A longitudinal study of brain atrophy in relapsing multiple sclerosis

Simon, Jack H.; Jacobs, Lawrence; Campion, Marilyn; Rudick, Richard A.; Cookfair, Diane L.; Herndon, Robert M.; Richert, John R.; Salazar, Andrés M.; Fischer, Jill S.; Goodkin, Donald E.; Simonian, Nancy A.; Lajaunie, M.; Miller, David E.; Wende, Karl; Martens-Davidson, A.; Kinkel, Revere P.; Munschauer, Frederick E.; Brownscheidle, Carol M.

doi:10.1212/wnl.53.1.139

Cited by 302 publications

(159 citation statements)

References 37 publications

Supporting

Mentioning

146

Contrasting

Unclassified

Order By: Relevance

“…The latter probably is a consequence of Wallerian degeneration following the axonal transection that occurs within frank lesions. Diffuse white matter axonal injury is also likely to result in the gross atrophy in the brains and spinal cords of MS patients that has been identified using newer neuroimaging methods (29)(30)(31)(32). Taken together, these studies suggest that even in early stages of the disease there is a degenerative component to MS pathogenesis and that progresses independently of the dramatic fluctuations in neurologic function that characterize clinical relapses and remissions.…”

Section: Neuronal/axonal Pathology In Lesions and Normal-appearing Whmentioning

confidence: 94%

The extracellular matrix in multiple sclerosis: an update

2001

Braz J Med Biol Res

View full text Add to dashboard Cite

Extracellular matrix (ECM) molecules play important roles in the pathobiology of the major human central nervous system (CNS) inflammatory/demyelinating disease multiple sclerosis (MS). This mini-review highlights some recent work on CNS endothelial cell interactions with vascular basement membrane ECM as part of the cellular immune response, and roles for white matter ECM molecules in demyelination and remyelination in MS lesions. Recent basic and clinical investigations of MS emphasize axonal injury, not only in chronic MS plaques, but also in acute lesions; progressive axonal degeneration in normal-appearing white matter also may contribute to brain and spinal cord atrophy in MS patients. Remodeling of the interstitial white matter ECM molecules that affect axon regeneration, however, is incompletely characterized. Our ongoing immunohistochemical studies demonstrate enhanced ECM versican, a neurite and axon growth-inhibiting white matter ECM proteoglycan, and dermatan sulfate proteoglycans at the edges of inflammatory MS lesions. This suggests that enhanced proteoglycan deposition in the ECM and axonal growth inhibition may occur early and are involved in expansion of active lesions. Decreased ECM proteoglycans and their phagocytosis by macrophages along with myelin in plaque centers imply that there is injury to the ECM itself. These results indicate that white matter ECM proteoglycan alterations are integral to MS pathology at all disease stages and that they contribute to a CNS ECM that is inhospitable to axon regrowth/regeneration.

show abstract

Section: Neuronal/axonal Pathology In Lesions and Normal-appearing Whmentioning

confidence: 94%

The extracellular matrix in multiple sclerosis: an update

2001

Braz J Med Biol Res

View full text Add to dashboard Cite

show abstract

“…An experienced observer is required who is familiar with normal neuroanatomy and pathology. Manual segmentation is useful in small structures or regions, e.g., third ventricle, where significant atrophy is reported in MS. 45 Disadvantages of manual segmentation include operator bias, long analysis time and poor reproducibility when compared with automated techniques.…”

Section: Atrophy Measuresmentioning

confidence: 99%

“…The most marked atrophy occurs in secondary progressive disease and correlates with disability. 45,72,73 In primary progressive MS, significant atrophy of brain and cord over 1 year was evident in a large cohort of primary progressive patients drawn from 6 European centers. 74 Change in cerebral volume over 1 year correlated only weakly with change in T1 and T2 brain load.…”

Section: Atrophy Measuresmentioning

confidence: 99%

Biomarkers and surrogate outcomes in neurodegenerative disease: Lessons from multiple sclerosis

Miller¹

2004

Neurotherapeutics

View full text Add to dashboard Cite

Summary:Multiple sclerosis (MS) is a chronic disease of the CNS that most commonly affects young adults. It is usually characterized in the early years by acute relapses followed by partial or complete remission; in later years progressive and irreversible disability develops. Because of the protracted and unpredictable clinical course, biological surrogate markers are much needed to make clinical trials of potential disease-modifying treatments more efficient. Magnetic resonance (MR) outcome measures are now widely used to monitor treatment outcome in MS trials. Areas of multifocal inflammation are detected with a high sensitivity as new areas of gadolinium enhancement and T2 abnormality, and these may be considered as surrogate markers for clinical relapses. However, progressive disability is not clearly related to inflammatory lesions but rather to a progressive and diffuse process with increasing neuroaxonal loss. MR surrogate measures for neuroaxonal loss include atrophy (tissue loss in brain and spinal cord), N-acetyl aspartate, and T1 hypointense lesions. Diffuse abnormality in normal appearing brain tissue may also be monitored using magnetization transfer ratio and other quantitative MR measures. For treatment trials of new agents aimed at preventing disability, measures of neuroaxonal damage should be acquired, especially atrophy, which occurs at all stages of MS and which can be quantified in a sensitive and reproducible manner. Because the MR surrogates for neuroaxonal loss are not yet validated as predicting future disability, definitive trials should continue to monitor an appropriate disability endpoint.

show abstract

“…Changes to its shape or structure, which occur because of aging 2,3 or degenerative disease, [4][5][6] is the subject of active study. There is an interest in linking these physical changes with neurological impairment.…”

Section: Introductionmentioning

confidence: 99%