Imaging of axonal damage in vivo in Rasmussen's syndrome

Brain ◽  
1995 ◽  
Vol 118 (3) ◽  
pp. 753-758 ◽  
Author(s):  
Fernando Cendes ◽  
Frederick Andermann ◽  
Kenneth Silver ◽  
Douglas L. Arnold
Keyword(s):  
Axonal Damage ◽  
Rasmussen’S Syndrome

scholarly journals Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis

2019 ◽  
Vol 116 (20) ◽  
pp. 10130-10139 ◽  
Author(s):  
Rhonda R. Voskuhl ◽  
Noriko Itoh ◽  
Alessia Tassoni ◽  
Macy Akiyo Matsukawa ◽  
Emily Ren ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Sclerosis ◽  
Corpus Callosum ◽  
Regional Differences ◽  
Cholesterol Synthesis ◽  
Brain Regions ◽  
Axonal Damage ◽  
Cholesterol Homeostasis ◽  
Sequencing Analysis

Regional differences in neurons, astrocytes, oligodendrocytes, and microglia exist in the brain during health, and regional differences in the transcriptome may occur for each cell type during neurodegeneration. Multiple sclerosis (MS) is multifocal, and regional differences in the astrocyte transcriptome occur in experimental autoimmune encephalomyelitis (EAE), an MS model. MS and EAE are characterized by inflammation, demyelination, and axonal damage, with minimal remyelination. Here, RNA-sequencing analysis of MS tissues from six brain regions suggested a focus on oligodendrocyte lineage cells (OLCs) in corpus callosum. Olig1-RiboTag mice were used to determine the translatome of OLCs in vivo in corpus callosum during the remyelination phase of a chronic cuprizone model with axonal damage. Cholesterol-synthesis gene pathways dominated as the top up-regulated pathways in OLCs during remyelination. In EAE, remyelination was induced with estrogen receptor-β (ERβ) ligand treatment, and up-regulation of cholesterol-synthesis gene expression was again observed in OLCs. ERβ-ligand treatment in the cuprizone model further increased cholesterol synthesis gene expression and enhanced remyelination. Conditional KOs of ERβ in OLCs demonstrated that increased cholesterol-synthesis gene expression in OLCs was mediated by direct effects in both models. To address this direct effect, ChIP assays showed binding of ERβ to the putative estrogen-response element of a key cholesterol-synthesis gene (Fdps). As fetal OLCs are exposed in utero to high levels of estrogens in maternal blood, we discuss how remyelinating properties of estrogen treatment in adults during injury may recapitulate normal developmental myelination through targeting cholesterol homeostasis in OLCs.

The role of mitochondria in axonal degeneration and tissue repair in MS

2012 ◽  
Vol 18 (8) ◽  
pp. 1058-1067 ◽  
Author(s):  
J van Horssen ◽  
ME Witte ◽  
O Ciccarelli
Keyword(s):  
Mitochondrial Dysfunction ◽  
Tissue Repair ◽  
Molecular Mechanisms ◽  
Axonal Degeneration ◽  
Axonal Damage ◽  
Mitochondrial Metabolism ◽  
Imaging Studies ◽  
And Function

Axonal injury is a key feature of multiple sclerosis (MS) pathology and is currently seen as the main correlate for permanent clinical disability. Although little is known about the pathogenetic mechanisms that drive axonal damage and loss, there is accumulating evidence highlighting the central role of mitochondrial dysfunction in axonal degeneration and associated neurodegeneration. The aim of this topical review is to provide a concise overview on the involvement of mitochondrial dysfunction in axonal damage and destruction in MS. Hereto, we will discuss putative pathological mechanisms leading to mitochondrial dysfunction and recent imaging studies performed in vivo in patients with MS. Moreover, we will focus on molecular mechanisms and novel imaging studies that address the role of mitochondrial metabolism in tissue repair. Finally, we will briefly review therapeutic strategies aimed at improving mitochondrial metabolism and function under neuroinflammatory conditions.

In-vivo evidence for stable neuroaxonal damage in the brain of patients with benign multiple sclerosis

2009 ◽  
Vol 15 (7) ◽  
pp. 789-794 ◽  
Author(s):  
B Benedetti ◽  
M Rovaris ◽  
MA Rocca ◽  
D Caputo ◽  
M Zaffaroni ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Duration ◽  
Axonal Damage ◽  
Lesion Volume ◽  
Hyperintense Lesion ◽  
Disease Evolution ◽  
Clinical Onset ◽  
Relapsing Remitting ◽  
Benign Multiple Sclerosis

Objective The term benign multiple sclerosis (BMS) is referred to patients who have a mild or absent disability several years after disease clinical onset. Axonal damage can be measured in vivo using proton MR spectroscopy (1H-MRS). In this study, we quantified the severity of “global” axonal damage in BMS and early relapsing–remitting (RR) MS patients, using whole brain N-acetylaspartate (WBNAA) 1H-MRS, to better elucidate the structural correlates of a non-disabling disease evolution. Methods WBNAA concentration was measured in 37 patients with BMS (mean disease duration 22.3 years) and 17 patients with early RRMS (mean disease duration 4.0 years), using an unlocalized 1H-MRS sequence. Dual echo and T1-weighted scans were also obtained to measure T2-hyperintense lesion volume (TLV) and normalized brain volume (NBV). Results TLV was higher in BMS (mean TLV = 13.1 mL) than in early RRMS patients (mean TLV = 7.2 mL) ( P = 0.018), whereas neither NBV (mean NBV: 1491.0 mL in BMS vs 1520.3 mL in RRMS) nor WBNAA concentration (mean WBNAA: 10.5 mmol in BMS vs 11.4 mmol in RRMS) significantly differed between the two groups. In MS patients, no correlation was found between WBNAA concentration and Expanded Disability Status Scale (EDSS), TLV and NBV. Conclusions The similar WBNAA concentrations seen in BMS and early RRMS patients fit with the notion that a non-disabling long-term evolution of MS may be due, at least in part, to non-progression of pathology. Such a condition seems to be independent from MRI-visible lesions burden.

Laquinimod prevents inflammation-induced synaptic alterations occurring in experimental autoimmune encephalomyelitis

2012 ◽  
Vol 19 (8) ◽  
pp. 1084-1094 ◽  
Author(s):  
Francesca Ruffini ◽  
Silvia Rossi ◽  
Andrea Bergamaschi ◽  
Elena Brambilla ◽  
Annamaria Finardi ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Neuronal Damage ◽  
Axonal Damage ◽  
Autoimmune Encephalomyelitis ◽  
Synaptic Currents ◽  
Striatal Slices ◽  
Gabaergic Synapses ◽  
Patch Clamp Electrophysiology ◽  
Experimental Autoimmune

Background There are two generally accepted strategies for treating multiple sclerosis (MS), preventing central nervous system (CNS) damage indirectly through immunomodulatory interventions and/or repairing CNS damage by promoting remyelination. Both approaches also provide neuroprotection since they can prevent, indirectly or directly, axonal damage. Objective Recent experimental and clinical evidence indicates that the novel immunomodulatory drug laquinimod can exert a neuroprotective role in MS. Whether laquinimod-mediated neuroprotection is exerted directly on neuronal cells or indirectly via peripheral immunomodulation is still unclear. Methods C57Bl/6 experimental autoimmune encephalomyelitis (EAE) mice, immunised with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide, were treated for 26 days with subcutaneous daily injections of laquinimod (from 1 to 25 mg/kg). Patch clamp electrophysiology was performed on acute brain striatal slices from EAE mice treated with daily (25 mg/kg) laquinimod and on acute brain striatal slices from control mice bathed with laquinimod (1–30 µM). Results Both preventive and therapeutic laquinimod treatment fully prevented the alterations of GABAergic synapses induced by EAE, the first limiting also glutamatergic synaptic alterations. This dual effect might, in turn, have limited glutamatergic excitotoxicity, a phenomenon previously observed early during EAE and possibly correlated with later axonal damage. Furthermore, laquinimod treatment also preserved cannabinoid CB1 receptor sensitivity, normally lost during EAE. Finally, laquinimod per se was able to regulate synaptic transmission by increasing inhibitory post-synaptic currents and, at the same time, reducing excitatory post-synaptic currents. Conclusions Our data suggest a novel neuroprotective mechanism by which laquinimod might in vivo protect from neuronal damage occurring as a consequence of inflammatory immune-mediated demyelination.

Intracerebral injection of AMPA causes axonal damage in vivo

2003 ◽  
Vol 991 (1-2) ◽  
pp. 104-112 ◽  
Author(s):  
Jill H. Fowler ◽  
Eileen McCracken ◽  
Deborah Dewar ◽  
James McCulloch
Keyword(s):  
Axonal Damage ◽  
Intracerebral Injection

scholarly journals Chronic White Matter Inflammation and Serum Neurofilament Levels in Multiple Sclerosis

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012326
Author(s):  
Pietro Maggi ◽  
Jens Kuhle ◽  
Sabine Schädelin ◽  
Franziska van der Meer ◽  
Matthias Weigel ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Disease Severity ◽  
Multivariable Analysis ◽  
Axonal Damage ◽  
Lesion Load ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Center Edge

ObjectiveTo assess whether chronic white matter inflammation in multiple sclerosis (MS) patients - as detected in-vivo by paramagnetic rim MRI lesions (PRL) - is associated with higher serum neurofilament light chain (sNfL) levels, a marker of neuro-axonal damage.MethodsIn 118 MS patients with no gadolinium-enhancing lesions or recent relapses, we analyzed 3D-submillimeter phase MRI and sNfL levels. Histopathological evaluation was performed in 25 MS lesions from 20 additional autopsy MS patients.ResultsIn univariable analyses, participants with ≥2 PRL (“PRL ≥2”, n=43) compared to those with ≤1 PRL (“PRL 0–1,” n=75) had higher age-adjusted sNfL percentiles (median, 91 and 68; p<0.001) and higher MS disease severity scale (MSSS median, 4.3 and 2.4; p=0.003). In multivariable analyses, sNfL percentile levels were higher in PRL ≥2 cases (βadd: 16.3; 95% CI: 4.6–28.0; p<0.01), whereas disease-modifying treatment (DMT), EDSS, and T2 lesion load did not affect sNfL. In a similar model, sNfL percentile levels were highest in cases with ≥4 PRL (n=30; βadd: 30.4; 95% CI, 15.6–45.2; p<0.01). Subsequent multivariable analysis revealed that PRL ≥2 cases had also higher MSSS (βadd: 1.1; 95% CI, 0.3–1.9; p<0.01), whereas MSSS was not affected by DMT or T2 lesion load. On histopathology, both chronic active and smoldering lesions exhibited more severe acute axonal damage at the lesion edge than in the lesion center (edge vs center: p=0.004 and p=0.0002, respectively).InterpretationChronic white matter inflammation was associated with increased levels of sNfL and disease severity in non-acute MS patients, suggesting that PRL contribute to clinically relevant, inflammation-driven neurodegeneration.

scholarly journals Focal and diffuse cortical degenerative changes in a marmoset model of multiple sclerosis

2010 ◽  
Vol 16 (5) ◽  
pp. 537-548 ◽  
Author(s):  
IM Pomeroy ◽  
EK Jordan ◽  
JA Frank ◽  
PM Matthews ◽  
MM Esiri
Keyword(s):  
Multiple Sclerosis ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Grey Matter ◽  
Neuronal Loss ◽  
Axonal Damage ◽  
Inflammatory Factors ◽  
Focal Lesions ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Background: Degenerative features, such as neuronal, glial, synaptic and axonal loss, have been identified in neocortical and other grey matter structures in patients with multiple sclerosis, but mechanisms for neurodegeneration are unclear. Cortical demyelinating lesions are a potential cause of this degeneration, but the pathological and clinical significance of these lesions is uncertain as they remain difficult to identify and study in vivo. In this study we aimed to describe and quantify cellular and subcellular pathology in the cortex of myelin oligodendrocyte glycoprotein-induced marmoset experimental autoimmune encephalomyelitis using quantitative immunohistochemical methods. Results: We found evidence of diffuse axonal damage occurring throughout cortical grey matter with evidence for synaptic loss and gliosis and a 13.6% decrease in neuronal size and occurring in deep cortical layers. Evidence of additional axonal damage and a 29.6—36.5% loss of oligodendrocytes was found in demyelinated cortical lesions. Leucocortical lesions also showed neuronal loss of 22.2% and a 15.8% increase in oligodendrocyte size. Conclusions: The marmoset experimental autoimmune encephalomyelitis model, therefore, shows both focal and generalized neurodegeneration. The generalized changes cannot be directly related to focal lesions, suggesting that they are either a consequence of diffusible inflammatory factors or secondary to remote lesions acting through trans-synaptic or retrograde degeneration.

Sign in / Sign up

Export Citation Format

Share Document