Overexpression of sphingosine-1-phosphate receptors on reactive astrocytes drives neuropathology of multiple sclerosis rebound after fingolimod discontinuation

2018 ◽  
Vol 24 (8) ◽  
pp. 1133-1137 ◽  
Author(s):  
Maria Teresa Giordana ◽  
Paola Cavalla ◽  
Antonio Uccelli ◽  
Alice Laroni ◽  
Fabio Bandini ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Disease Activity ◽  
Multiple Sclerosis Patient ◽  
Fatal Outcome ◽  
Reactive Astrocytes ◽  
Normal Appearing White Matter ◽  
Sphingosine 1 Phosphate ◽  
Demyelinating Lesions

We present the neuropathological description of an autoptic case of fatal rebound of disease activity after fingolimod discontinuation in a multiple sclerosis patient. MRI prior to the fatal outcome showed several large tumefactive demyelinating lesions. These lesions were characterized by prominent astrocytic gliosis, with a remarkable preponderance of large hypertrophic reactive astrocytes showing intense expression of sphingosine-1-phosphate receptor 1. Prominent astrocytic gliosis was also diffusely observed in the normal-appearing white matter. Dysregulated sphingosine-1-phosphate signaling on astrocytes following fingolimod withdrawal might represent a possible contributing mechanism to disease rebound and might account for the unusual radiological and neuropathological features observed in the present case.

scholarly journals Hypoperfusion of the Cerebral White Matter in Multiple Sclerosis: Possible Mechanisms and Pathophysiological Significance

2008 ◽  
Vol 28 (10) ◽  
pp. 1645-1651 ◽  
Author(s):  
Jacques De Keyser ◽  
Christel Steen ◽  
Jop P Mostert ◽  
Marcus W Koch
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Adrenergic Receptors ◽  
Perfusion Magnetic Resonance Imaging ◽  
Cerebral White Matter ◽  
Perivascular Spaces ◽  
Axonal Loss ◽  
Normal Appearing White Matter ◽  
Demyelinating Lesions ◽  
The Central Nervous System

Multiple sclerosis (MS) is a disease of the central nervous system characterized by patchy areas of demyelination, inflammation, axonal loss and gliosis, and a diffuse axonal degeneration throughout the so-called normal-appearing white matter (NAWM). A number of recent studies using perfusion magnetic resonance imaging in both relapsing and progressive forms of MS have shown a decreased perfusion of the NAWM, which does not appear to be secondary to axonal loss. The reduced perfusion of the NAWM in MS might be caused by a widespread astrocyte dysfunction, possibly related to a deficiency in astrocytic β2-adrenergic receptors and a reduced formation of cAMP, resulting in a reduced uptake of K+ at the nodes of Ranvier and a reduced release of K+ in the perivascular spaces. Pathologic and imaging studies suggest that ischemic changes might be involved in the development of a subtype of focal demyelinating lesions (type III lesions), and there appears to exist a relationship between decreased white matter perfusion and cognitive dysfunction in patients with MS.

Multi-parametric quantitative MRI of normal appearing white matter in multiple sclerosis, and the effect of disease activity on T2

2016 ◽  
Vol 11 (3) ◽  
pp. 744-753 ◽  
Author(s):  
Sarah C. Reitz ◽  
Stephanie-Michelle Hof ◽  
Vinzenz Fleischer ◽  
Alla Brodski ◽  
Adriane Gröger ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Disease Activity ◽  
Quantitative Mri ◽  
Normal Appearing White Matter

NODDI discloses early changes in the normal appearing white matter in paediatric multiple sclerosis

2021 ◽  
Vol 429 ◽  
pp. 118881
Author(s):  
Monica Margoni ◽  
Umberto Villani ◽  
Silvia Franciotta ◽  
Martina Rubin ◽  
Margherita Nosadini ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Normal Appearing White Matter ◽  
Paediatric Multiple Sclerosis

scholarly journals A higher proportion of ermin-immunopositive oligodendrocytes in areas of remyelination

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256155
Author(s):  
Intakhar Ahmad ◽  
Stig Wergeland ◽  
Eystein Oveland ◽  
Lars Bø
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Corpus Callosum ◽  
Mouse Model ◽  
Grey Matter ◽  
Early Stage ◽  
Relative Proportion ◽  
Normal Appearing White Matter ◽  
The Brain

Incomplete remyelination is frequent in multiple sclerosis (MS)-lesions, but there is no established marker for recent remyelination. We investigated the role of the oligodendrocyte/myelin protein ermin in de- and remyelination in the cuprizone (CPZ) mouse model, and in MS. The density of ermin+ oligodendrocytes in the brain was significantly decreased after one week of CPZ exposure (p < 0.02). The relative proportion of ermin+ cells compared to cells positive for the late-stage oligodendrocyte marker Nogo-A increased at the onset of remyelination in the corpus callosum (p < 0.02). The density of ermin-positive cells increased in the corpus callosum during the CPZ-phase of extensive remyelination (p < 0.0001). In MS, the density of ermin+ cells was higher in remyelinated lesion areas compared to non-remyelinated areas both in white- (p < 0.0001) and grey matter (p < 0.0001) and compared to normal-appearing white matter (p < 0.001). Ermin immunopositive cells in MS-lesions were not immunopositive for the early-stage oligodendrocyte markers O4 and O1, but a subpopulation was immunopositive for Nogo-A. The data suggest a relatively higher proportion of ermin immunopositivity in oligodendrocytes compared to Nogo-A indicates recent or ongoing remyelination.

Normal-appearing white matter changes in multiple sclerosis: the contribution of magnetic resonance techniques

1999 ◽  
Vol 5 (4) ◽  
pp. 273-282 ◽  
Author(s):  
Massimo Filippi ◽  
Carla Tortorella ◽  
Marco Bozzali
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Magnetic Resonance ◽  
Clinical Manifestations ◽  
Present Knowledge ◽  
Pathological Changes ◽  
White Matter Changes ◽  
Disease Evolution ◽  
Normal Appearing White Matter ◽  
Neurological Conditions

Several magnetic resonance (MR) techniques have proved to be sensitive enough to detect the subtle pathological changes that post-mortem studies showed to occur in the normal-appearing white matter (NAWM) from patients with multiple sclerosis (MS). Although these abnormalities can be detected in other neurological conditions, they seem to be more frequent and diffuse in MS. However, the contribution of NAWM changes to the diagnosis is still unclear. Their nature is also unknown and perhaps differs in different phases and clinical manifestations of the disease. Nevertheless, the extent and severity of NAWM damage seems to be relevant in causing disability and influencing the clinical evolution in MS patients. This review will summarize the present knowledge about MR-detected NAWM changes in MS and their relevance to the diagnosis and the understanding of disease evolution.

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