Pathology and Immunology (J.C.M., R.J.P.), and Department of Radiology (T.L.S.B., B.A.G., M.G.), Washington University School of Medicine, St. Louis, MO; Department of Nuclear Medicine (I.Y.), and Klinikum rechts der Isar (I.Y.), School of Medicine, Neuroimaging Center (TUM-NIC), Technical University of Munich, Germany; and Department of Neurology (G.S.D.), Mayo Clinic, Jacksonville, FL
| | - Jeremy F Strain
- From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., Y.M., F.J.A., E.G., C.X.), Knight Alzheimer Disease Research Center (Y.M., F.J.A., E.G., J.C.M., A.M.F., T.L.S.B., J.H., R.J.B., R.J.P., B.A.G., C.X.), Department of Neurology (J.C.M., E.M., A.M.F., J.H., R.J.B., R.J.P., M.G., J.F.S.), Department of Pathology and Immunology (J.C.M., R.J.P.), and Department of Radiology (T.L.S.B., B.A.G., M.G.), Washington University School of Medicine, St. Louis, MO; Department of Nuclear Medicine (I.Y.), and Klinikum rechts der Isar (I.Y.), School of Medicine, Neuroimaging Center (TUM-NIC), Technical University of Munich, Germany; and Department of Neurology (G.S.D.), Mayo Clinic, Jacksonville, FL
| | - Igor Yakushev
- From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., Y.M., F.J.A., E.G., C.X.), Knight Alzheimer Disease Research Center (Y.M., F.J.A., E.G., J.C.M., A.M.F., T.L.S.B., J.H., R.J.B., R.J.P., B.A.G., C.X.), Department of Neurology (J.C.M., E.M., A.M.F., J.H., R.J.B., R.J.P., M.G., J.F.S.), Department of Pathology and Immunology (J.C.M., R.J.P.), and Department of Radiology (T.L.S.B., B.A.G., M.G.), Washington University School of Medicine, St. Louis, MO; Department of Nuclear Medicine (I.Y.), and Klinikum rechts der Isar (I.Y.), School of Medicine, Neuroimaging Center (TUM-NIC), Technical University of Munich, Germany; and Department of Neurology (G.S.D.), Mayo Clinic, Jacksonville, FL
| | - Gregory S Day
- From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., Y.M., F.J.A., E.G., C.X.), Knight Alzheimer Disease Research Center (Y.M., F.J.A., E.G., J.C.M., A.M.F., T.L.S.B., J.H., R.J.B., R.J.P., B.A.G., C.X.), Department of Neurology (J.C.M., E.M., A.M.F., J.H., R.J.B., R.J.P., M.G., J.F.S.), Department of Pathology and Immunology (J.C.M., R.J.P.), and Department of Radiology (T.L.S.B., B.A.G., M.G.), Washington University School of Medicine, St. Louis, MO; Department of Nuclear Medicine (I.Y.), and Klinikum rechts der Isar (I.Y.), School of Medicine, Neuroimaging Center (TUM-NIC), Technical University of Munich, Germany; and Department of Neurology (G.S.D.), Mayo Clinic, Jacksonville, FL
| | - Chengjie Xiong
- From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., Y.M., F.J.A., E.G., C.X.), Knight Alzheimer Disease Research Center (Y.M., F.J.A., E.G., J.C.M., A.M.F., T.L.S.B., J.H., R.J.B., R.J.P., B.A.G., C.X.), Department of Neurology (J.C.M., E.M., A.M.F., J.H., R.J.B., R.J.P., M.G., J.F.S.), Department of Pathology and Immunology (J.C.M., R.J.P.), and Department of Radiology (T.L.S.B., B.A.G., M.G.), Washington University School of Medicine, St. Louis, MO; Department of Nuclear Medicine (I.Y.), and Klinikum rechts der Isar (I.Y.), School of Medicine, Neuroimaging Center (TUM-NIC), Technical University of Munich, Germany; and Department of Neurology (G.S.D.), Mayo Clinic, Jacksonville, FL.
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Lindblad C, Neumann S, Kolbeinsdóttir S, Zachariadis V, Thelin EP, Enge M, Thams S, Brundin L, Svensson M. Stem cell-derived brainstem mouse astrocytes obtain a neurotoxic phenotype in vitro upon neuroinflammation. J Inflamm (Lond) 2023; 20:22. [PMID: 37370141 PMCID: PMC10303821 DOI: 10.1186/s12950-023-00349-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND Astrocytes respond to injury and disease through a process known as reactive astrogliosis, of which inflammatory signaling is one subset. This inflammatory response is heterogeneous with respect to the inductive stimuli and the afflicted central nervous system region. This is of plausible importance in e.g. traumatic axonal injury (TAI), where lesions in the brainstem carries a particularly poor prognosis. In fact, astrogliotic forebrain astrocytes were recently suggested to cause neuronal death following axotomy. We therefore sought to assess if ventral brainstem- or rostroventral spinal astrocytes exert similar effects on motor neurons in vitro. METHODS We derived brainstem/rostroventral spinal astrocyte-like cells (ES-astrocytes) and motor neurons using directed differentiation of mouse embryonic stem cells (ES). We activated the ES-astrocytes using the neurotoxicity-eliciting cytokines interleukin- (IL-) 1α and tumor necrosis factor-(TNF-)α and clinically relevant inflammatory mediators. In co-cultures with reactive ES-astrocytes and motor neurons, we assessed neurotoxic ES-astrocyte activity, similarly to what has previously been shown for other central nervous system (CNS) regions. RESULTS We confirmed the brainstem/rostroventral ES-astrocyte identity using RNA-sequencing, immunocytochemistry, and by comparison with primary subventricular zone-astrocytes. Following cytokine stimulation, the c-Jun N-terminal kinase pathway down-stream product phosphorylated c-Jun was increased, thus demonstrating ES-astrocyte reactivity. These reactive ES-astrocytes conferred a contact-dependent neurotoxic effect upon co-culture with motor neurons. When exposed to IL-1β and IL-6, two neuroinflammatory cytokines found in the cerebrospinal fluid and serum proteome following human severe traumatic brain injury (TBI), ES-astrocytes exerted similar effects on motor neurons. Activation of ES-astrocytes by these cytokines was associated with pathways relating to endoplasmic reticulum stress and altered regulation of MYC. CONCLUSIONS Ventral brainstem and rostroventral spinal cord astrocytes differentiated from mouse ES can exert neurotoxic effects in vitro. This highlights how neuroinflammation following CNS lesions can exert region- and cell-specific effects. Our in vitro model system, which uniquely portrays astrocytes and neurons from one niche, allows for a detailed and translationally relevant model system for future studies on how to improve neuronal survival in particularly vulnerable CNS regions following e.g. TAI.
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Affiliation(s)
- Caroline Lindblad
- Department of Clinical Neuroscience, Karolinska Institutet, J5:20 Svensson Group, Karolinska Universitetssjukhuset Solna, SE-171 77, Stockholm, Sweden.
| | - Susanne Neumann
- Department of Clinical Neuroscience, Karolinska Institutet, J5:20 Svensson Group, Karolinska Universitetssjukhuset Solna, SE-171 77, Stockholm, Sweden
| | | | | | - Eric P Thelin
- Department of Clinical Neuroscience, Karolinska Institutet, J5:20 Svensson Group, Karolinska Universitetssjukhuset Solna, SE-171 77, Stockholm, Sweden
- Department of Neurology, Karolinska University Hospital, Stockholm, Sweden
| | - Martin Enge
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Sebastian Thams
- Department of Clinical Neuroscience, Karolinska Institutet, J5:20 Svensson Group, Karolinska Universitetssjukhuset Solna, SE-171 77, Stockholm, Sweden
- Department of Neurology, Karolinska University Hospital, Stockholm, Sweden
| | - Lou Brundin
- Department of Clinical Neuroscience, Karolinska Institutet, J5:20 Svensson Group, Karolinska Universitetssjukhuset Solna, SE-171 77, Stockholm, Sweden
- Department of Neurology, Karolinska University Hospital, Stockholm, Sweden
| | - Mikael Svensson
- Department of Clinical Neuroscience, Karolinska Institutet, J5:20 Svensson Group, Karolinska Universitetssjukhuset Solna, SE-171 77, Stockholm, Sweden
- Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden
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15
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Hou Y, Yan W, Guo L, Li G, Sang N. Prenatal PM 2.5 exposure impairs spatial learning and memory in male mice offspring: from transcriptional regulation to neuronal morphogenesis. Part Fibre Toxicol 2023; 20:13. [PMID: 37081511 PMCID: PMC10116824 DOI: 10.1186/s12989-023-00520-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 03/12/2023] [Indexed: 04/22/2023] Open
Abstract
BACKGROUND As one of the environmental risk factors for human health, atmospheric fine particulate matter (PM2.5) contributes to cognitive deterioration in addition to respiratory and cardiovascular injuries. Recently, increasing evidence implicates that PM2.5 inhalation can affect neurological functions in offspring, but the sex-specific outcomes and the underlying biological processes are largely unknown. OBJECTIVES To observe the influence of prenatal PM2.5 exposure on cognitive performance in offspring, to elucidate the neuronal morphological alterations and possible transcriptional regulation based on mRNA-sequencing (mRNA-Seq) data after birth, and to determine the key components of PM2.5 contributing to the adverse effects. METHODS Pregnant C57BL/6J mice were exposed to sterile saline or PM2.5 suspension. Morris water maze test was used to assess the cognitive function in weanling offspring. Microscopic observation was applied to detect neuronal morphogenesis in vivo and in vitro. The cortex tissues from male offspring were collected on postnatal days (PNDs) 1, 7, and 21 for mRNA-Seq analysis. The organic and inorganic components of PM2.5 were separated to assess their contributions using primary cultured neurons. RESULTS Prenatal PM2.5 exposure impaired spatial learning and memory in weanling male mice, but not female mice. The sex-specific outcomes were associated with mRNA expression profiles of the cortex during postnatal critical windows, and the annotations in Gene Ontology (GO) of differentially expressed genes (DEGs) revealed that the exposure persistently disrupted the expression of genes involved in neuronal features in male offspring. Consistently, axonal growth impairment and dendritic complexity reduction were observed. Importantly, Homeobox A5 (Hoxa5), a critical transcription factor regulating all of the neuronal morphogenesis-associated hub genes on PNDs 1, 7, and 21, significantly decreased in the cortex of male offspring following PM2.5 exposure. In addition, both inorganic and organic components were harmful to axonal and dendritic growth, with organic components exhibiting stronger inhibition than inorganic ones. CONCLUSION Prenatal PM2.5 exposure affected spatial learning and memory in male mice by disrupting Hoxa5-mediated neuronal morphogenesis, and the organic components, including polycyclic aromatic hydrocarbons (PAHs), posed more adverse effects than the inorganic components.
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Affiliation(s)
- Yanwen Hou
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi, 030006, PR China
| | - Wei Yan
- Xuzhou Engineering Research Center of Medical Genetics and Transformation, Key Laboratory of Genetic Foundation and Clinical Application, Department of Genetics, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, PR China
| | - Lin Guo
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi, 030006, PR China
| | - Guangke Li
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi, 030006, PR China.
| | - Nan Sang
- College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi, 030006, PR China.
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16
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Neel DV, Basu H, Gunner G, Bergstresser MD, Giadone RM, Chung H, Miao R, Chou V, Brody E, Jiang X, Lee E, Watts ME, Marques C, Held A, Wainger B, Lagier-Tourenne C, Zhang YJ, Petrucelli L, Young-Pearse TL, Chen-Plotkin AS, Rubin LL, Lieberman J, Chiu IM. Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration. Neuron 2023; 111:1222-1240.e9. [PMID: 36917977 PMCID: PMC10121894 DOI: 10.1016/j.neuron.2023.02.019] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 10/27/2022] [Accepted: 02/10/2023] [Indexed: 03/14/2023]
Abstract
Mitochondrial dysfunction and axon loss are hallmarks of neurologic diseases. Gasdermin (GSDM) proteins are executioner pore-forming molecules that mediate cell death, yet their roles in the central nervous system (CNS) are not well understood. Here, we find that one GSDM family member, GSDME, is expressed by both mouse and human neurons. GSDME plays a role in mitochondrial damage and axon loss. Mitochondrial neurotoxins induced caspase-dependent GSDME cleavage and rapid localization to mitochondria in axons, where GSDME promoted mitochondrial depolarization, trafficking defects, and neurite retraction. Frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS)-associated proteins TDP-43 and PR-50 induced GSDME-mediated damage to mitochondria and neurite loss. GSDME knockdown protected against neurite loss in ALS patient iPSC-derived motor neurons. Knockout of GSDME in SOD1G93A ALS mice prolonged survival, ameliorated motor dysfunction, rescued motor neuron loss, and reduced neuroinflammation. We identify GSDME as an executioner of neuronal mitochondrial dysfunction that may contribute to neurodegeneration.
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Affiliation(s)
- Dylan V Neel
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
| | - Himanish Basu
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
| | - Georgia Gunner
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
| | | | - Richard M Giadone
- Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
| | - Haeji Chung
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
| | - Rui Miao
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
| | - Vicky Chou
- Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Eliza Brody
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Xin Jiang
- Department of Neurology, Mass General Institute for Neurodegenerative Disease (MIND), Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Edward Lee
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Michelle E Watts
- Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
| | - Christine Marques
- Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Aaron Held
- Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Brian Wainger
- Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Clotilde Lagier-Tourenne
- Department of Neurology, Mass General Institute for Neurodegenerative Disease (MIND), Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA
| | - Yong-Jie Zhang
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
| | | | - Tracy L Young-Pearse
- Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Alice S Chen-Plotkin
- Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Lee L Rubin
- Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
| | - Judy Lieberman
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
| | - Isaac M Chiu
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
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17
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Maddison DC, Mattedi F, Vagnoni A, Smith GA. Analysis of Mitochondrial Dynamics in Adult Drosophila Axons. Cold Spring Harb Protoc 2023; 2023:75-83. [PMID: 36180217 DOI: 10.1101/pdb.top107819] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Neuronal survival depends on the generation of ATP from an ever-changing mitochondrial network. This requires a fine balance between the constant degradation of damaged mitochondria, biogenesis of new mitochondria, movement along microtubules, dynamic processes, and adequate functional capacity to meet firing demands. The distribution of mitochondria needs to be tightly controlled throughout the entire neuron, including its projections. Axons in particular can be enormous structures compared to the size of the cell soma, and how mitochondria are maintained in these compartments is poorly defined. Mitochondrial dysfunction in neurons is associated with aging and neurodegenerative diseases, with the axon being preferentially vulnerable to destruction. Drosophila offer a unique way to study these organelles in fully differentiated adult neurons in vivo. Here, we briefly review the regulation of neuronal mitochondria in health, aging, and disease and introduce two methodological approaches to study mitochondrial dynamics and transport in axons using the Drosophila wing system.
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Affiliation(s)
- Daniel C Maddison
- UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff CF24 4HQ, United Kingdom
| | - Francesca Mattedi
- Department of Basic and Clinical Neurosciences, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 9RX, United Kingdom
| | - Alessio Vagnoni
- Department of Basic and Clinical Neurosciences, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 9RX, United Kingdom
| | - Gaynor Ann Smith
- UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff CF24 4HQ, United Kingdom
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18
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Akide Ndunge OB, Kilian N, Salman MM. Cerebral Malaria and Neuronal Implications of Plasmodium Falciparum Infection: From Mechanisms to Advanced Models. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2202944. [PMID: 36300890 PMCID: PMC9798991 DOI: 10.1002/advs.202202944] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 09/22/2022] [Indexed: 06/01/2023]
Abstract
Reorganization of host red blood cells by the malaria parasite Plasmodium falciparum enables their sequestration via attachment to the microvasculature. This artificially increases the dwelling time of the infected red blood cells within inner organs such as the brain, which can lead to cerebral malaria. Cerebral malaria is the deadliest complication patients infected with P. falciparum can experience and still remains a major public health concern despite effective antimalarial therapies. Here, the current understanding of the effect of P. falciparum cytoadherence and their secreted proteins on structural features of the human blood-brain barrier and their involvement in the pathogenesis of cerebral malaria are highlighted. Advanced 2D and 3D in vitro models are further assessed to study this devastating interaction between parasite and host. A better understanding of the molecular mechanisms leading to neuronal and cognitive deficits in cerebral malaria will be pivotal in devising new strategies to treat and prevent blood-brain barrier dysfunction and subsequent neurological damage in patients with cerebral malaria.
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Affiliation(s)
- Oscar Bate Akide Ndunge
- Department of Internal MedicineSection of Infectious DiseasesYale University School of Medicine300 Cedar StreetNew HavenCT06510USA
| | - Nicole Kilian
- Centre for Infectious Diseases, ParasitologyHeidelberg University HospitalIm Neuenheimer Feld 32469120HeidelbergGermany
| | - Mootaz M. Salman
- Department of PhysiologyAnatomy and GeneticsUniversity of OxfordOxfordOX1 3QUUK
- Kavli Institute for NanoScience DiscoveryUniversity of OxfordOxfordUK
- Oxford Parkinson's Disease CentreUniversity of OxfordOxfordUK
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19
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Filley CM. White matter dementia then… and now. Front Neurol 2022; 13:1043583. [PMID: 36479053 PMCID: PMC9721363 DOI: 10.3389/fneur.2022.1043583] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 10/19/2022] [Indexed: 03/27/2024] Open
Abstract
White matter dementia (WMD) is a concept introduced in 1988 to highlight the importance of white matter pathology in producing cognitive dysfunction and dementia. Whereas gray matter, particularly the cerebral cortex, has been primarily investigated in the dementias, subcortical pathology has long been correlated with cognitive loss, and a corticocentric perspective cannot account for the full range of neurobehavioral disorders. Within the subcortical regions, white matter is prominent, accounting for about half the volume of the adult brain, and many white matter diseases, injuries, and intoxications can produce cognitive dysfunction so severe as to justify the term dementia. Recognition of this novel syndrome relied heavily on the introduction of magnetic resonance imaging (MRI) that permitted in vivo visualization of white matter lesions. Neuropsychological studies clarified the clinical presentation of WMD by identifying a profile dominated by cognitive slowing and executive dysfunction, and a precursor syndrome of mild cognitive dysfunction was proposed to identify early cognitive impairment that may later evolve to WMD. As knowledge advanced, the role of white matter in structural connectivity within distributed neural networks was elucidated. In addition, highlighting the frequent commingling of gray and white matter involvement, white matter pathology was associated with neurodegenerative diseases such as Alzheimer's disease and chronic traumatic encephalopathy, with potentially transformative clinical implications. In particular, preventive measures and treatments exploiting white matter restoration and plasticity are gaining much attention. Today, WMD has matured into a concept that not only integrates knowledge from across the spectrum of clinical neuroscience, but also informs new investigations into many perplexing disorders and enables a more complete understanding of brain-behavior relationships.
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Affiliation(s)
- Christopher M. Filley
- Behavioral Neurology Section, Department of Neurology and Psychiatry, University of Colorado School of Medicine, Marcus Institute for Brain Health, Aurora, CO, United States
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20
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Macchi ZA, Carlisle TC, Filley CM. Prognosis in substance abuse-related acute toxic leukoencephalopathy: A scoping review. J Neurol Sci 2022; 442:120420. [PMID: 36156344 PMCID: PMC11008924 DOI: 10.1016/j.jns.2022.120420] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 08/26/2022] [Accepted: 09/07/2022] [Indexed: 12/01/2022]
Abstract
OBJECTIVES Abuse of opiates, cocaine, and lipophilic inhalants (e.g., toluene) can damage brain myelin and cause acute toxic leukoencephalopathy (TL), but little is known about recovery or prognosis in this condition. In light of the ongoing opiate epidemic in the United States, it is important to understand the natural history of patients who have acute neurological complications from illicit drug exposure. Our aim was to conduct a scoping review of the literature regarding prognosis in described cases of substance abuse-related TL. METHODS A strategic search of PubMed, Ovid, Cumulative Index to Nursing, and Allied Health Literature (CINAHL) databases yielded adult cases of acute TL from opiates, cocaine, or inhalants. Cases and case series were eligible for inclusion if they described acute leukoencephalopathy with a clear temporal association with opiate, cocaine, or inhalant abuse. Inclusion was contingent on availability of clinical descriptions until death or ≥ 4 weeks follow-up with neuroimaging consistent with TL. RESULTS Among 52 cases from 14 articles, 21 (40.4%) individuals died with mean time to death of 28.2 days; with mean follow-up of 12.8 months, 10 (19.2%) survived with no recovery, 17 (32.7%) had partial recovery, and 4 (7.7%) individuals had full recovery. CONCLUSION Substance abuse-related acute TL often has a poor prognosis, but partial or even full recovery is possible in a subgroup of individuals over months to years.
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Affiliation(s)
- Zachary A Macchi
- Department of Neurology, University of Colorado School of Medicine, 1635 Aurora Ct, Aurora, CO 80045, USA; Behavioral Neurology Section, University of Colorado School of Medicine, 12649 E 17(th) Place, Aurora, CO 80045, USA.
| | - Tara C Carlisle
- Department of Neurology, University of Colorado School of Medicine, 1635 Aurora Ct, Aurora, CO 80045, USA; Movement Disorders Center, University of Colorado School of Medicine, 12631 E 17(th) Ave, Aurora, CO 80045, USA
| | - Christopher M Filley
- Department of Neurology, University of Colorado School of Medicine, 1635 Aurora Ct, Aurora, CO 80045, USA; Behavioral Neurology Section, University of Colorado School of Medicine, 12649 E 17(th) Place, Aurora, CO 80045, USA; Department of Psychiatry, University of Colorado School of Medicine, 1890 N Revere Ct, Suite 4020, Aurora, CO 80045, USA; Marcus Institute for Brain Health, University of Colorado, 12348 E Montview Blvd, Aurora, CO 80045, USA
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21
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Noristani HN. Intrinsic regulation of axon regeneration after spinal cord injury: Recent advances and remaining challenges. Exp Neurol 2022; 357:114198. [DOI: 10.1016/j.expneurol.2022.114198] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 07/20/2022] [Accepted: 08/02/2022] [Indexed: 11/16/2022]
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22
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Kauthankar AA, Jaseemudheen M. Diffusion Tensor Imaging in Spinal Cord Injury: A Review. JOURNAL OF HEALTH AND ALLIED SCIENCES NU 2022. [DOI: 10.1055/s-0042-1751068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
AbstractMagnetic resonance diffusion tensor imaging (DTI) is a recent technique that can measure the direction and magnitude of diffusion of water. It is widely being utilized to evaluate several brain and spinal cord pathologies. The objective of this review is to evaluate the importance of the DTI in patients with spinal cord injury (SCI). It aims to review various articles on DTI SCI and includes both animal and human studies. This will help to describe the current status of the clinical applications of DTI and show its potential as a helpful instrument in clinical practice. The PubMed database was searched for articles relating to the application of DTI in SCI. Relevant articles were also used for the review. A variety of DTI parameters have been studied in various articles. The standard parameters are fractional anisotropy (FA) values, apparent diffusion coefficient (ADC) values, radial diffusivity values, and axial diffusivity values, followed by tractography. FA and ADC values are the most commonly used parameters. The findings observed in most of the studies are increased FA and reduced ADC values following injury to the spinal cord. DTI data metrics possess the potential to become a potent clinical tool in patients with SCI. It is helpful for diagnosis, prognosis, treatment planning, as well as to evaluate the recovery. Nonetheless, to overcome the limitations and determine its reliability clinically, more research has to be performed.
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Affiliation(s)
- Akshada Atchut Kauthankar
- Department of Radio-diagnosis and Imaging, K S Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, Karnataka, India
| | - M.M Jaseemudheen
- Department of Radio-diagnosis and Imaging, K S Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, Karnataka, India
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Costa AC, Sousa MM. The Role of Spastin in Axon Biology. Front Cell Dev Biol 2022; 10:934522. [PMID: 35865632 PMCID: PMC9294387 DOI: 10.3389/fcell.2022.934522] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 06/07/2022] [Indexed: 12/05/2022] Open
Abstract
Neurons are highly polarized cells with elaborate shapes that allow them to perform their function. In neurons, microtubule organization—length, density, and dynamics—are essential for the establishment of polarity, growth, and transport. A mounting body of evidence shows that modulation of the microtubule cytoskeleton by microtubule-associated proteins fine tunes key aspects of neuronal cell biology. In this respect, microtubule severing enzymes—spastin, katanin and fidgetin—a group of microtubule-associated proteins that bind to and generate internal breaks in the microtubule lattice, are emerging as key modulators of the microtubule cytoskeleton in different model systems. In this review, we provide an integrative view on the latest research demonstrating the key role of spastin in neurons, specifically in the context of axonal cell biology. We focus on the function of spastin in the regulation of microtubule organization, and axonal transport, that underlie its importance in the intricate control of axon growth, branching and regeneration.
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Affiliation(s)
- Ana Catarina Costa
- Nerve Regeneration Group, Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação Em Saúde (i3S), University of Porto, Porto, Portugal
- Graduate Program in Molecular and Cell Biology, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, Porto, Portugal
- *Correspondence: Ana Catarina Costa, ; Monica Mendes Sousa,
| | - Monica Mendes Sousa
- Nerve Regeneration Group, Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação Em Saúde (i3S), University of Porto, Porto, Portugal
- *Correspondence: Ana Catarina Costa, ; Monica Mendes Sousa,
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Axonal injury is detected by βAPP immunohistochemistry in rapid death from head injury following road traffic collision. Int J Legal Med 2022; 136:1321-1339. [PMID: 35488928 PMCID: PMC9375765 DOI: 10.1007/s00414-022-02807-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 02/21/2022] [Indexed: 11/23/2022]
Abstract
The accumulation of βAPP caused by axonal injury is an active energy-dependent process thought to require blood circulation; therefore, it is closely related to the post-injury survival time. Currently, the earliest reported time at which axonal injury can be detected in post-mortem traumatic brain injury (TBI) tissue by βAPP (Beta Amyloid Precursor Protein) immunohistochemistry is 35 min. The aim of this study is to investigate whether βAPP staining for axonal injury can be detected in patients who died rapidly after TBI in road traffic collision (RTC), in a period of less than 30 min. We retrospectively studied thirty-seven patients (group 1) died very rapidly at the scene; evidenced by forensic assessment of injuries short survival, four patients died after a survival period of between 31 min and 12 h (group 2) and eight patients between 2 and 31 days (group 3). The brains were comprehensively examined and sampled at the time of the autopsy, and βAPP immunohistochemistry carried out on sections from a number of brain areas. βAPP immunoreactivity was demonstrated in 35/37 brains in group 1, albeit with a low frequency and in a variable pattern, and with more intensity and frequency in all brains of group 2 and 7/8 brains from group 3, compared with no similar βAPP immunoreactivity in the control group. The results suggest axonal injury can be detected in those who died rapidly after RTC in a period of less than 30 min, which can help in the diagnosis of severe TBI with short survival time.
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Sihvonen AJ, Siponkoski ST, Martínez-Molina N, Laitinen S, Holma M, Ahlfors M, Kuusela L, Pekkola J, Koskinen S, Särkämö T. Neurological Music Therapy Rebuilds Structural Connectome after Traumatic Brain Injury: Secondary Analysis from a Randomized Controlled Trial. J Clin Med 2022; 11:jcm11082184. [PMID: 35456277 PMCID: PMC9032739 DOI: 10.3390/jcm11082184] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 04/06/2022] [Accepted: 04/11/2022] [Indexed: 02/04/2023] Open
Abstract
Background: Traumatic brain injury (TBI) is a common and devastating neurological condition, associated often with poor functional outcome and deficits in executive function. Due to the neuropathology of TBI, neuroimaging plays a crucial role in its assessment, and while diffusion MRI has been proposed as a sensitive biomarker, longitudinal studies evaluating treatment-related diffusion MRI changes are scarce. Recent evidence suggests that neurological music therapy can improve executive functions in patients with TBI and that these effects are underpinned by neuroplasticity changes in the brain. However, studies evaluating music therapy induced structural connectome changes in patients with TBI are lacking. Design: Single-blind crossover (AB/BA) randomized controlled trial (NCT01956136). Objective: Here, we report secondary outcomes of the trial and set out to assess the effect of neurological music therapy on structural white matter connectome changes and their association with improved execute function in patients with TBI. Methods: Using an AB/BA design, 25 patients with moderate or severe TBI were randomized to receive a 3-month neurological music therapy intervention either during the first (AB, n = 16) or second (BA, n = 9) half of a 6-month follow-up period. Neuropsychological testing and diffusion MRI scans were performed at baseline and at the 3-month and 6-month stage. Findings: Compared to the control group, the music therapy group increased quantitative anisotropy (QA) in the right dorsal pathways (arcuate fasciculus, superior longitudinal fasciculus) and in the corpus callosum and the right frontal aslant tract, thalamic radiation and corticostriatal tracts. The mean increased QA in this network of results correlated with improved executive function. Conclusions: This study shows that music therapy can induce structural white matter neuroplasticity in the post-TBI brain that underpins improved executive function.
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Affiliation(s)
- Aleksi J. Sihvonen
- Cognitive Brain Research Unit, Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland; (S.-T.S.); (N.M.-M.); (T.S.)
- Centre of Excellence in Music, Mind, Body and Brain, University of Jyväskylä & University of Helsinki, 00014 Helsinki, Finland;
- School of Health and Rehabilitation Sciences, Queensland Aphasia Research Centre and UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia
- Correspondence:
| | - Sini-Tuuli Siponkoski
- Cognitive Brain Research Unit, Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland; (S.-T.S.); (N.M.-M.); (T.S.)
- Centre of Excellence in Music, Mind, Body and Brain, University of Jyväskylä & University of Helsinki, 00014 Helsinki, Finland;
| | - Noelia Martínez-Molina
- Cognitive Brain Research Unit, Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland; (S.-T.S.); (N.M.-M.); (T.S.)
- Centre of Excellence in Music, Mind, Body and Brain, University of Jyväskylä & University of Helsinki, 00014 Helsinki, Finland;
| | - Sari Laitinen
- Centre of Excellence in Music, Mind, Body and Brain, University of Jyväskylä & University of Helsinki, 00014 Helsinki, Finland;
- Espoo Hospital, 02740 Espoo, Finland
| | - Milla Holma
- Independent Researcher, 00550 Helsinki, Finland;
| | | | - Linda Kuusela
- Department of Physics, University of Helsinki, 00014 Helsinki, Finland;
- HUS Medical Imaging Center, Department of Radiology, Helsinki Central University Hospital and University of Helsinki, 00014 Helsinki, Finland;
| | - Johanna Pekkola
- HUS Medical Imaging Center, Department of Radiology, Helsinki Central University Hospital and University of Helsinki, 00014 Helsinki, Finland;
| | - Sanna Koskinen
- Clinical Neuropsychology Research Group, Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland;
| | - Teppo Särkämö
- Cognitive Brain Research Unit, Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland; (S.-T.S.); (N.M.-M.); (T.S.)
- Centre of Excellence in Music, Mind, Body and Brain, University of Jyväskylä & University of Helsinki, 00014 Helsinki, Finland;
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26
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Mavroudis I, Kazis D, Chowdhury R, Petridis F, Costa V, Balmus IM, Ciobica A, Luca AC, Radu I, Dobrin RP, Baloyannis S. Post-Concussion Syndrome and Chronic Traumatic Encephalopathy: Narrative Review on the Neuropathology, Neuroimaging and Fluid Biomarkers. Diagnostics (Basel) 2022; 12:diagnostics12030740. [PMID: 35328293 PMCID: PMC8947595 DOI: 10.3390/diagnostics12030740] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/14/2022] [Accepted: 03/15/2022] [Indexed: 01/08/2023] Open
Abstract
Traumatic brain injury is a significant public health issue and represents the main contributor to death and disability globally among all trauma-related injuries. Martial arts practitioners, military veterans, athletes, victims of physical abuse, and epileptic patients could be affected by the consequences of repetitive mild head injuries (RMHI) that do not resume only to short-termed traumatic brain injuries (TBI) effects but also to more complex and time-extended outcomes, such as post-concussive syndrome (PCS) and chronic traumatic encephalopathy (CTE). These effects in later life are not yet well understood; however, recent studies suggested that even mild head injuries can lead to an elevated risk of later-life cognitive impairment and neurodegenerative disease. While most of the PCS hallmarks consist in immediate consequences and only in some conditions in long-termed processes undergoing neurodegeneration and impaired brain functions, the neuropathological hallmark of CTE is the deposition of p-tau immunoreactive pre-tangles and thread-like neurites at the depths of cerebral sulci and neurofibrillary tangles in the superficial layers I and II which are also one of the main hallmarks of neurodegeneration. Despite different CTE diagnostic criteria in clinical and research approaches, their specificity and sensitivity remain unclear and CTE could only be diagnosed post-mortem. In CTE, case risk factors include RMHI exposure due to profession (athletes, military personnel), history of trauma (abuse), or pathologies (epilepsy). Numerous studies aimed to identify imaging and fluid biomarkers that could assist diagnosis and probably lead to early intervention, despite their heterogeneous outcomes. Still, the true challenge remains the prediction of neurodegeneration risk following TBI, thus in PCS and CTE. Further studies in high-risk populations are required to establish specific, preferably non-invasive diagnostic biomarkers for CTE, considering the aim of preventive medicine.
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Affiliation(s)
- Ioannis Mavroudis
- Department of Neuroscience, Leeds Teaching Hospitals, NHS Trust, Leeds LS2 9JT, UK; (I.M.); (R.C.)
- Laboratory of Neuropathology and Electron Microscopy, Aristotle University of Thessaloniki, 54634 Thessaloniki, Greece; (V.C.); (S.B.)
- Research Institute for Alzheimer’s Disease and Neurodegenerative Diseases, Heraklion Langada, 57200 Thessaloniki, Greece
| | - Dimitrios Kazis
- Third Department of Neurology, Aristotle University of Thessaloniki, 57010 Thessaloniki, Greece; (D.K.); (F.P.)
| | - Rumana Chowdhury
- Department of Neuroscience, Leeds Teaching Hospitals, NHS Trust, Leeds LS2 9JT, UK; (I.M.); (R.C.)
| | - Foivos Petridis
- Third Department of Neurology, Aristotle University of Thessaloniki, 57010 Thessaloniki, Greece; (D.K.); (F.P.)
| | - Vasiliki Costa
- Laboratory of Neuropathology and Electron Microscopy, Aristotle University of Thessaloniki, 54634 Thessaloniki, Greece; (V.C.); (S.B.)
| | - Ioana-Miruna Balmus
- Department of Exact Sciences and Natural Sciences, Institute of Interdisciplinary Research, “Alexandru Ioan Cuza” University of Iași, 700057 Iași, Romania;
| | - Alin Ciobica
- Department of Biology, Faculty of Biology, Alexandru Ioan Cuza University, 700506 Iași, Romania
- Correspondence: (A.C.); (A.-C.L.); (R.P.D.)
| | - Alina-Costina Luca
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania;
- Correspondence: (A.C.); (A.-C.L.); (R.P.D.)
| | - Iulian Radu
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania;
| | - Romeo Petru Dobrin
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania;
- Correspondence: (A.C.); (A.-C.L.); (R.P.D.)
| | - Stavros Baloyannis
- Laboratory of Neuropathology and Electron Microscopy, Aristotle University of Thessaloniki, 54634 Thessaloniki, Greece; (V.C.); (S.B.)
- Research Institute for Alzheimer’s Disease and Neurodegenerative Diseases, Heraklion Langada, 57200 Thessaloniki, Greece
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27
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Cruz Navarro J, Ponce Mejia LL, Robertson C. A Precision Medicine Agenda in Traumatic Brain Injury. Front Pharmacol 2022; 13:713100. [PMID: 35370671 PMCID: PMC8966615 DOI: 10.3389/fphar.2022.713100] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 02/25/2022] [Indexed: 11/13/2022] Open
Abstract
Traumatic brain injury remains a leading cause of death and disability across the globe. Substantial uncertainty in outcome prediction continues to be the rule notwithstanding the existing prediction models. Additionally, despite very promising preclinical data, randomized clinical trials (RCTs) of neuroprotective strategies in moderate and severe TBI have failed to demonstrate significant treatment effects. Better predictive models are needed, as the existing validated ones are more useful in prognosticating poor outcome and do not include biomarkers, genomics, proteonomics, metabolomics, etc. Invasive neuromonitoring long believed to be a "game changer" in the care of TBI patients have shown mixed results, and the level of evidence to support its widespread use remains insufficient. This is due in part to the extremely heterogenous nature of the disease regarding its etiology, pathology and severity. Currently, the diagnosis of traumatic brain injury (TBI) in the acute setting is centered on neurological examination and neuroimaging tools such as CT scanning and MRI, and its treatment has been largely confronted using a "one-size-fits-all" approach, that has left us with many unanswered questions. Precision medicine is an innovative approach for TBI treatment that considers individual variability in genes, environment, and lifestyle and has expanded across the medical fields. In this article, we briefly explore the field of precision medicine in TBI including biomarkers for therapeutic decision-making, multimodal neuromonitoring, and genomics.
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Affiliation(s)
- Jovany Cruz Navarro
- Departments of Anesthesiology and Neurosurgery, Baylor College of Medicine, Houston, TX, United States
| | - Lucido L. Ponce Mejia
- Departments of Neurosurgery and Neurology, LSU Health Science Center, New Orleans, LA, United States
| | - Claudia Robertson
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, United States
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28
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Marcinkowska AB, Mankowska ND, Kot J, Winklewski PJ. Impact of Hyperbaric Oxygen Therapy on Cognitive Functions: a Systematic Review. Neuropsychol Rev 2022; 32:99-126. [PMID: 33847854 PMCID: PMC8888529 DOI: 10.1007/s11065-021-09500-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 03/07/2021] [Indexed: 12/13/2022]
Abstract
Hyperbaric oxygen therapy (HBOT) is a modality of treatment in which patients inhale 100% oxygen inside a hyperbaric chamber pressurised to greater than 1 atmosphere. The aim of this review is to discuss neuropsychological findings in various neurological disorders treated with HBOT and to open new perspectives for therapeutic improvement. A literature search was conducted in the MEDLINE (via PubMed) database from the inception up 10 May 2020. Eligibility criteria included original articles published in English. Case studies were excluded. Full-text articles were obtained from the selected studies and were reviewed on the following inclusion criteria (1) performed cognitive processes assessment (2) performed HBOT with described protocol. Two neuropsychologists independently reviewed titles, abstracts, full texts and extracted data. The initial search retrieved 1024 articles, and a total of 42 studies were finally included after applying inclusion and exclusion criteria. The search yielded controversial results with regard to the efficiency of HBOT in various neurological conditions with cognitive disturbance outcome. To the best of our knowledge this is the first state-of-the art, systematic review in the field. More objective and precise neuropsychological assessment methods are needed to exact evaluation of the efficacy of HBOT for neuropsychological deficits. Future studies should widen the assessment of HBOT effects on different cognitive domains because most of the existing studies have focussed on a single process. Finally, there is a need for further longitudinal studies.
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Affiliation(s)
- Anna B Marcinkowska
- Applied Cognitive Neuroscience Lab, Department of Human Physiology, Medical University of Gdańsk, Tuwima Str. 15 80-210, Gdańsk, Poland.
- 2nd Department of Radiology, Medical University of Gdańsk, Gdańsk, Poland.
| | - Natalia D Mankowska
- Applied Cognitive Neuroscience Lab, Department of Human Physiology, Medical University of Gdańsk, Tuwima Str. 15 80-210, Gdańsk, Poland
| | - Jacek Kot
- National Centre for Hyperbaric Medicine, Institute of Maritime and Tropical Medicine in Gdynia, Medical University of Gdansk, Gdańsk, Poland
| | - Pawel J Winklewski
- Applied Cognitive Neuroscience Lab, Department of Human Physiology, Medical University of Gdańsk, Tuwima Str. 15 80-210, Gdańsk, Poland
- 2nd Department of Radiology, Medical University of Gdańsk, Gdańsk, Poland
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29
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Alashram AR, Padua E, Romagnoli C, Annino G. Hyperbaric oxygen therapy for cognitive impairments in patients with traumatic brain injury: A systematic review. APPLIED NEUROPSYCHOLOGY. ADULT 2022:1-12. [PMID: 35213282 DOI: 10.1080/23279095.2022.2041418] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Cognitive deficits are the most common impairments after traumatic brain injury (TBI). It can be linked with poor physical function. Hyperbaric oxygen therapy (HBOT) increases blood flow and oxygen supply to the brain. This review aimed to summarize and evaluate the available literature on the influences of HBOT on cognitive deficits in patients with TBI. PubMed, SCOPUS, PEDro, REHABDATA, MIDLINE, CHINAL, EMBASE, and Web of Science were searched from inception until June 2021. The methodological quality was measured using the physiotherapy evidence database (PEDro) scale. Ten studies met the eligibility criteria. Six studies were randomized controlled trials, and four were pilot studies. The scores on the PEDro scale ranged from two to nine, with a median score of seven. The included studies showed heterogeneity results for the beneficial effects of HBOT on improving cognitive functions in patients with TBI. The evidence for the beneficial effects of HBOT on cognitive functions post-TBI was limited. Further randomized controlled trials with large sample sizes are strongly needed to understand the effects of HBOT on cognitive functions in patients with TBI.
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Affiliation(s)
| | - Elvira Padua
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy
| | - Cristian Romagnoli
- PhD School in Science and Culture of Well-being and Lifestyle, Alma Mater University, Bologna, Italy
| | - Giuseppe Annino
- Department of Medicine Systems, University of Rome "Tor Vergata", Rome, Italy
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30
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Gutiérrez‑Vargas J, Castro‑Álvarez J, Zapata‑Berruecos J, Abdul‑Rahim K, Arteaga‑Noriega A. Neurodegeneration and convergent factors contributing to the deterioration of the cytoskeleton in Alzheimer's disease, cerebral ischemia and multiple sclerosis (Review). Biomed Rep 2022; 16:27. [PMID: 35251614 PMCID: PMC8889542 DOI: 10.3892/br.2022.1510] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 01/21/2022] [Indexed: 11/26/2022] Open
Abstract
The cytoskeleton is the main intracellular structure that determines the morphology of neurons and maintains their integrity. Therefore, disruption of its structure and function may underlie several neurodegenerative diseases. This review summarizes the current literature on the tau protein, microtubule-associated protein 2 (MAP2) and neurofilaments as common denominators in pathological conditions such as Alzheimer's disease (AD), cerebral ischemia, and multiple sclerosis (MS). Insights obtained from experimental models using biochemical and immunocytochemical techniques highlight that changes in these proteins may be potentially used as protein targets in clinical settings, which provides novel opportunities for the detection, monitoring and treatment of patients with these neurodegenerative diseases.
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Affiliation(s)
- Johanna Gutiérrez‑Vargas
- Neuroscience and Aging Group (GISAM), Faculty of Health Sciences, Life Sciences Laboratory, Remington University Corporation, Medellín 050023, Colombia
| | - John Castro‑Álvarez
- Neuroscience and Aging Group (GISAM), Faculty of Health Sciences, Life Sciences Laboratory, Remington University Corporation, Medellín 050023, Colombia
| | - Jose Zapata‑Berruecos
- INDEC‑CES Research Group, Neurological Institute of Colombia, Medellín 050023, Colombia
| | | | - Anibal Arteaga‑Noriega
- Family and Community Health Group, Faculty of Health Sciences, Life Sciences Laboratory, Remington University Corporation, Medellín 050023, Colombia
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31
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Elevated microglial oxidative phosphorylation and phagocytosis stimulate post-stroke brain remodeling and cognitive function recovery in mice. Commun Biol 2022; 5:35. [PMID: 35017668 PMCID: PMC8752825 DOI: 10.1038/s42003-021-02984-4] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 12/09/2021] [Indexed: 12/27/2022] Open
Abstract
New research shows that disease-associated microglia in neurodegenerative brains present features of elevated phagocytosis, lysosomal functions, and lipid metabolism, which benefit brain repair. The underlying mechanisms remain poorly understood. Intracellular pH (pHi) is important for regulating aerobic glycolysis in microglia, where Na/H exchanger (NHE1) is a key pH regulator by extruding H+ in exchange of Na+ influx. We report here that post-stroke Cx3cr1-CreER+/-;Nhe1flox/flox (Nhe1 cKO) brains displayed stimulation of microglial transcriptomes of rate-limiting enzyme genes for glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation. The other upregulated genes included genes for phagocytosis and LXR/RXR pathway activation as well as the disease-associated microglia hallmark genes (Apoe, Trem2, Spp1). The cKO microglia exhibited increased oxidative phosphorylation capacity, and higher phagocytic activity, which likely played a role in enhanced synaptic stripping and remodeling, oligodendrogenesis, and remyelination. This study reveals that genetic blockade of microglial NHE1 stimulated oxidative phosphorylation immunometabolism, and boosted phagocytosis function which is associated with tissue remodeling and post-stroke cognitive function recovery.
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32
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Heckova E, Dal-Bianco A, Strasser B, Hangel GJ, Lipka A, Motyka S, Hingerl L, Rommer PS, Berger T, Hnilicová P, Kantorová E, Leutmezer F, Kurča E, Gruber S, Trattnig S, Bogner W. Extensive Brain Pathologic Alterations Detected with 7.0-T MR Spectroscopic Imaging Associated with Disability in Multiple Sclerosis. Radiology 2022; 303:141-150. [PMID: 34981978 DOI: 10.1148/radiol.210614] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Background MR spectroscopic imaging (MRSI) allows in vivo assessment of brain metabolism and is of special interest in multiple sclerosis (MS), where morphologic MRI cannot depict major parts of disease activity. Purpose To evaluate the ability of 7.0-T MRSI to depict and visualize pathologic alterations in the normal-appearing white matter (NAWM) and cortical gray matter (CGM) in participants with MS and to investigate their relation to disability. Materials and Methods Free-induction decay MRSI was performed at 7.0 T. Participants with MS and age- and sex-matched healthy controls were recruited prospectively between January 2016 and December 2017. Metabolic ratios were obtained in white matter lesions, NAWM, and CGM regions. Subgroup analysis for MS-related disability based on Expanded Disability Status Scale (EDSS) scores was performed using analysis of covariance. Partial correlations were applied to explore associations between metabolic ratios and disability. Results Sixty-five participants with MS (mean age ± standard deviation, 34 years ± 9; 34 women) and 20 age- and sex-matched healthy controls (mean age, 32 years ± 7; 11 women) were evaluated. Higher signal intensity of myo-inositol (mI) with and without reduced signal intensity of N-acetylaspartate (NAA) was visible on metabolic images in the NAWM of participants with MS. A higher ratio of mI to total creatine (tCr) was observed in the NAWM of the centrum semiovale of all MS subgroups, including participants without disability (marginal mean ± standard error, healthy controls: 0.78 ± 0.04; EDSS 0-1: 0.86 ± 0.03 [P = .02]; EDSS 1.5-3: 0.95 ± 0.04 [P < .001]; EDSS ≥3.5: 0.94 ± 0.04 [P = .001]). A lower ratio of NAA to tCr was found in MS subgroups with disabilities, both in their NAWM (marginal mean ± standard error, healthy controls: 1.46 ± 0.04; EDSS 1.5-3: 1.33 ± 0.03 [P = .03]; EDSS ≥3.5: 1.30 ± 0.04 [P = .01]) and CGM (marginal mean ± standard error, healthy controls: 1.42 ± 0.05; EDSS ≥3.5: 1.23 ± 0.05 [P = .006]). mI/NAA correlated with EDSS (NAWM of centrum semiovale: r = 0.47, P < .001; parietal NAWM: r = 0.43, P = .002; frontal NAWM: r = 0.34, P = .01; frontal CGM: r = 0.37, P = .004). Conclusion MR spectroscopic imaging at 7.0 T allowed in vivo visualization of multiple sclerosis pathologic findings not visible at T1- or T2-weighted MRI. Metabolic abnormalities in the normal-appearing white matter and cortical gray matter were associated with disability. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Barker in this issue.
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Affiliation(s)
- Eva Heckova
- From the High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Lazarettgasse 14, A-1090 Vienna, Austria (E.H., B.S., G.J.H., A.L., S.M., L.H., S.G., S.T., W.B.); Departments of Neurology (A.D.B., P.S.R., T.B., F.L.) and Neurosurgery (G.J.H.), Medical University of Vienna, Vienna, Austria; Biomedical Center Martin (P.H.) and Clinic of Neurology (E. Kantorová, E. Kurča), Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia; and Karl Landsteiner Institute for Clinical Molecular MRI in Musculoskeletal System, Vienna, Austria (S.T.)
| | - Assunta Dal-Bianco
- From the High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Lazarettgasse 14, A-1090 Vienna, Austria (E.H., B.S., G.J.H., A.L., S.M., L.H., S.G., S.T., W.B.); Departments of Neurology (A.D.B., P.S.R., T.B., F.L.) and Neurosurgery (G.J.H.), Medical University of Vienna, Vienna, Austria; Biomedical Center Martin (P.H.) and Clinic of Neurology (E. Kantorová, E. Kurča), Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia; and Karl Landsteiner Institute for Clinical Molecular MRI in Musculoskeletal System, Vienna, Austria (S.T.)
| | - Bernhard Strasser
- From the High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Lazarettgasse 14, A-1090 Vienna, Austria (E.H., B.S., G.J.H., A.L., S.M., L.H., S.G., S.T., W.B.); Departments of Neurology (A.D.B., P.S.R., T.B., F.L.) and Neurosurgery (G.J.H.), Medical University of Vienna, Vienna, Austria; Biomedical Center Martin (P.H.) and Clinic of Neurology (E. Kantorová, E. Kurča), Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia; and Karl Landsteiner Institute for Clinical Molecular MRI in Musculoskeletal System, Vienna, Austria (S.T.)
| | - Gilbert J Hangel
- From the High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Lazarettgasse 14, A-1090 Vienna, Austria (E.H., B.S., G.J.H., A.L., S.M., L.H., S.G., S.T., W.B.); Departments of Neurology (A.D.B., P.S.R., T.B., F.L.) and Neurosurgery (G.J.H.), Medical University of Vienna, Vienna, Austria; Biomedical Center Martin (P.H.) and Clinic of Neurology (E. Kantorová, E. Kurča), Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia; and Karl Landsteiner Institute for Clinical Molecular MRI in Musculoskeletal System, Vienna, Austria (S.T.)
| | - Alexandra Lipka
- From the High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Lazarettgasse 14, A-1090 Vienna, Austria (E.H., B.S., G.J.H., A.L., S.M., L.H., S.G., S.T., W.B.); Departments of Neurology (A.D.B., P.S.R., T.B., F.L.) and Neurosurgery (G.J.H.), Medical University of Vienna, Vienna, Austria; Biomedical Center Martin (P.H.) and Clinic of Neurology (E. Kantorová, E. Kurča), Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia; and Karl Landsteiner Institute for Clinical Molecular MRI in Musculoskeletal System, Vienna, Austria (S.T.)
| | - Stanislav Motyka
- From the High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Lazarettgasse 14, A-1090 Vienna, Austria (E.H., B.S., G.J.H., A.L., S.M., L.H., S.G., S.T., W.B.); Departments of Neurology (A.D.B., P.S.R., T.B., F.L.) and Neurosurgery (G.J.H.), Medical University of Vienna, Vienna, Austria; Biomedical Center Martin (P.H.) and Clinic of Neurology (E. Kantorová, E. Kurča), Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia; and Karl Landsteiner Institute for Clinical Molecular MRI in Musculoskeletal System, Vienna, Austria (S.T.)
| | - Lukas Hingerl
- From the High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Lazarettgasse 14, A-1090 Vienna, Austria (E.H., B.S., G.J.H., A.L., S.M., L.H., S.G., S.T., W.B.); Departments of Neurology (A.D.B., P.S.R., T.B., F.L.) and Neurosurgery (G.J.H.), Medical University of Vienna, Vienna, Austria; Biomedical Center Martin (P.H.) and Clinic of Neurology (E. Kantorová, E. Kurča), Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia; and Karl Landsteiner Institute for Clinical Molecular MRI in Musculoskeletal System, Vienna, Austria (S.T.)
| | - Paulus S Rommer
- From the High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Lazarettgasse 14, A-1090 Vienna, Austria (E.H., B.S., G.J.H., A.L., S.M., L.H., S.G., S.T., W.B.); Departments of Neurology (A.D.B., P.S.R., T.B., F.L.) and Neurosurgery (G.J.H.), Medical University of Vienna, Vienna, Austria; Biomedical Center Martin (P.H.) and Clinic of Neurology (E. Kantorová, E. Kurča), Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia; and Karl Landsteiner Institute for Clinical Molecular MRI in Musculoskeletal System, Vienna, Austria (S.T.)
| | - Thomas Berger
- From the High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Lazarettgasse 14, A-1090 Vienna, Austria (E.H., B.S., G.J.H., A.L., S.M., L.H., S.G., S.T., W.B.); Departments of Neurology (A.D.B., P.S.R., T.B., F.L.) and Neurosurgery (G.J.H.), Medical University of Vienna, Vienna, Austria; Biomedical Center Martin (P.H.) and Clinic of Neurology (E. Kantorová, E. Kurča), Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia; and Karl Landsteiner Institute for Clinical Molecular MRI in Musculoskeletal System, Vienna, Austria (S.T.)
| | - Petra Hnilicová
- From the High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Lazarettgasse 14, A-1090 Vienna, Austria (E.H., B.S., G.J.H., A.L., S.M., L.H., S.G., S.T., W.B.); Departments of Neurology (A.D.B., P.S.R., T.B., F.L.) and Neurosurgery (G.J.H.), Medical University of Vienna, Vienna, Austria; Biomedical Center Martin (P.H.) and Clinic of Neurology (E. Kantorová, E. Kurča), Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia; and Karl Landsteiner Institute for Clinical Molecular MRI in Musculoskeletal System, Vienna, Austria (S.T.)
| | - Ema Kantorová
- From the High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Lazarettgasse 14, A-1090 Vienna, Austria (E.H., B.S., G.J.H., A.L., S.M., L.H., S.G., S.T., W.B.); Departments of Neurology (A.D.B., P.S.R., T.B., F.L.) and Neurosurgery (G.J.H.), Medical University of Vienna, Vienna, Austria; Biomedical Center Martin (P.H.) and Clinic of Neurology (E. Kantorová, E. Kurča), Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia; and Karl Landsteiner Institute for Clinical Molecular MRI in Musculoskeletal System, Vienna, Austria (S.T.)
| | - Fritz Leutmezer
- From the High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Lazarettgasse 14, A-1090 Vienna, Austria (E.H., B.S., G.J.H., A.L., S.M., L.H., S.G., S.T., W.B.); Departments of Neurology (A.D.B., P.S.R., T.B., F.L.) and Neurosurgery (G.J.H.), Medical University of Vienna, Vienna, Austria; Biomedical Center Martin (P.H.) and Clinic of Neurology (E. Kantorová, E. Kurča), Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia; and Karl Landsteiner Institute for Clinical Molecular MRI in Musculoskeletal System, Vienna, Austria (S.T.)
| | - Egon Kurča
- From the High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Lazarettgasse 14, A-1090 Vienna, Austria (E.H., B.S., G.J.H., A.L., S.M., L.H., S.G., S.T., W.B.); Departments of Neurology (A.D.B., P.S.R., T.B., F.L.) and Neurosurgery (G.J.H.), Medical University of Vienna, Vienna, Austria; Biomedical Center Martin (P.H.) and Clinic of Neurology (E. Kantorová, E. Kurča), Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia; and Karl Landsteiner Institute for Clinical Molecular MRI in Musculoskeletal System, Vienna, Austria (S.T.)
| | - Stephan Gruber
- From the High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Lazarettgasse 14, A-1090 Vienna, Austria (E.H., B.S., G.J.H., A.L., S.M., L.H., S.G., S.T., W.B.); Departments of Neurology (A.D.B., P.S.R., T.B., F.L.) and Neurosurgery (G.J.H.), Medical University of Vienna, Vienna, Austria; Biomedical Center Martin (P.H.) and Clinic of Neurology (E. Kantorová, E. Kurča), Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia; and Karl Landsteiner Institute for Clinical Molecular MRI in Musculoskeletal System, Vienna, Austria (S.T.)
| | - Siegfried Trattnig
- From the High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Lazarettgasse 14, A-1090 Vienna, Austria (E.H., B.S., G.J.H., A.L., S.M., L.H., S.G., S.T., W.B.); Departments of Neurology (A.D.B., P.S.R., T.B., F.L.) and Neurosurgery (G.J.H.), Medical University of Vienna, Vienna, Austria; Biomedical Center Martin (P.H.) and Clinic of Neurology (E. Kantorová, E. Kurča), Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia; and Karl Landsteiner Institute for Clinical Molecular MRI in Musculoskeletal System, Vienna, Austria (S.T.)
| | - Wolfgang Bogner
- From the High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Lazarettgasse 14, A-1090 Vienna, Austria (E.H., B.S., G.J.H., A.L., S.M., L.H., S.G., S.T., W.B.); Departments of Neurology (A.D.B., P.S.R., T.B., F.L.) and Neurosurgery (G.J.H.), Medical University of Vienna, Vienna, Austria; Biomedical Center Martin (P.H.) and Clinic of Neurology (E. Kantorová, E. Kurča), Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia; and Karl Landsteiner Institute for Clinical Molecular MRI in Musculoskeletal System, Vienna, Austria (S.T.)
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Filley CM. Cognitive Dysfunction in White Matter Disorders: New Perspectives in Treatment and Recovery. J Neuropsychiatry Clin Neurosci 2021; 33:349-355. [PMID: 34340526 DOI: 10.1176/appi.neuropsych.21030080] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
White matter disorders are increasingly appreciated as capable of disrupting cognitive function, and this impairment may be sufficiently severe to produce the syndrome of white matter dementia. Although recognizing this problem is important for diagnostic accuracy, the treatment of cognitive dysfunction and dementia in the white matter disorders has received relatively little attention. Similarly, few data are available regarding the potential for cognitive recovery in these disorders. Recent clinical and laboratory advances, however, indicate that effective treatment and meaningful recovery may be achievable goals for many patients with macrostructural or microstructural white matter pathology. One recent observation is that leukoaraiosis has been observed to regress with treatment of hypertension, often with concomitant improvement in cognition. Equally novel is emerging evidence that white matter exhibits substantial plasticity related to activity-dependent myelination and that this phenomenon may produce clinical benefit. These insights suggest that noninvasive and inexpensive interventions targeting white matter are warranted for a wide range of cognitively impaired patients. Moreover, given the well-established risk that vascular white matter pathology portends for developing dementia-including both vascular dementia and Alzheimer's disease-the application of these principles before dementia onset may also be efficacious for prevention. In view of the increasingly compelling case for early white matter involvement in the etiopathogenesis of late-life dementia and the continuing lack of disease-modifying therapy, progress in treating cognitive disturbances arising from white matter disorders offers the prospect that this approach may enhance the prevention of dementia as well as the treatment of cognitive dysfunction.
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Affiliation(s)
- Christopher M Filley
- Behavioral Neurology Section, Departments of Neurology and Psychiatry, University of Colorado School of Medicine, Aurora; and Marcus Institute for Brain Health, Aurora, Colo
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34
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Thomas BP, Tarumi T, Wang C, Zhu DC, Tomoto T, Munro Cullum C, Dieppa M, Diaz-Arrastia R, Bell K, Madden C, Zhang R, Ding K. Hippocampal and rostral anterior cingulate blood flow is associated with affective symptoms in chronic traumatic brain injury. Brain Res 2021; 1771:147631. [PMID: 34464600 DOI: 10.1016/j.brainres.2021.147631] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 08/02/2021] [Accepted: 08/21/2021] [Indexed: 11/30/2022]
Abstract
OBJECTIVE The purpose of this study was to assess cerebral blood flow (CBF) and its association with self-reported symptoms in chronic traumatic brain injury (TBI). PARTICIPANTS Sixteen participants with mild to severe TBI and persistent self-reported neurological symptoms, 6 to 72 months post-injury were included. For comparison, 16 age- and gender-matched healthy normal control participants were also included. MAIN MEASURES Regional CBF and brain volume were assessed using pseudo-continuous Arterial Spin Labeling (PCASL) and T1-weighted data respectively. Cognitive function and self-reported symptoms were assessed in TBI participants using the national institutes of health (NIH) Toolbox Cognition Battery and Patient-Reported Outcome Measurement Information System respectively. Associations between CBF and cognitive function, symptoms were assessed. RESULTS Global CBF and regional brain volumes were similar between groups, but region of interest (ROI) analysis revealed lower CBF bilaterally in the thalamus, hippocampus, left caudate, and left amygdala in the TBI group. Voxel-wise analysis revealed that CBF in the hippocampus, parahippocampus, rostral anterior cingulate, inferior frontal gyrus, and other temporal regions were negatively associated with self-reported anger, anxiety, and depression symptoms. Furthermore, region of interest (ROI) analysis revealed that hippocampal and rostral anterior cingulate CBF were negatively associated with symptoms of fatigue, anxiety, depression, and sleep issues. CONCLUSION Regional CBF deficit was observed in the group with chronic TBI compared to the normal control (NC) group despite similar volume of cerebral structures. The observed negative correlation between regional CBF and affective symptoms suggests that CBF-targeted intervention may potentially improve affective symptoms and quality of life after TBI, which needs to be assessed in future studies.
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Affiliation(s)
- Binu P Thomas
- Advanced Imaging Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, TX 75390, USA; Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, TX 75390, USA; Department of Bioengineering, University of Texas at Arlington, 500 UTA Blvd., Arlington, TX 76010, USA.
| | - Takashi Tarumi
- Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, TX 75390, USA; Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, 8200 Walnut Hill Ln, Dallas, TX 75231, USA.
| | - Ciwen Wang
- Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, TX 75390, USA
| | - David C Zhu
- Department of Radiology and Cognitive Imaging Research Center, Michigan State University, 86 Service Road, East Lansing, MI 48824, USA
| | - Tsubasa Tomoto
- Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, TX 75390, USA; Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, 8200 Walnut Hill Ln, Dallas, TX 75231, USA
| | - C Munro Cullum
- Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, TX 75390, USA; Department of Radiology and Cognitive Imaging Research Center, Michigan State University, 86 Service Road, East Lansing, MI 48824, USA; Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, TX 75390, USA; Department of Neurological Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, TX 75390, USA
| | - Marisara Dieppa
- Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, TX 75390, USA
| | - Ramon Diaz-Arrastia
- Department of Neurology, University of Pennsylvania Perelman School of Medicine, 51 North 39(th) St, Philadelphia, PA 19104, USA
| | - Kathleen Bell
- Department of Physical Medicine and Rehabilitation, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, TX 75390, USA
| | - Christopher Madden
- Department of Radiology and Cognitive Imaging Research Center, Michigan State University, 86 Service Road, East Lansing, MI 48824, USA
| | - Rong Zhang
- Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, TX 75390, USA; Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, 8200 Walnut Hill Ln, Dallas, TX 75231, USA
| | - Kan Ding
- Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, TX 75390, USA
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35
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Alia C, Cangi D, Massa V, Salluzzo M, Vignozzi L, Caleo M, Spalletti C. Cell-to-Cell Interactions Mediating Functional Recovery after Stroke. Cells 2021; 10:3050. [PMID: 34831273 PMCID: PMC8623942 DOI: 10.3390/cells10113050] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 10/27/2021] [Accepted: 11/02/2021] [Indexed: 12/22/2022] Open
Abstract
Ischemic damage in brain tissue triggers a cascade of molecular and structural plastic changes, thus influencing a wide range of cell-to-cell interactions. Understanding and manipulating this scenario of intercellular connections is the Holy Grail for post-stroke neurorehabilitation. Here, we discuss the main findings in the literature related to post-stroke alterations in cell-to-cell interactions, which may be either detrimental or supportive for functional recovery. We consider both neural and non-neural cells, starting from astrocytes and reactive astrogliosis and moving to the roles of the oligodendrocytes in the support of vulnerable neurons and sprouting inhibition. We discuss the controversial role of microglia in neural inflammation after injury and we conclude with the description of post-stroke alterations in pyramidal and GABAergic cells interactions. For all of these sections, we review not only the spontaneous evolution in cellular interactions after ischemic injury, but also the experimental strategies which have targeted these interactions and that are inspiring novel therapeutic strategies for clinical application.
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Affiliation(s)
- Claudia Alia
- Neuroscience Institute, National Research Council (CNR), Via G. Moruzzi 1, 56124 Pisa, Italy; (V.M.); (M.S.); (M.C.); (C.S.)
| | - Daniele Cangi
- Department of Neurosciences, Psychology, Drugs and Child Health Area, School of Psychology, University of Florence, 50121 Florence, Italy;
| | - Verediana Massa
- Neuroscience Institute, National Research Council (CNR), Via G. Moruzzi 1, 56124 Pisa, Italy; (V.M.); (M.S.); (M.C.); (C.S.)
| | - Marco Salluzzo
- Neuroscience Institute, National Research Council (CNR), Via G. Moruzzi 1, 56124 Pisa, Italy; (V.M.); (M.S.); (M.C.); (C.S.)
- Department of Neurosciences, Psychology, Drugs and Child Health Area, School of Psychology, University of Florence, 50121 Florence, Italy;
| | - Livia Vignozzi
- Department of Biomedical Sciences, University of Padua, Viale G. Colombo 3, 35121 Padua, Italy;
| | - Matteo Caleo
- Neuroscience Institute, National Research Council (CNR), Via G. Moruzzi 1, 56124 Pisa, Italy; (V.M.); (M.S.); (M.C.); (C.S.)
- Department of Biomedical Sciences, University of Padua, Viale G. Colombo 3, 35121 Padua, Italy;
| | - Cristina Spalletti
- Neuroscience Institute, National Research Council (CNR), Via G. Moruzzi 1, 56124 Pisa, Italy; (V.M.); (M.S.); (M.C.); (C.S.)
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Murphy SA, Furger R, Kurpad SN, Arpinar VE, Nencka A, Koch K, Budde MD. Filtered Diffusion-Weighted MRI of the Human Cervical Spinal Cord: Feasibility and Application to Traumatic Spinal Cord Injury. AJNR Am J Neuroradiol 2021; 42:2101-2106. [PMID: 34620590 DOI: 10.3174/ajnr.a7295] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 07/07/2021] [Indexed: 11/07/2022]
Abstract
BACKGROUND AND PURPOSE In traumatic spinal cord injury, DTI is sensitive to injury but is unable to differentiate multiple pathologies. Axonal damage is a central feature of the underlying cord injury, but prominent edema confounds its detection. The purpose of this study was to examine a filtered DWI technique in patients with acute spinal cord injury. MATERIALS AND METHODS The MR imaging protocol was first evaluated in a cohort of healthy subjects at 3T (n = 3). Subsequently, patients with acute cervical spinal cord injury (n = 8) underwent filtered DWI concurrent with their acute clinical MR imaging examination <24 hours postinjury at 1.5T. DTI was obtained with 25 directions at a b-value of 800 s/mm2. Filtered DWI used spinal cord-optimized diffusion-weighting along 26 directions with a "filter" b-value of 2000 s/mm2 and a "probe" maximum b-value of 1000 s/mm2. Parallel diffusivity metrics obtained from DTI and filtered DWI were compared. RESULTS The high-strength diffusion-weighting perpendicular to the cord suppressed signals from tissues outside of the spinal cord, including muscle and CSF. The parallel ADC acquired from filtered DWI at the level of injury relative to the most cranial region showed a greater decrease (38.71%) compared with the decrease in axial diffusivity acquired by DTI (17.68%). CONCLUSIONS The results demonstrated that filtered DWI is feasible in the acute setting of spinal cord injury and reveals spinal cord diffusion characteristics not evident with conventional DTI.
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Affiliation(s)
- S A Murphy
- From the Department of Neurosurgery (S.A.M., R.F., S.N.K., M.D.B.)
| | - R Furger
- From the Department of Neurosurgery (S.A.M., R.F., S.N.K., M.D.B.)
- Center for Neurotrauma Research (R.F., S.N.K., M.D.B.)
| | - S N Kurpad
- From the Department of Neurosurgery (S.A.M., R.F., S.N.K., M.D.B.)
- Center for Neurotrauma Research (R.F., S.N.K., M.D.B.)
| | - V E Arpinar
- Center for Imaging Research (V.E.A., A.N., K.K.), Medical College of Wisconsin, Milwaukee, Wisconsin
| | - A Nencka
- Center for Imaging Research (V.E.A., A.N., K.K.), Medical College of Wisconsin, Milwaukee, Wisconsin
| | - K Koch
- Center for Imaging Research (V.E.A., A.N., K.K.), Medical College of Wisconsin, Milwaukee, Wisconsin
| | - M D Budde
- From the Department of Neurosurgery (S.A.M., R.F., S.N.K., M.D.B.)
- Center for Neurotrauma Research (R.F., S.N.K., M.D.B.)
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Lunkova E, Guberman GI, Ptito A, Saluja RS. Noninvasive magnetic resonance imaging techniques in mild traumatic brain injury research and diagnosis. Hum Brain Mapp 2021; 42:5477-5494. [PMID: 34427960 PMCID: PMC8519871 DOI: 10.1002/hbm.25630] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 08/06/2021] [Accepted: 08/07/2021] [Indexed: 12/13/2022] Open
Abstract
Mild traumatic brain injury (mTBI), frequently referred to as concussion, is one of the most common neurological disorders. The underlying neural mechanisms of functional disturbances in the brains of concussed individuals remain elusive. Novel forms of brain imaging have been developed to assess patients postconcussion, including functional magnetic resonance imaging (fMRI), susceptibility-weighted imaging (SWI), diffusion MRI (dMRI), and perfusion MRI [arterial spin labeling (ASL)], but results have been mixed with a more common utilization in the research environment and a slower integration into the clinical setting. In this review, the benefits and drawbacks of the methods are described: fMRI is an effective method in the diagnosis of concussion but it is expensive and time-consuming making it difficult for regular use in everyday practice; SWI allows detection of microhemorrhages in acute and chronic phases of concussion; dMRI is primarily used for the detection of white matter abnormalities, especially axonal injury, specific for mTBI; and ASL is an alternative to the BOLD method with its ability to track cerebral blood flow alterations. Thus, the absence of a universal diagnostic neuroimaging method suggests a need for the adoption of a multimodal approach to the neuroimaging of mTBI. Taken together, these methods, with their underlying functional and structural features, can contribute from different angles to a deeper understanding of mTBI mechanisms such that a comprehensive diagnosis of mTBI becomes feasible for the clinician.
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Affiliation(s)
- Ekaterina Lunkova
- Department of Neurology & NeurosurgeryMcGill UniversityMontrealQuebecCanada
| | - Guido I. Guberman
- Department of Neurology & NeurosurgeryMcGill UniversityMontrealQuebecCanada
| | - Alain Ptito
- Department of Neurology & NeurosurgeryMcGill UniversityMontrealQuebecCanada
- Montreal Neurological InstituteMontrealQuebecCanada
- Department of PsychologyMcGill University Health CentreMontrealQuebecCanada
| | - Rajeet Singh Saluja
- Department of Neurology & NeurosurgeryMcGill UniversityMontrealQuebecCanada
- McGill University Health Centre Research InstituteMontrealQuebecCanada
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38
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Fedorova J, Kellerova E, Bimbova K, Pavel J. The Histopathology of Severe Graded Compression in Lower Thoracic Spinal Cord Segment of Rat, Evaluated at Late Post-injury Phase. Cell Mol Neurobiol 2021; 42:173-193. [PMID: 34410553 PMCID: PMC8732890 DOI: 10.1007/s10571-021-01139-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 08/04/2021] [Indexed: 11/28/2022]
Abstract
Spontaneous recovery of lost motor functions is relative fast in rodent models after inducing a very mild/moderate spinal cord injury (SCI), and this may complicate a reliable evaluation of the effectiveness of potential therapy. Therefore, a severe graded (30 g, 40 g and 50 g) weight-compression SCI at the Th9 spinal segment, involving an acute mechanical impact followed by 15 min of persistent compression, was studied in adult female Wistar rats. Functional parameters, such as spontaneous recovery of motor hind limb and bladder emptying function, and the presence of hematuria were evaluated within 28 days of the post-traumatic period. The disruption of the blood-spinal cord barrier, measured by extravasated Evans Blue dye, was examined 24 h after the SCI, when maximum permeability occurs. At the end of the survival period, the degradation of gray and white matter associated with the formation of cystic cavities, and quantitative changes of glial structural proteins, such as GFAP, and integral components of axonal architecture, such as neurofilaments and myelin basic protein, were evaluated in the lesioned area of the spinal cord. Based on these functional and histological parameters, and taking the animal’s welfare into account, the 40 g weight can be considered as an upper limit for severe traumatic injury in this compression model.
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Affiliation(s)
- Jana Fedorova
- Department of Neurodegeneration, Plasticity and Repair, Institute of Neurobiology, Biomedical Research Center of the Slovak Academy of Sciences, Soltesovej 4-6, 040 01, Kosice, Slovakia
| | - Erika Kellerova
- Department of Neurodegeneration, Plasticity and Repair, Institute of Neurobiology, Biomedical Research Center of the Slovak Academy of Sciences, Soltesovej 4-6, 040 01, Kosice, Slovakia
| | - Katarina Bimbova
- Department of Neurodegeneration, Plasticity and Repair, Institute of Neurobiology, Biomedical Research Center of the Slovak Academy of Sciences, Soltesovej 4-6, 040 01, Kosice, Slovakia
| | - Jaroslav Pavel
- Department of Neurodegeneration, Plasticity and Repair, Institute of Neurobiology, Biomedical Research Center of the Slovak Academy of Sciences, Soltesovej 4-6, 040 01, Kosice, Slovakia.
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39
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Haddad AF, Burke JF, Dhall SS. The Natural History of Spinal Cord Injury. Neurosurg Clin N Am 2021; 32:315-321. [PMID: 34053719 DOI: 10.1016/j.nec.2021.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The natural history of spinal cord injury is in a state of flux. Our knowledge about the prevalence, epidemiology, and natural history spinal cord injury is in evolution. In this article, we summarize these considerations to provide a state-of-the-art synopsis of the neurologic outcomes of this condition.
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Affiliation(s)
- Alexander F Haddad
- Department of Neurological Surgery, University of California, San Francisco, 505 Parnassus Avenue, M779, San Francisco, CA 94143, USA
| | - John F Burke
- Department of Neurological Surgery, University of California, San Francisco, 505 Parnassus Avenue, M779, San Francisco, CA 94143, USA
| | - Sanjay S Dhall
- Department of Neurological Surgery, University of California, San Francisco, 505 Parnassus Avenue, M779, San Francisco, CA 94143, USA.
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40
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Takase H, Hamanaka G, Ohtomo R, Ishikawa H, Chung KK, Mandeville ET, Lok J, Fornage M, Herrup K, Tse KH, Lo EH, Arai K. Transcriptome Profiling of Mouse Corpus Callosum After Cerebral Hypoperfusion. Front Cell Dev Biol 2021; 9:685261. [PMID: 34222254 PMCID: PMC8248229 DOI: 10.3389/fcell.2021.685261] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 05/12/2021] [Indexed: 02/01/2023] Open
Abstract
White matter damage caused by cerebral hypoperfusion is a major hallmark of subcortical ischemic vascular dementia (SIVD), which is the most common subtype of vascular cognitive impairment and dementia (VCID) syndrome. In an aging society, the number of SIVD patients is expected to increase; however, effective therapies have yet to be developed. To understand the pathological mechanisms, we analyzed the profiles of the cells of the corpus callosum after cerebral hypoperfusion in a preclinical SIVD model. We prepared cerebral hypoperfused mice by subjecting 2-month old male C57BL/6J mice to bilateral carotid artery stenosis (BCAS) operation. BCAS-hypoperfusion mice exhibited cognitive deficits at 4 weeks after cerebral hypoperfusion, assessed by novel object recognition test. RNA samples from the corpus callosum region of sham- or BCAS-operated mice were then processed using RNA sequencing. A gene set enrichment analysis using differentially expressed genes between sham and BCAS-operated mice showed activation of oligodendrogenesis pathways along with angiogenic responses. This database of transcriptomic profiles of BCAS-hypoperfusion mice will be useful for future studies to find a therapeutic target for SIVD.
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Affiliation(s)
- Hajime Takase
- Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
| | - Gen Hamanaka
- Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
| | - Ryo Ohtomo
- Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
| | - Hidehiro Ishikawa
- Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
| | - Kelly K Chung
- Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
| | - Emiri T Mandeville
- Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
| | - Josephine Lok
- Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
| | - Myriam Fornage
- Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States.,Human Genetics Center, Division of Epidemiology, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Karl Herrup
- Department of Neurobiology and ADRC, University of Pittsburgh, Pittsburgh, PA, United States
| | - Kai-Hei Tse
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong
| | - Eng H Lo
- Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
| | - Ken Arai
- Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
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Ochiai M, Nguyen HT, Kurihara N, Hirano M, Tajima Y, Yamada TK, Iwata H. Directly Reprogrammed Neurons as a Tool to Assess Neurotoxicity of the Contaminant 4-Hydroxy-2',3,5,5'-tetrachlorobiphenyl (4'OH-CB72) in Melon-Headed Whales. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2021; 55:8159-8168. [PMID: 34061511 DOI: 10.1021/acs.est.1c01074] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Whales accumulate high levels of environmental pollutants. Exposure to polychlorinated biphenyls (PCBs) and their metabolites (OH-PCBs) could be linked to abnormal behavior, which may lead to mass stranding of marine mammals. Whales may thus suffer from adverse effects such as neuronal dysfunction, yet testing the neurotoxicity of these compounds has never been feasible for these species. This study established neurons chemically reprogrammed from fibroblasts of mass stranded melon-headed whales (Peponocephala electra) and used them for in vitro neurotoxicity assays. Exposure to 4-hydroxy-2',3,5,5'-tetrachlorobiphenyl (4'OH-CB72), a metabolite of PCBs, caused apoptosis in the reprogrammed neurons. Transcriptome analysis of 4'OH-CB72-treated whale neurons showed altered expressions of genes associated with oxidative phosphorylation, chromatin degradation, axonal transport, and neurodegenerative diseases. These results suggest that 4'OH-CB72 exposure may induce neurodegeneration through disrupted apoptotic processes. A comparison of the results with human reprogrammed neurons revealed the specific effects on the whale neurons. Our noninvasive approach using fibroblast-derived neurons is useful for hazard and risk assessments of neurotoxicity in whales.
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Affiliation(s)
- Mari Ochiai
- Center for Marine Environmental Studies (CMES), Ehime University, 2-5 Bunkyo-cho, Matsuyama City, Ehime 790-8577, Japan
| | - Hoa Thanh Nguyen
- Center for Marine Environmental Studies (CMES), Ehime University, 2-5 Bunkyo-cho, Matsuyama City, Ehime 790-8577, Japan
| | - Nozomi Kurihara
- Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677-1, Yoshida, Yamaguchi City, Yamaguchi 753-8515, Japan
| | - Masashi Hirano
- Center for Marine Environmental Studies (CMES), Ehime University, 2-5 Bunkyo-cho, Matsuyama City, Ehime 790-8577, Japan
| | - Yuko Tajima
- Division of Vertebrates, Department of Zoology, National Museum of Nature and Science, 4-1-1, Amakubo, Tsukuba, Ibaraki 305-0005, Japan
| | - Tadasu K Yamada
- Division of Vertebrates, Department of Zoology, National Museum of Nature and Science, 4-1-1, Amakubo, Tsukuba, Ibaraki 305-0005, Japan
| | - Hisato Iwata
- Center for Marine Environmental Studies (CMES), Ehime University, 2-5 Bunkyo-cho, Matsuyama City, Ehime 790-8577, Japan
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42
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Zhang J, Boska M, Zheng Y, Liu J, Fox HS, Xiong H. Minocycline attenuation of rat corpus callosum abnormality mediated by low-dose lipopolysaccharide-induced microglia activation. J Neuroinflammation 2021; 18:100. [PMID: 33902641 PMCID: PMC8077939 DOI: 10.1186/s12974-021-02142-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 03/29/2021] [Indexed: 12/11/2022] Open
Abstract
Background Microglia are resident innate immune cells in the brain, and activation of these myeloid cells results in secretion of a variety of pro-inflammatory molecules, leading to the development of neurodegenerative disorders. Lipopolysaccharide (LPS) is a widely used experimental stimulant in microglia activation. We have previously shown that LPS produced microglia activation and evoked detectable functional abnormalities in rat corpus callosum (CC) in vitro. Here, we further validated the effects of low-dose LPS-induced microglia activation and resultant white matter abnormality in the CC in an animal model and examined its attenuation by an anti-inflammatory agent minocycline. Methods Twenty-four SD rats were divided randomly into three groups and intra-peritoneally injected daily with saline, LPS, and LPS + minocycline, respectively. All animals were subject to MRI tests 6 days post-injection. The animals were then sacrificed to harvest the CC tissues for electrophysiology, western blotting, and immunocytochemistry. One-way ANOVA with Tukey’s post-test of all pair of columns was employed statistical analyses. Results Systemic administration of LPS produced microglial activation in the CC as illustrated by Iba-1 immunofluorescent staining. We observed that a large number of Iba-1-positive microglial cells were hyper-ramified with hypertrophic somata or even amoeba like in the LPS-treated animals, and such changes were significantly reduced by co-administration of minocycline. Electrophysiological recordings of axonal compound action potential (CAP) in the brain slices contained the CC revealed an impairment on the CC functionality as detected by a reduction in CAP magnitude. Such an impairment was supported by a reduction of fast axonal transportation evidenced by β-amyloid precursor protein accumulation. These alterations were attenuated by minocycline, demonstrating minocycline reduction of microglia-mediated interruption of white matter integrity and function in the CC. Conclusions Systemic administration of LPS produced microglia activation in the CC and resultant functional abnormalities that were attenuated by an anti-inflammatory agent minocycline.
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Affiliation(s)
- Jingdong Zhang
- Department of Pharmacology & Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA. .,Present Address: Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
| | - Michael Boska
- Department of Radiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Ya Zheng
- Department of Pharmacology & Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.,Present address: Department of Rehabilitation Medicine, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, 200065, China
| | - Jianuo Liu
- Department of Pharmacology & Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Howard S Fox
- Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Huangui Xiong
- Department of Pharmacology & Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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43
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Ammendolia DA, Bement WM, Brumell JH. Plasma membrane integrity: implications for health and disease. BMC Biol 2021; 19:71. [PMID: 33849525 PMCID: PMC8042475 DOI: 10.1186/s12915-021-00972-y] [Citation(s) in RCA: 124] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 02/01/2021] [Indexed: 12/12/2022] Open
Abstract
Plasma membrane integrity is essential for cellular homeostasis. In vivo, cells experience plasma membrane damage from a multitude of stressors in the extra- and intra-cellular environment. To avoid lethal consequences, cells are equipped with repair pathways to restore membrane integrity. Here, we assess plasma membrane damage and repair from a whole-body perspective. We highlight the role of tissue-specific stressors in health and disease and examine membrane repair pathways across diverse cell types. Furthermore, we outline the impact of genetic and environmental factors on plasma membrane integrity and how these contribute to disease pathogenesis in different tissues.
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Affiliation(s)
- Dustin A Ammendolia
- Cell Biology Program, Hospital for Sick Children, 686 Bay Street PGCRL, Toronto, ON, M5G 0A4, Canada.,Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A1, Canada
| | - William M Bement
- Center for Quantitative Cell Imaging and Department of Integrative Biology, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - John H Brumell
- Cell Biology Program, Hospital for Sick Children, 686 Bay Street PGCRL, Toronto, ON, M5G 0A4, Canada. .,Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A1, Canada. .,Institute of Medical Science, University of Toronto, Toronto, ON, M5S 1A1, Canada. .,SickKids IBD Centre, Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada.
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44
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White matter microstructure in women with acute and remitted anorexia nervosa: an exploratory neuroimaging study. Brain Imaging Behav 2021; 14:2429-2437. [PMID: 31605281 DOI: 10.1007/s11682-019-00193-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Anorexia nervosa (AN) is a highly heritable psychiatric disorder characterized by starvation and emaciation and associated with changes in brain structure. The precise nature of these changes remains unclear, as does their developmental time course and capacity for reversal with weight restoration. In this exploratory neuroimaging study, we sought to characterize changes in white matter microstructure in women with acute and remitted AN. Diffusion-weighted MRI data was collected from underweight women with a current diagnosis of AN (acAN: n = 23), weight-recovered women with a past diagnosis of AN (recAN: n = 23), and age-matched healthy control women (HC: n = 24). Image processing and analysis were performed with Tract-Based Spatial Statistics, part of FSL, and group differences in voxelwise, brain-wide fractional anisotropy (FA) and mean diffusivity (MD), indices of white matter microstructure, were tested with nonparametric permutation and threshold-free cluster enhancement. No significant main effect of group on FA was identified. A significant main effect of group on MD was observed in a large cluster covering 9.2% of white matter and including substantial portions of the corpus callosum, corona radiata, internal capsule, and superior longitudinal fasciculus, and post hoc analyses revealed similar effects of group on axial diffusivity (AD) and radial diffusivity (RD). Clusterwise MD was significantly higher in acAN participants (+3.8%) and recAN participants (+2.9%) than healthy controls, and the same was true for clusterwise AD and RD. Trait-based increases in diffusivity, changes in which have been associated with atypical myelination and impaired axon integrity, suggest a link between altered white matter microstructure and vulnerability to AN, and evidence of reduced oligodendrocyte density in AN provides further support for this hypothesis. Potential mechanisms of action include atypical neurodevelopment and systemic inflammation.
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45
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Prokop A. A common theme for axonopathies? The dependency cycle of local axon homeostasis. Cytoskeleton (Hoboken) 2021; 78:52-63. [PMID: 33713552 DOI: 10.1002/cm.21657] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 02/21/2021] [Accepted: 02/23/2021] [Indexed: 12/12/2022]
Abstract
The number of acquired or inherited conditions leading to axon degeneration (from now on referred to as axonopathies) is vast. To diagnose patients, clinicians use a range of indicators including physiology, morphology, family and patient history, as well as genetics, with the specific location of the lesion within the nervous system being a prominent feature. For the neurobiologist, these criteria are often unsatisfactory, and key questions remain unanswered. For example, does it make sense that different axonopathies affect distinct neuron groups through distinct mechanisms? Would it not be more likely that there are common routes to axon degeneration? In this opinion piece, I shall pose this fundamental question and try to find answers that are hopefully thought-provoking and trigger some conceptual rethinking in the field. I will conclude by describing the 'dependency cycle of axon homeostasis' as a new approach to make sense of the intricate connections of axon biology and physiology, also suggesting that different axonopathies might share common paths to axon degeneration.
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Affiliation(s)
- Andreas Prokop
- Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biology, The University of Manchester, Manchester, UK
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46
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Bhargava P, Kim S, Reyes AA, Grenningloh R, Boschert U, Absinta M, Pardo C, Van Zijl P, Zhang J, Calabresi PA. Imaging meningeal inflammation in CNS autoimmunity identifies a therapeutic role for BTK inhibition. Brain 2021; 144:1396-1408. [PMID: 33724342 DOI: 10.1093/brain/awab045] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 11/17/2020] [Accepted: 12/03/2020] [Indexed: 02/06/2023] Open
Abstract
Leptomeningeal inflammation in multiple sclerosis is associated with worse clinical outcomes and greater cortical pathology. Despite progress in identifying this process in multiple sclerosis patients using post-contrast fluid-attenuated inversion recovery imaging, early trials attempting to target meningeal inflammation have been unsuccessful. There is a lack of appropriate model systems to screen potential therapeutic agents targeting meningeal inflammation. We utilized ultra-high field (11.7 T) MRI to perform post-contrast imaging in SJL/J mice with experimental autoimmune encephalomyelitis induced via immunization with proteolipid protein peptide (PLP139-151) and complete Freund's adjuvant. Imaging was performed in both a cross-sectional and longitudinal fashion at time points ranging from 2 to 14 weeks post-immunization. Following imaging, we euthanized animals and collected tissue for pathological evaluation, which revealed dense cellular infiltrates corresponding to areas of contrast enhancement involving the leptomeninges. These areas of meningeal inflammation contained B cells (B220+), T cells (CD3+) and myeloid cells (Mac2+). We also noted features consistent with tertiary lymphoid tissue within these areas, namely the presence of peripheral node addressin-positive structures, C-X-C motif chemokine ligand-13 (CXCL13)-producing cells and FDC-M1+ follicular dendritic cells. In the cortex adjacent to areas of meningeal inflammation we identified astrocytosis, microgliosis, demyelination and evidence of axonal stress/damage. Since areas of meningeal contrast enhancement persisted over several weeks in longitudinal experiments, we utilized this model to test the effects of a therapeutic intervention on established meningeal inflammation. We randomized mice with evidence of meningeal contrast enhancement on MRI scans performed at 6 weeks post-immunization, to treatment with either vehicle or evobrutinib [a Bruton tyrosine kinase (BTK) inhibitor] for a period of 4 weeks. These mice underwent serial imaging; we examined the effect of treatment on the areas of meningeal contrast enhancement and noted a significant reduction in the evobrutinib group compared to vehicle (30% reduction versus 5% increase; P = 0.003). We used ultra-high field MRI to identify areas of meningeal inflammation and to track them over time in SJL/J mice with experimental autoimmune encephalomyelitis, and then used this model to identify BTK inhibition as a novel therapeutic approach to target meningeal inflammation. The results of this study provide support for future studies in multiple sclerosis patients with imaging evidence of meningeal inflammation.
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Affiliation(s)
- Pavan Bhargava
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Sol Kim
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Arthur A Reyes
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | | | - Martina Absinta
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Carlos Pardo
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Peter Van Zijl
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA
| | - Jiangyang Zhang
- Department of Radiology, New York University, New York, NY, USA
| | - Peter A Calabresi
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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47
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Lin TH, Zhan J, Song C, Wallendorf M, Sun P, Niu X, Yang R, Cross AH, Song SK. Diffusion Basis Spectrum Imaging Detects Axonal Loss After Transient Dexamethasone Treatment in Optic Neuritis Mice. Front Neurosci 2021; 14:592063. [PMID: 33551721 PMCID: PMC7862582 DOI: 10.3389/fnins.2020.592063] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 12/28/2020] [Indexed: 11/24/2022] Open
Abstract
Optic neuritis is a frequent first symptom of multiple sclerosis (MS) for which corticosteroids are a widely employed treatment option. The Optic Neuritis Treatment Trial (ONTT) reported that corticosteroid treatment does not improve long-term visual acuity, although the evolution of underlying pathologies is unclear. In this study, we employed non-invasive diffusion basis spectrum imaging (DBSI)-derived fiber volume to quantify 11% axonal loss 2 months after corticosteroid treatment (vs. baseline) in experimental autoimmune encephalomyelitis mouse optic nerves affected by optic neuritis. Longitudinal DBSI was performed at baseline (before immunization), after a 2-week corticosteroid treatment period, and 1 and 2 months after treatment, followed by histological validation of neuropathology. Pathological metrics employed to assess the optic nerve revealed axonal protection and anti-inflammatory effects of dexamethasone treatment that were transient. Two months after treatment, axonal injury and loss were indistinguishable between PBS- and dexamethasone-treated optic nerves, similar to results of the human ONTT. Our findings in mice further support that corticosteroid treatment alone is not sufficient to prevent eventual axonal loss in ON, and strongly support the potential of DBSI as an in vivo imaging outcome measure to assess optic nerve pathology.
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Affiliation(s)
- Tsen-Hsuan Lin
- Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
| | - Jie Zhan
- Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States.,Department of Radiology, The First Affiliated Hospital, Nanchang University, Jiangxi, China
| | - Chunyu Song
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
| | - Michael Wallendorf
- Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
| | - Peng Sun
- Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
| | - Xuan Niu
- Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
| | - Ruimeng Yang
- Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States.,Department of Radiology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Anne H Cross
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States.,Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
| | - Sheng-Kwei Song
- Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States.,Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States.,Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
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48
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Datta D, Conroy AL, Castelluccio PF, Ssenkusu JM, Park GS, Opoka RO, Bangirana P, Idro R, Saykin AJ, John CC. Elevated Cerebrospinal Fluid Tau Protein Concentrations on Admission Are Associated With Long-term Neurologic and Cognitive Impairment in Ugandan Children With Cerebral Malaria. Clin Infect Dis 2021; 70:1161-1168. [PMID: 31044219 DOI: 10.1093/cid/ciz325] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 04/18/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Elevated concentrations of cerebrospinal fluid (CSF) tau, a marker of axonal injury, have been associated with coma in severe malaria (cerebral malaria [CM]). However, it is unknown whether axonal injury is related to long-term neurologic deficits and cognitive impairment in children with CM. METHODS Admission CSF tau concentrations were measured in 145 Ugandan children with CM and compared to clinical and laboratory factors and acute and chronic neurologic and cognitive outcomes. RESULTS Elevated CSF tau concentrations were associated with younger age, increased disease severity (lower glucose and hemoglobin concentrations, malaria retinopathy, acute kidney injury, and prolonged coma duration, all P < .05), and an increased CSF:plasma albumin ratio, a marker of blood-brain barrier breakdown (P < .001). Admission CSF tau concentrations were associated with the presence of neurologic deficits at hospital discharge, and at 6, 12, and 24 months postdischarge (all P ≤ .02). After adjustment for potential confounding factors, elevated log10-transformed CSF tau concentrations correlated with worse cognitive outcome z scores over 2-year follow-up for associative memory (β coefficient, -0.31 [95% confidence interval [CI], -.53 to -.10]) in children <5 years of age, and for overall cognition (-0.69 [95% CI, -1.19 to -.21]), attention (-0.78 [95% CI, -1.34 to -.23]), and working memory (-1.0 [95% CI, -1.68 to -.31]) in children ≥5 years of age (all P < .006). CONCLUSIONS Acute axonal injury in children with CM is associated with long-term neurologic deficits and cognitive impairment. CSF tau concentrations at the time of the CM episode may identify children at high risk of long-term neurocognitive impairment.
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Affiliation(s)
- Dibyadyuti Datta
- Department of Pediatrics, Ryan White Center for Pediatric Infectious Disease and Global Health, Indianapolis
| | - Andrea L Conroy
- Department of Pediatrics, Ryan White Center for Pediatric Infectious Disease and Global Health, Indianapolis
| | - Peter F Castelluccio
- Department of Biostatistics, Indiana University School of Medicine, Indianapolis
| | - John M Ssenkusu
- Department of Epidemiology and Biostatistics, Makerere University, Kampala, Uganda
| | | | - Robert O Opoka
- Departments of Paediatrics and Child Health, Kampala, Uganda
| | - Paul Bangirana
- Departments of Psychiatry, Makerere University, Kampala, Uganda
| | - Richard Idro
- Departments of Paediatrics and Child Health, Kampala, Uganda
| | - Andrew J Saykin
- Indiana Alzheimer Disease Center and Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis
| | - Chandy C John
- Department of Pediatrics, Ryan White Center for Pediatric Infectious Disease and Global Health, Indianapolis.,University of Minnesota Medical School, Minneapolis
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49
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Qian W, Khattar N, Cortina LE, Spencer RG, Bouhrara M. Nonlinear associations of neurite density and myelin content with age revealed using multicomponent diffusion and relaxometry magnetic resonance imaging. Neuroimage 2020; 223:117369. [PMID: 32931942 PMCID: PMC7775614 DOI: 10.1016/j.neuroimage.2020.117369] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 09/07/2020] [Accepted: 09/08/2020] [Indexed: 12/18/2022] Open
Abstract
Most magnetic resonance imaging (MRI) studies investigating the relationship between regional brain myelination or axonal density and aging have relied upon nonspecific methods to probe myelin and axonal content, including diffusion tensor imaging and relaxation time mapping. While these studies have provided pivotal insights into changes in cerebral architecture with aging and pathology, details of the underlying microstructural alterations have not been fully elucidated. In the current study, we used the BMC-mcDESPOT analysis, a direct and specific multicomponent relaxometry method for imaging of myelin water fraction (MWF), a marker of myelin content, and NODDI, an emerging multicomponent diffusion technique, for neurite density index (NDI) imaging, a proxy of axonal density. We investigated age-related differences in MWF and NDI in several white matter brain regions in a cohort of cognitively unimpaired participants over a wide age range. Our results indicate a quadratic, inverted U-shape, relationship between MWF and age in all brain regions investigated, suggesting that myelination continues until middle age followed by a decrease at older ages, in agreement with previous work. We found a similarly complex regional association between NDI and age, with several cerebral structures also exhibiting a quadratic, inverted U-shape, relationship. This novel observation suggests an increase in axonal density until the fourth decade of age followed by a rapid loss at older ages. We also observed that these age-related differences in MWF and NDI vary across different brain regions, as expected. Finally, our study indicates no significant association between MWF and NDI in most cerebral structures investigated, although this association approached significance in a limited number of brain regions, indicating the complementary nature of their information and encouraging further investigation. Overall, we find evidence of nonlinear associations between age and myelin or axonal density in a sample of well-characterized adults, using direct myelin and axonal content imaging methods.
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Affiliation(s)
- Wenshu Qian
- Magnetic Resonance Physics of Aging and Dementia Unit, Laboratory of Clinical Investigations, National Institute on Aging, National Institutes of Health, NIA, NIH, 251 Bayview Blvd., Baltimore, MD 21224, USA
| | - Nikkita Khattar
- Magnetic Resonance Physics of Aging and Dementia Unit, Laboratory of Clinical Investigations, National Institute on Aging, National Institutes of Health, NIA, NIH, 251 Bayview Blvd., Baltimore, MD 21224, USA
| | - Luis E Cortina
- Magnetic Resonance Physics of Aging and Dementia Unit, Laboratory of Clinical Investigations, National Institute on Aging, National Institutes of Health, NIA, NIH, 251 Bayview Blvd., Baltimore, MD 21224, USA
| | - Richard G Spencer
- Magnetic Resonance Physics of Aging and Dementia Unit, Laboratory of Clinical Investigations, National Institute on Aging, National Institutes of Health, NIA, NIH, 251 Bayview Blvd., Baltimore, MD 21224, USA
| | - Mustapha Bouhrara
- Magnetic Resonance Physics of Aging and Dementia Unit, Laboratory of Clinical Investigations, National Institute on Aging, National Institutes of Health, NIA, NIH, 251 Bayview Blvd., Baltimore, MD 21224, USA.
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50
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Gaetani L, Paolini Paoletti F, Bellomo G, Mancini A, Simoni S, Di Filippo M, Parnetti L. CSF and Blood Biomarkers in Neuroinflammatory and Neurodegenerative Diseases: Implications for Treatment. Trends Pharmacol Sci 2020; 41:1023-1037. [PMID: 33127098 DOI: 10.1016/j.tips.2020.09.011] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 09/25/2020] [Accepted: 09/30/2020] [Indexed: 12/11/2022]
Abstract
Neuroinflammatory and neurodegenerative diseases are characterized by the interplay of a number of molecular pathways that can be assessed through biofluids, especially cerebrospinal fluid and blood. Accordingly, the definition and classification of these disorders will move from clinical and pathological to biological criteria. The consequences of this biomarker-based diagnostic and prognostic approach are highly relevant to the field of drug development. Indeed, in view of the availability of disease-modifying drugs, fluid biomarkers offer a unique opportunity for improving the quality and applicability of results from clinical trials. Herein, we discuss the benefits of using fluid biomarkers for patient stratification, target engagement, and outcome assessment, as well as the most recent developments in neuroinflammatory and neurodegenerative diseases.
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Affiliation(s)
- Lorenzo Gaetani
- Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy
| | | | - Giovanni Bellomo
- Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy
| | - Andrea Mancini
- Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy
| | - Simone Simoni
- Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy
| | | | - Lucilla Parnetti
- Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy.
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