Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study

Trapp, Bruce D.; Vignos, Megan; Dudman, Jessica; Chang, Ansi; Fisher, Elizabeth; Staugaitis, Susan M.; Battapady, Harsha; Mörk, Sverre; Ontaneda, Daniel; Jones, Stephen E.; Fox, Robert J.; Chen, Jacqueline; Nakamura, Kunio; Rudick, Richard A.

doi:10.1016/s1474-4422(18)30245-x

Cited by 119 publications

(98 citation statements)

References 29 publications

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“…The lack of a significant relationship between white matter fraction (WMF) and T2 lesion load [34,38] further support this hypothesis. Biopsy studies also confirm that the atrophy may proceed even in the absence of inflammation [39,40].…”

Section: Pathogenesis Of Brain Atrophymentioning

confidence: 79%

Brain atrophy in multiple sclerosis: mechanisms, clinical relevance and treatment options

Andravizou

Dardiotis

Artemiadis

et al. 2019

Autoimmun Highlights

115

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Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system characterized by focal or diffuse inflammation, demyelination, axonal loss and neurodegeneration. Brain atrophy can be seen in the earliest stages of MS, progresses faster compared to healthy adults, and is a reliable predictor of future physical and cognitive disability. In addition, it is widely accepted to be a valid, sensitive and reproducible measure of neurodegeneration in MS. Reducing the rate of brain atrophy has only recently been incorporated as a critical endpoint into the clinical trials of new or emerging disease modifying drugs (DMDs) in MS. With the advent of easily accessible neuroimaging softwares along with the accumulating evidence, clinicians may be able to use brain atrophy measures in their everyday clinical practice to monitor disease course and response to DMDs. In this review, we will describe the different mechanisms contributing to brain atrophy, their clinical relevance on disease presentation and course and the effect of current or emergent DMDs on brain atrophy and neuroprotection. which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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Section: Pathogenesis Of Brain Atrophymentioning

confidence: 79%

Brain atrophy in multiple sclerosis: mechanisms, clinical relevance and treatment options

Andravizou

Dardiotis

Artemiadis

et al. 2019

Autoimmun Highlights

115

View full text Add to dashboard Cite

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“…Neuronal loss as the cellular substrate of disability worsening occurs in the course of demyelination, but to an even larger extent outside and independent of focal demyelination. Additionally, it seems that a relevant fraction of patients have a form of MS where no white matter demyelination occurs [183]. Further, the phenotypic characterization of MS subtypes is not based on distinct molecular mechanisms.…”

Section: Matrix Metalloproteinases In Multiple Sclerosismentioning

confidence: 99%

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

Muri

Leppert

Grandgirard

et al. 2019

Cell. Mol. Life Sci.

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Metalloproteinases-such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs)-are involved in various diseases of the nervous system but also contribute to nervous system development, synaptic plasticity and neuroregeneration upon injury. MMPs and ADAMs proteolytically cleave many substrates including extracellular matrix components but also signaling molecules and receptors. During neuroinfectious disease with associated neuroinflammation, MMPs and ADAMs regulate blood-brain barrier breakdown, bacterial invasion, neutrophil infiltration and cytokine signaling. Specific and broad-spectrum inhibitors for MMPs and ADAMs have experimentally been shown to decrease neuroinflammation and brain damage in diseases with excessive neuroinflammation as a common denominator, such as pneumococcal meningitis and multiple sclerosis, thereby improving the disease outcome. Timing of metalloproteinase inhibition appears to be critical to effectively target the cascade of pathophysiological processes leading to brain damage without inhibiting the neuroregenerative effects of metalloproteinases. As the critical role of metalloproteinases in neuronal repair mechanisms and regeneration was only lately recognized, the original idea of chronic MMP inhibition needs to be conceptually revised. Recently accumulated research urges for a second chance of metalloproteinase inhibitors, which-when correctly applied and dosed-harbor the potential to improve the outcome of different neuroinflammatory diseases.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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“…A variety of techniques have indicated structural and functional changes inside and outside of lesions. For instance, there is evidence that myelin injury extends beyond the lesion boundaries at varying distances from MS lesion centers . Magnetization transfer imaging indexes myelin integrity by assessing a ratio of macromolecule‐bound protons (ie, myelin) to free water protons in tissue .…”

Section: Introductionmentioning

confidence: 99%

“…For instance, there is evidence that myelin injury extends beyond the lesion boundaries at varying distances from MS lesion centers. [12][13][14] Magnetization transfer imaging indexes myelin integrity by assessing a ratio of macromolecule-bound protons (ie, myelin) to free water protons in tissue. 15 Magentization Transfer Ratio (MTR) is known to increase at increasing distances from MS lesion centers.…”

Section: Introductionmentioning

confidence: 99%

Three‐Dimensional Lesion Phenotyping and Physiologic Characterization Inform Remyelination Ability in Multiple Sclerosis

Sivakolundu

Hansen

West

et al. 2019

Journal of Neuroimaging

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BACKGROUND AND PURPOSE Multiple sclerosis (MS) clinical management is based upon lesion characterization from 2‐dimensional (2D) magnetic resonance imaging (MRI) views. Such views fail to convey the lesion‐phenotype (ie, shape and surface texture) complexity, underlying metabolic alterations, and remyelination potential. We utilized a 3‐dimensional (3D) lesion phenotyping approach coupled with imaging to study physiologic profiles within and around MS lesions and their impacts on lesion phenotypes. METHODS Lesions were identified in 3T T2‐FLAIR images and segmented using geodesic active contouring. A calibrated fMRI sequence permitted measurement of cerebral blood flow (CBF), blood‐oxygen‐level‐dependent signal (BOLD), and cerebral metabolic rate of oxygen (CMRO2). These metrics were measured within lesions and surrounding tissue in concentric layers exact to the 3D‐lesion shape. BOLD slope was calculated as BOLD changes from a lesion to its surrounding perimeters. White matter integrity was measured using diffusion kurtosis imaging. Associations between these metrics and 3D‐lesion phenotypes were studied. RESULTS One hundred nine lesions from 23 MS patients were analyzed. We identified a noninvasive biomarker, BOLD slope, to metabolically characterize lesions. Positive BOLD slope lesions were metabolically active with higher CMRO2 and CBF compared to negative BOLD slope or inactive lesions. Metabolically active lesions with more intact white matter integrity had more symmetrical shapes and more complex surface textures compared to inactive lesions with less intact white matter integrity. CONCLUSION The association of lesion phenotypes with their metabolic signatures suggests the prospect for translation of such data to clinical management by providing information related to metabolic activity, lesion age, and risk for disease reactivation and self‐repair. Our findings also provide a platform for disease surveillance and outcome quantification involving myelin repair therapeutics.

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Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study

Abstract: US National Institutes of Health and National Multiple Sclerosis Society.

Cited by 119 publications

References 29 publications

Brain atrophy in multiple sclerosis: mechanisms, clinical relevance and treatment options

Brain atrophy in multiple sclerosis: mechanisms, clinical relevance and treatment options

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

Three‐Dimensional Lesion Phenotyping and Physiologic Characterization Inform Remyelination Ability in Multiple Sclerosis

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