Electron Microscopic Features of Multiple Sclerosis Lesions

Périer, O; Grégoire, Anne

doi:10.1093/brain/88.5.937

Cited by 192 publications

(81 citation statements)

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“…5 Despite the presence of oligodendrocyte precursors in multiple sclerosis lesions, [6][7][8] remyelination is generally unsuccessful-and at best partial-after demyelinating injury in multiple sclerosis. 9,10 Current treatments for multiple sclerosis block access of immune cells to their target tissue or otherwise suppress inflammatory injury, but do not fully prevent neuroaxonal degeneration and disability. 11,12 No proven treatments are available to remyelinate or otherwise sustainably repair myelin-related injury.…”

Section: Introductionmentioning

confidence: 99%

Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial

et al. 2017

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Section: Introductionmentioning

confidence: 99%

Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial

et al. 2017

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“…The interest in neuronal pathology has arisen in part because some magnetic resonance imaging (MRI) parameters of inflammatory demyelination have only modestly correlated with clinical parameters in many studies (1)(2)(3)(4)(5)(6)(7)(8)(9). Investigators have long recognized that axonal loss can occur in MS lesions, although the extent of reported losses has been variable (10)(11)(12)(13)(14)(15)(16). Axonal injury, as identified by intra-axonal accumulations of amyloid precursor protein (17) or by axonal ovoids (18), appears to occur mostly in acute lesions where inflammatory cells are present, although axonal ovoids can also be found in the core of chronic lesions where inflammatory cells are largely absent (18).…”

Section: Introductionmentioning

confidence: 99%

Extensive Injury of Descending Neurons Demonstrated by Retrograde Labeling in a Virus-Induced Murine Model of Chronic Inflammatory Demyelination

Ure¹,

Rodriguez²

2000

J Neuropathol Exp Neurol

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Abstract. Persistent Theiler's virus infection of SJL/J mice was used as a model to quantitatively assess the extent of descending neuron injury by chronic inflammatory demyelination of the spinal cord. By 9 months postinfection, inflammatory demyelinating lesions were present throughout the spinal cord, affecting up to 31% of the cross-sectional area of the ventrolateral columns. Axon dropout was evident in the lesions by electron microscopy and by quantitation of axons in normalappearing white matter. Axon number in the ventrolateral columns at L1/L2 was reduced by 23% and total axon area was reduced by 37%, compared with uninfected mice. The most informative data on descending neuron injury, however, was a reduction in retrograde, Fluoro-Gold labeling. Labeling from T11/T12 of rubrospinal, reticulospinal/raphespinal, and vestibulospinal neurons was reduced by 60%, 70%, and 93%, respectively. Retrograde responses to axonal injury were observed, consisting of atrophied cell bodies, indented nuclei, and abundant lipofuscin, but cell body dropout was minimal. The number of cell bodies of vestibulospinal neurons was reduced by only 35%, whereas the number of cell bodies of rubrospinal neurons was unchanged. These results demonstrate that chronic inflammatory demyelination can severely injure axons and emphasize the need to design neuroprotective therapies in human multiple sclerosis.

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“…Remyelination results in the formation of short and thin myelinated internodes, but it enables the restoration of a sufficient conduction along axons and allows some functional recovery (4,5). In demyelinating diseases such as MS, this regenerative process does occur and sometimes proceeds to completion (6), but it is less efficient than in experimental animal models (7). Improving repair processes can theoretically be achieved by either promoting endogenous repair mechanisms or providing an exogenous source of myelinating cells by transplantation (8)(9)(10).…”

mentioning

confidence: 99%

Imaging of CNS myelin by positron-emission tomography

Stankoff

Wang

Bottlaender³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

141

150

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Promoting myelin repair is one of the most promising therapeutic avenues in the field of myelin disorders. In future clinical trials, evaluation of remyelination will require a reliable and quantifiable myelin marker to be used as a surrogate marker. To date, MRI assessment lacks specificity for evaluating the level of remyelination within the brain. Here, we describe 1,4-bis(p-aminostyryl)-2-methoxy benzene (BMB), a synthesized fluorescent molecule, that binds selectively to myelin both ex vivo and in vivo. The binding of BMB to myelin allows the detection of demyelinating lesions in an experimental autoimmune encephalitis model of demyelination and allows a mean for quantifying myelin loss in dysmyelinating mutants. In multiple sclerosis brain, different levels of BMB binding differentiated remyelination in shadow plaques from either demyelinated lesions or normal-appearing white matter. After systemic injection, BMB crosses the blood-brain barrier and binds to myelin in a dose-dependent and reversible manner. Finally, we provide evidence that 11 C-radiolabeled BMB can be used in vivo to image CNS myelin by positron-emission tomography in baboon. Our results provide a perspective for developing a brain myelin imaging technique by positron-emission tomography.multiple sclerosis ͉ remyelination ͉ leukodystrophy M yelin is a unique structure in the nervous system that allows rapid, economic, and secure conduction of impulses along axons. The loss or lack of myelin resulting from an acquired or inherited disease may produce a delay or failure of conduction in affected fibers, with concomitant neurological dysfunction. In the human CNS, multiple sclerosis (MS) is the most common acquired demyelinating disease, affecting Ϸ2 million people worldwide (1). The leukodystrophies, induced by inherited enzyme deficiencies, also affect CNS white matter, resulting in abnormal formation, destruction, or turnover of myelin sheaths (2). Both acquired and inherited myelin disorders share a poor prognosis, leading to major disability in young people.Spontaneous remyelination can occur in the CNS and was first demonstrated by electron microscopy of lesions in the adult mammalian spinal cord (3). Remyelination results in the formation of short and thin myelinated internodes, but it enables the restoration of a sufficient conduction along axons and allows some functional recovery (4, 5). In demyelinating diseases such as MS, this regenerative process does occur and sometimes proceeds to completion (6), but it is less efficient than in experimental animal models (7). Improving repair processes can theoretically be achieved by either promoting endogenous repair mechanisms or providing an exogenous source of myelinating cells by transplantation (8-10). Clinical trials are expected to be carried out in the latter field soon.A major clinical issue of such trials is to assess and quantify myelin repair in vivo. To date, MRI is the reference test for diagnosing and monitoring the evolution of white-matter diseases (2, 11, 12). Unfortunatel...

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Electron Microscopic Features of Multiple Sclerosis Lesions

Cited by 192 publications

References 0 publications

Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial

Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial

Extensive Injury of Descending Neurons Demonstrated by Retrograde Labeling in a Virus-Induced Murine Model of Chronic Inflammatory Demyelination

Imaging of CNS myelin by positron-emission tomography

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