Imaging correlates of axonal swelling in chronic multiple sclerosis brains

Fisher, Elizabeth; Chang, Ansi; Fox, Robert J.; Tkach, Jean A.; Svarovsky, Therese; Nakamura, Kunio; Rudick, Richard A.; Trapp, Bruce D.

doi:10.1002/ana.21113

Cited by 114 publications

(123 citation statements)

References 47 publications

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“…Such technologic advancements offer unprecedented resolution of micron-sized axons (12,16) in the living human brain. We hypothesized that MS lesions on high-gradient-diffusion MR images obtained by using a gradient strength of up to 300 mT/m would show decreased axon density and increased axon diameter, as has been shown in prior histopathologic studies (17)(18)(19). The purpose of this study was to evaluate the ability of high-gradient-diffusion MR imaging using gradient strengths of up to 300 mT/m to characterize axonal disease in lesions and normal-appearing white matter (NAWM) in patients …”

Section: Discussionmentioning

confidence: 95%

Characterization of Axonal Disease in Patients with Multiple Sclerosis Using High-Gradient-Diffusion MR Imaging

Huang¹,

Tobyne²,

Nummenmaa³

et al. 2016

Radiology

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).q RSNA, 2016 Purpose:To evaluate the ability of high-gradient-diffusion magnetic resonance (MR) imaging by using gradient strengths of up to 300 mT/m to depict axonal disease in lesions and normal-appearing white matter (NAWM) in patients with multiple sclerosis (MS) and to compare high-gradient-diffusion MR findings in these patients with those in healthy control subjects. Materials and Methods:In this HIPAA-compliant institutional review board-approved prospective study in which all subjects provided written informed consent, six patients with relapsing-remitting MS and six healthy control subjects underwent diffusion-weighted imaging with a range of diffusion weightings performed with a 3-T human MR imager by using gradient strengths of up to 300 mT/m. A model of intraaxonal, extra-axonal, and free water diffusion was fitted to obtain estimates of axon diameter and density. Differences in axon diameter and density between lesions and NAWM in patients with MS were assessed by using the nonparametric Wilcoxon matched-pairs signed rank test, and differences between NAWM in subjects with MS and white matter in healthy control subjects were assessed by using the Mann-Whitney U test. Results:MS lesions showed increased mean axon diameter (10.3 vs 7.9 mm in the genu, 10.4 vs 9.3 mm in the body, and 10.6 vs 8.2 mm in the splenium; P , .05) and decreased axon density ([0.48 vs 1.1] 3 10 10 /m 2 in the genu, [0.40 vs 0.70] 3 10 10 /m 2 in the body, and [0.35 vs 1.1] 3 10 10 /m 2 in the splenium; P , .05) compared with adjacent NAWM. No significant difference in mean axon diameter or axon density was detected between NAWM in subjects with MS and white matter in healthy control subjects. Conclusion:High-gradient-diffusion MR imaging using gradient strengths of up to 300 mT/m can be used to characterize axonal disease in patients with MS, with results that agree with known trends from neuropathologic data showing increased axon diameter and decreased axon density in MS lesions when compared with NAWM.q RSNA, 2016

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Section: Discussionmentioning

confidence: 95%

Characterization of Axonal Disease in Patients with Multiple Sclerosis Using High-Gradient-Diffusion MR Imaging

Huang¹,

Tobyne²,

Nummenmaa³

et al. 2016

Radiology

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“…Those that show profound hypointensity and permanence primarily reflect irreversible tissue destruction (i.e., irreversible demyelination and axonal loss) whereas those that are transient reflect edema and demyelination with subsequent remyelination. 21,22 Not surprisingly, chronic persistent T1-hypointense lesions are associated to a moderate degree with global brain atrophy. 23,24 However, there are technical considerations to be kept in mind with regard to T1-hypointense lesions.…”

Section: T1 Hypointense Lesionsmentioning

confidence: 99%

“…31 Profoundly reduced MTR indicates a chronic inactive lesion with axonal swelling, axonal loss, and severe demyelination. 22,89,90 MTI is also capable of revealing microscopic damage in normal appearing brain tissue that is free from any visible lesions on conventional MRI scans. 86,91,92 Many studies have demonstrated MTR changes in NAWM in all the MS phenotypic subtypes, [91][92][93] including patients very early in the course of the disease (FIG.…”

Section: Fig 5 Axial Magnetization Transfer (Mt) Images and Maps Ofmentioning

confidence: 99%

MRI in Multiple Sclerosis: What’s Inside the Toolbox?

et al. 2007

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Summary: Magnetic resonance imaging (MRI) has played a central role in the diagnosis and management of multiple sclerosis (MS). In addition, MRI metrics have become key supportive outcome measures to explore drug efficacy in clinical trials. Conventional MRI measures have contributed to the understanding of MS pathophysiology at the macroscopic level yet have failed to provide a complete picture of underlying MS pathology. They also show relatively weak relationships to clinical status such as predictive strength for clinical progression. Advanced quantitative MRI measures such as magnetization transfer, spectroscopy, diffusion imaging, and relaxometry techniques are somewhat more specific and sensitive for underlying pathology. These measures are particularly useful in revealing diffuse damage in cerebral white and gray matter and therefore may help resolve the dissociation between clinical and conventional MRI findings. In this article, we provide an overview of the array of tools available with brain and spinal cord MRI technology as it is applied to MS. We review the most recent data regarding the role of conventional and advanced MRI techniques in the assessment of MS. We focus on the most relevant pathologic and clinical correlation studies relevant to these measures.

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“…Postmortem in situ brain imaging was performed and tissue was processed as described previously. 9 For this study, we analyzed brain MRI and tissue from 7 patients with MS (table).…”

mentioning

confidence: 99%

“…After fixation, the hemisphere was reimaged in a custom-designed polycarbonate slicing box. 9 After postfixation MRI, the brain was sliced (1 cm coronal sections) within the box and photographed. The postmortem T1W MRI was registered to the postfixation MRI using rigid-body followed by affine transformations with FLIRT 10 ; in 4 of the cases, additional nonlinear registration was performed using FNIRT (http://www.…”

mentioning

confidence: 99%

Clinically feasible MTR is sensitive to cortical demyelination in MS

et al. 2013

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Objective: Presently there is no clinically feasible imaging modality that can effectively detect cortical demyelination in patients with multiple sclerosis (MS). The objective of this study is to determine if clinically feasible magnetization transfer ratio (MTR) imaging is sensitive to cortical demyelination in MS.Methods: MRI were acquired in situ on 7 recently deceased patients with MS using clinically feasible sequences at 3 T, including relatively high-resolution T1-weighted and proton density-weighted images with/without a magnetization transfer pulse for calculation of MTR. The brains were rapidly removed and placed in fixative. Multiple cortical regions from each brain were immunostained for myelin proteolipid protein and classified as mostly myelinated (MM ctx ), mostly demyelinated (MD ctx ), or intermediately demyelinated (ID ctx ). MRIs were registered with the cortical sections so that the cortex corresponding to each cortical section could be identified, along with adjacent subcortical white matter (WM). Mean cortical MTR normalized to mean WM MTR was calculated for each cortical region. Linear mixed-effects models were used to test if mean normalized cortical MTR was significantly lower in demyelinated cortex. Conclusions: This result demonstrates that clinically feasible MTR imaging is sensitive to cortical demyelination and suggests that MTR will be a useful tool to help detect MS cortical lesions in living patients with MS. Neurology â 2013;80:246-252 GLOSSARY CL 5 cortical demyelinated lesions; HSD 5 honestly significant difference; ID ctx 5 intermediately demyelinated; LSM 5 least-squares mean; MD ctx 5 mostly demyelinated; MM ctx 5 mostly myelinated; MR 5 magnetic resonance; MS 5 multiple sclerosis; MTR 5 magnetization transfer ratio; MTR ctx 5 mean cortical magnetization transfer ratio; normMTR ctx 5 normalized cortical magnetization transfer ratio; PLP 5 proteolipid protein; TE 5 echo time; TR 5 repetition time; T1W 5 T1-weighted; WM 5 white matter.Cortical demyelinated lesions (CL) have been detected in patients with multiple sclerosis (MS) for more than 5 decades.1,2 Postmortem studies have raised the possibility that CL may be more prevalent than white matter (WM) demyelination 3 and that intracortical and mixed cortical/ WM lesions together may account for .50% of all MS brain lesions. 4 Despite their detection on postmortem tissue, most CL are invisible on conventional MRI. 4,5 The double inversion recovery sequence improves detection but does not reveal most CL. 5,6 While nonquantitative imaging features low sensitivity to CL, the sensitivity of semiquantitative and quantitative MRI is unclear. Although one ex vivo imaging study performed at 1.5 T revealed that T1 and T2 relaxation rates (not magnetization transfer ratio [MTR]) are sensitive to CL, 7 a separate study performed at 9.4 T found MTR and T2 relaxation rate (not T1) to be most sensitive.

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Imaging correlates of axonal swelling in chronic multiple sclerosis brains

Abstract: Axonal swelling and axonal loss were major pathological features that distinguish T2T1MTR regions from T2-only regions.

Cited by 114 publications

References 47 publications

Characterization of Axonal Disease in Patients with Multiple Sclerosis Using High-Gradient-Diffusion MR Imaging

Characterization of Axonal Disease in Patients with Multiple Sclerosis Using High-Gradient-Diffusion MR Imaging

MRI in Multiple Sclerosis: What’s Inside the Toolbox?

Clinically feasible MTR is sensitive to cortical demyelination in MS

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