Spinal Cord Neuronal Pathology in Multiple Sclerosis

Gilmore, Christopher P.; DeLuca, Gabriele C.; Liu, Bo; Owens, Trudy; Lowe, James; Esiri, Margaret M.; Evangelou, Nikos

doi:10.1111/j.1750-3639.2008.00228.x

Cited by 85 publications

(79 citation statements)

References 35 publications

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“…Ultra-high field MRI may also prove to be a valuable tool to assess GM damage in CNS areas other than the cortex and including the spinal cord and the cerebellum as histopathologic examinations described GM demyelination and neuronal pathology in these structures in MS. [33][34][35] …”

Section: Discussionmentioning

confidence: 99%

In vivo imaging of cortical pathology in multiple sclerosis using ultra-high field MRI

Mainero¹,

Benner²,

Radding³

et al. 2009

Neurology

235

219

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Objective: We used ultra-high field MRI to visualize cortical lesion types described by neuropathology in 16 patients with multiple sclerosis (MS) compared with 8 age-matched controls; to characterize the contrast properties of cortical lesions including T2*, T2, T1, and phase images; and to investigate the relationship between cortical lesion types and clinical data. Methods:We collected, on a 7-T scanner, 2-dimensional fast low-angle shot (FLASH)-T2*-weighted spoiled gradient-echo, T2-weighted turbo spin-echo (TSE) images (0.33 ϫ 033 ϫ 1 mm 3 ), and a 3-dimensional magnetization-prepared rapid gradient echo.Results: Overall, 199 cortical lesions were detected in patients on both FLASH-T2* and T2-TSE scans. Seven-tesla MRI allowed for characterization of cortical plaques into type I (leukocortical), type II (intracortical), and type III/IV (subpial extending partly or completely through the cortical width) lesions as described histopathologically. Types III and IV were the most frequent type of cortical plaques (50.2%), followed by type I (36.2%) and type II (13.6%) lesions. Each lesion type was more frequent in secondary progressive than in relapsing-remitting MS. This difference, however, was significant only for type III/IV lesions. T2*-weighted images showed the highest, while phase images showed the lowest, contrast-to-noise ratio for all cortical lesion types. In patients, the number of type III/IV lesions was associated with greater disability (p Ͻ 0.02 by Spearman test) and older age (p Ͻ 0.04 by Spearman test).Conclusions: Seven-tesla MRI detected different histologic cortical lesion types in our small multiple sclerosis (MS) sample, suggesting, if validated in a larger population, that it may prove a valuable tool to assess the contribution of cortical MS pathology to clinical disability. GLOSSARY ANOVA ϭ analysis of variance; BN ϭ background noise; CNR ϭ contrast-to-noise ratio; DIR ϭ double-inversion recovery; EDSS ϭ Expanded Disability Status Scale; FLAIR ϭ fluid-attenuated inversion recovery; FLASH ϭ fast low-angle shot; GM ϭ gray matter; MPRAGE ϭ magnetization-prepared rapid gradient echo; MR ϭ magnetic resonance; MS ϭ multiple sclerosis; NACGM ϭ normal-appearing cortical gray matter; RF ϭ radiofrequency; ROI ϭ region of interest; RRMS ϭ relapsingremitting multiple sclerosis; SNR ϭ signal-to-noise ratio; SPMS ϭ secondary progressive multiple sclerosis; TA ϭ time of acquisition; TE ϭ echo time; TR ϭ repetition time; TSE ϭ turbo spin-echo; WM ϭ white matter.Although cortical lesions were identified as a common finding in multiple sclerosis (MS) from the earliest pathologic studies, 1-3 their significance was underestimated until recent histopathologic data revealed that they constitute a substantial proportion of the total brain MS lesion load. 4,5 The ability of standard field strength scanners (1.5 T, 3 T) to detect and characterize cortical MS pathology is still significantly lower than neuropathology.6 Ultra-high field systems (7 T to 9.4 T) allow a 2-to 3-fold improvement in image sign...

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Section: Discussionmentioning

confidence: 99%

In vivo imaging of cortical pathology in multiple sclerosis using ultra-high field MRI

Mainero¹,

Benner²,

Radding³

et al. 2009

Neurology

235

219

View full text Add to dashboard Cite

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“…For example, several recent studies of grey and white matter demyelination in different regions of the CNS found that the extent of cortical demyelination is greater than that found in white matter 34 and that, although cortical demyelination sometimes occurred together with demyelination in the adjacent white matter (leukocortical lesions), in most instances, the cortex was affected independently from white matter lesions 35,36 . Another study observed a gradient of neuronal loss in the precentral gyrus of MS cases that exhibited extensive subpial demyelination with the greatest loss in the outer cortical layers 17 .…”

Section: Evidence For Independent Grey Matter Damagementioning

confidence: 99%

Exploring the origins of grey matter damage in multiple sclerosis

et al. 2015

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Multiple sclerosis is characterized at the gross pathological level by the presence of widespread focal demyelinating lesions of the myelin-rich white matter. However, it is becoming clear that grey matter is not spared, even during the earliest phases of the disease. Furthermore, grey matter damage may have an important role both in physical and cognitive disability. Grey matter pathology involves both inflammatory and neurodegenerative mechanisms, but the relationship between the two is unclear. Histological, immunological and neuroimaging studies have provided new insight in this rapidly expanding field, and form the basis of the most recent hypotheses on the pathogenesis of grey matter damage. DOI: https://doi.org/10.1038/nrn3900Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-111099 Accepted Version Originally published at: Calabrese, Massimiliano; Magliozzi, Roberta; Ciccarelli, Olga; Geurts, Jeroen J G; Reynolds, Richard; Martin, Roland (2015). Exploring the origins of grey matter damage in multiple sclerosis. Nature Reviews Neuroscience, 16 (3) AbstractMultiple sclerosis is characterised at the gross pathological level by the presence of widespread focal demyelinating lesions of the myelin-rich white matter. However, in recent years it has become clear that grey matter is not spared, even during the earliest phases of the disease. Furthermore, grey matter damage has been suggested to have an important role both in physical and cognitive disability. Grey matter pathology involves both inflammatory and neurodegenerative mechanisms, but the relationship between the two is unclear. This review will summarize and highlight important histological, immunological, and neuroimaging results from this rapidly expanding field and will address the most recent hypotheses on the pathogenesis of grey matter damage.

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“…Schirmer et al also reported a number of phosphorylated NF-H positive neurons in anterior horn cells of MS patients and noted that they were more pronounced in early and active lesions [12]. Considering the significant depletion of spinal motor neurons in MS that has been described in previous studies [10][11][12], it is likely that in non-immunoreactive areas of spinal cord, most damaged neurons have disappeared, although some may also have recovered. This hypothesis is supported by our comparison of the motor neuron count in a lumbar subgroup of 4 MS cases.…”

mentioning

confidence: 88%

“…Axonal damage [2][3][4][5], neuronal apoptosis [6,7] and neuronal loss [8] in grey and white matter lesions have been described both in MS and its widely-used animal model, experimental autoimmune encephalomyelitis (EAE). In spinal cord, substantially reduced nerve cell counts were found both in EAE [9] and MS [10][11][12].…”

Section: Introductionmentioning

confidence: 95%

Multiple Sclerosis: Neurofilament Pathology in Spinal Motor Neurons

Müller-Wielsch¹,

Cannella²,

Raine³

2017

J Mult Scler

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Objective: While traditionally a disorder of myelin, in multiple sclerosis (MS) neuronal and axonal damage has in recent years become an important topic of clinical relevance. To address this, alterations in neurofilament phosphorylation, known markers of neuronal health, were investigated in anterior horn cells in MS spinal cord tissue for signs of motor neuron damage. Methods:Spinal cord tissue was examined from 13 MS and 6 control patients. Fresh frozen sections were labelled with antibodies against phosphorylated and non-phosphorylated epitopes of neurofilament H (NF-H) and analyzed by light microscopy. Results:In MS, increased expression of phosphorylated NF-H in spinal motor neuron perikarya (abnormal for neurons) occurred in 61.5% of cases, mostly in chronic active lesions, with the strongest immunoreactivity at the lumbar level. Inflammatory activity was common in chronic active but rare in chronic silent lesions. In one case with an acute lesion, we saw swollen axons positive for non-phosphorylated NF-H, a pathologic marker in axons, but no signs of perikaryal damage. Expression of non-phosphorylated NF-H in spinal motor neuron perikarya was similar in both MS and controls. Conclusion:In line with previous studies, our findings implicate anterior horn cell damage as a common feature in MS. We propose that underlying mechanisms may involve reduced synaptic input and/or retrograde degeneration, subjects which remain to be investigated. For the neuron count of a subgroup of MS cases, 5 serial sections of each patient stained with Nissl stain (0.075 % cresyl violet) were examined with stereological methods using StereoInvestigator software (MicroBrightField Inc., Williston, VT, USA). In the anterior horn as the region of interest, all neuronal perikarya were counted, measured and grouped according to their size into motor neurons (diameter ≥ 24 μm) and interneurons (diameter (≥ 10-24 μm) [21]. For evaluation, total numbers of motor neurons per patient were compared. Further details of the procedure can be found in an earlier publication [11].Images were captured with a digital camera (Axiocam and software by Carl Zeiss); GraphPadPrism software was used for graph production. ResultsEstablished, gliotic lesions devoid of myelin and displaying variable degrees of axonal degeneration were common in all cases with chronic lesions but inflammatory changes (reflecting ongoing demyelination), were only seen in chronic active lesions. Such changes comprised perivascular cuffs and scattered lipid-laden macrophages in the white matter (mainly anterior or lateral columns) and occasional collections of small lymphocytes within the meninges.By immunocytochemistry, clear differences were seen between MS and control cases in the expression of phosphorylated NF-H in anterior horn cell perikarya. Specifically, eight of thirteen MS patients showed widespread phosphorylated (abnormal) NF-H positivity compared to none of the controls (3 healthy, 2 OND: olivopontocerebellar degeneration and polyglucosan inclusion disease...

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Spinal Cord Neuronal Pathology in Multiple Sclerosis

Cited by 85 publications

References 35 publications

In vivo imaging of cortical pathology in multiple sclerosis using ultra-high field MRI

In vivo imaging of cortical pathology in multiple sclerosis using ultra-high field MRI

Exploring the origins of grey matter damage in multiple sclerosis

Multiple Sclerosis: Neurofilament Pathology in Spinal Motor Neurons

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