Evidence of Axonal Damage in the Early Stages of Multiple Sclerosis and Its Relevance to Disability

Stefano, Nicola De; Narayanan, Sridar; Francis, Gordon; Arnaoutelis, Rozie; Tartaglia, Maria Carmela; Antel, Jack P.; Matthews, Paul M.; Arnold, Douglas L.

doi:10.1001/archneur.58.1.65

Cited by 464 publications

(301 citation statements)

References 52 publications

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“…Remyelination becomes less efficient in the later stage of MS in part due to a failure of OPC differentiation (Franklin and ffrench‐Constant, 2008; Kuhlmann et al, 2008; Wolswijk, 1998). Failure of remyelination is a major contributor to the accumulation of axonal and neuronal degeneration that characterizes the progressive stage of the disease in which clinical deficits accumulate over time (Bjartmar et al, 2000; De Stefano et al, 2001). The axonal degeneration observed after toxin‐induced demyelination in mice depleted of OPCs is prevented by the transplantation of exogenous OPCs that restore remyelination capacity (Irvine and Blakemore, 2008).…”

Section: Introductionmentioning

confidence: 99%

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Ossola

Zhao

Compston

et al. 2015

Glia

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Oligodendrocyte progenitor cell (OPC) differentiation is an important therapeutic target to promote remyelination in multiple sclerosis (MS). We previously reported hyperphosphorylated and aggregated microtubule‐associated protein tau in MS lesions, suggesting its involvement in axonal degeneration. However, the influence of pathological tau‐induced axonal damage on the potential for remyelination is unknown. Therefore, we investigated OPC differentiation in human P301S tau (P301S‐htau) transgenic mice, both in vitro and in vivo following focal demyelination. In 2‐month‐old P301S‐htau mice, which show hyperphosphorylated tau in neurons, we found atrophic axons in the spinal cord in the absence of prominent axonal degeneration. These signs of early axonal damage were associated with microgliosis and an upregulation of IL‐1β and TNFα. Following in vivo focal white matter demyelination we found that OPCs differentiated more efficiently in P301S‐htau mice than wild type (Wt) mice. We also found an increased level of myelin basic protein within the lesions, which however did not translate into increased remyelination due to higher susceptibility of P301S‐htau axons to demyelination‐induced degeneration compared to Wt axons. In vitro experiments confirmed higher differentiation capacity of OPCs from P301S‐htau mice compared with Wt mice‐derived OPCs. Because the OPCs from P301S‐htau mice do not ectopically express the transgene, and when isolated from newborn mice behave like Wt mice‐derived OPCs, we infer that their enhanced differentiation capacity must have been acquired through microenvironmental priming. Our data suggest the intriguing concept that damaged axons may signal to OPCs and promote their differentiation in the attempt at rescue by remyelination. GLIA 2016;64:457–471

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Section: Introductionmentioning

confidence: 99%

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Ossola

Zhao

Compston

et al. 2015

Glia

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“…However, in the recent few years, several studies demonstrated the presence of axonal degeneration even in the initial stages of MS. [1][2][3][4] Axonal loss is an irreversible process and is related to permanent disability observed in MS; therefore, the monitoring of axonal loss is important for the follow-up of the disease and the development of a targeted treatment strategy. 2 Retinal cell axons are part of the CNS, and do not have a myelin sheath until they penetrate the lamina cribrosa, thus the investigation of retina might be ideal for visualising the processes of neuroaxonal degeneration and understanding mechanisms of brain tissue damage in multiple sclerosis.…”

Section: Introductionmentioning

confidence: 99%

Optical Coherence Tomography in Patients with Relapsing-Remitting Multiple Sclerosis without Optic Neuritis: A 20-Month Longitudinal Study

Huseyinoglu¹,

Özben²,

Ekinci

et al. 2013

Neuro-Ophthalmology

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Optical coherence tomography is supported and used as a technique for visualisation of neuro-axonal loss in multiple sclerosis, but there are also a few studies expressing the opposite view. The aim of our study was to investigate retinal nerve fibre layer and optic nerve head parameters in patients with multiple sclerosis without a history of prior optic neuritis and symptoms of a new clinical attack during the follow-up for a total of 20-month period. Full ophthalmic evaluation was performed for all of the participants. The baseline retinal nerve fibre layer and macular thicknesses and focal and global loss of macular volume values were significantly lower in the eyes of the patients with multiple sclerosis compared with the healthy controls. No significant change between baseline and follow-up scans were found in all optical coherence tomography parameters in the multiple sclerosis group. Statistical analyses revealed significant retinal nerve fibre layer and macular thickness differences between baseline and second measurements in the controls. No significant difference in percent change between baseline and second measurements was observed between the patient and control groups. We conclude that whereas healthy subjects have an age-related tendency toward a decrease in retinal nerve fibre layer thickness, patients with multiple sclerosis patients are likely to pass through different stages of retinal thinning and thickening due to subclinical optic neuritis and, as a result, we could not detect any statistically significant change between baseline and second measurements in our multiple sclerosis patients.

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“…Two-dimensional 1 H-MRSI scans were obtained using a 90°-180°-180°pulse sequence (TR 2000 ms, TE 272 ms, 32 × 32 phase-encoding steps with 1 signal average per step, and a 250-mm field of view), the effective spatial resolution being about 12 × 12 × 20 mm after k-space filtering. These methods are presented in more detail elsewhere [17,18]. 1 H-MRSI findings: The superimposed grid in each image represents the 1 H-MRSI voxels, and the large, thick, white box represents the 1 H-MRSI volume of interest for that individual.…”

Section: Metabolites Of Interest In Msmentioning

confidence: 99%

Primary Progressive Multiple Sclerosis

Fuchs¹,

DeLuca²

2017

Encyclopedia of Clinical Neuropsychology

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Evidence of Axonal Damage in the Early Stages of Multiple Sclerosis and Its Relevance to Disability

Abstract: Cerebral axonal damage begins and contributes to disability from the earliest stages of the disease.

Cited by 464 publications

References 52 publications

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Optical Coherence Tomography in Patients with Relapsing-Remitting Multiple Sclerosis without Optic Neuritis: A 20-Month Longitudinal Study

Primary Progressive Multiple Sclerosis

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