Multiple sclerosis normal‐appearing white matter: Pathology–imaging correlations

Moll, Natalia M.; Rietsch, Anna; Thomas, Smitha; Ransohoff, Amy; Lee, Jar Chi; Fox, Robert J.; Chang, Ansi; Ransohoff, Richard M.; Fisher, Elizabeth

doi:10.1002/ana.22521

Cited by 258 publications

(227 citation statements)

References 45 publications

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“…The [ 11 C]TMSX-V T in the total NAWM ROI had a significant positive 32 Detailed pathology imaging correlation studies of SPMS brain have, however, demonstrated increased microglial activation and axonal degeneration associated with reduced FA in the NAWM. 3 Our study demonstrates, using a specific A2AR-binding radioligand and in vivo PET imaging, that A2ARs are increased in the NAWM of SPMS patients compared with healthy controls. The increased A2AR binding observed in the present study was associated with (1) decreased FA in DWI, (2) high EDSS, and (3) increased brain tissue loss.…”

Section: Mri Variablesmentioning

confidence: 54%

Adenosine A2A Receptors in Secondary Progressive Multiple Sclerosis: A [11C]TMSX Brain PET Study

Rissanen

Virta

Paavilainen

et al. 2013

J Cereb Blood Flow Metab

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In this study, positron emission tomography (PET) imaging with a radioligand to adenosine A2A receptors (A2AR)-a potent regulator of inflammation-was used to gain insight into the molecular alterations in normal-appearing white matter (NAWM) and gray matter (GM) in secondary progressive multiple sclerosis (SPMS). Normal-appearing white matter and GM, despite seeming normal in conventional mangnetic resonance imaging (MRI), are important loci of widespread inflammation, neuronal damage, and source of progressive disability in multiple sclerosis (MS). Dynamic PET imaging using A2AR-specific [ 11 C]TMSX and brain MRI with diffusion tensor imaging were performed to eight SPMS patients and seven healthy controls. Distribution volumes (V T ) of [ 11 C]TMSX were analyzed from 13 regions of interest using Logan plot with arterial plasma input. The SPMS patients had significantly increased [ 11 C]TMSX-V T in NAWM compared with controls (mean (s.d.): 0.55 ( ± 0.08) vs. 0.45 ( ± 0.05); P ¼ 0.036). Both the increased V T and the decreased fractional anisotropy (FA) in NAWM were associated with higher expanded disability status scale (EDSS) scores (P ¼ 0.030 and P ¼ 0.012, respectively), whereas the T2-lesion load of SPMS patients did not correlate with EDSS. This study shows, that A2ARs are increased in the brain of SPMS patients, and that [ 11 C]TMSX-PET provides a novel approach to learn about central nervous system pathology in SPMS in vivo.

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Section: Mri Variablesmentioning

confidence: 54%

Adenosine A2A Receptors in Secondary Progressive Multiple Sclerosis: A [11C]TMSX Brain PET Study

Rissanen

Virta

Paavilainen

et al. 2013

J Cereb Blood Flow Metab

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“…Regarding the MRI‐histopathology correlations, it should be noted that each specimens offers the possibility of investigating several different types of cytoarchitecture, which were probed by drawing ROIs in all types of tissue. Practically, this led to the construction of a data set of 48 data points, whose size suffices to fit the regression models and evaluate correlations (other high‐impact studies on MRI‐histopathology correlation relied on the same amount of data20 or even less17). …”

Section: Discussionmentioning

confidence: 99%

“…We tested this hypothesis by evaluating the statistical associations between ROI‐wise median values of NODDI and histological indices, for a total of N = 48 ROIs (28 for the multiple sclerosis cases; 20 for the controls), similar in number to other studies 17, 20…”

Section: Methodsmentioning

confidence: 99%

“…In vivo mapping of myelin density15 and g‐ratio16; iron deposition17; sodium concentration18; inflammation and axonal injury19 are examples of quantitative MRI techniques being developed to detect early multiple sclerosis pathology. Similar quantitative MRI metrics require extensive validation, in order to confirm their specificity and relevance to clinical outcomes 20, 21, 22…”

Section: Introductionmentioning

confidence: 99%

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Neurite dispersion: a new marker of multiple sclerosis spinal cord pathology?

Grussu

Schneider

Tur

et al. 2017

Ann Clin Transl Neurol

265

243

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ObjectiveConventional magnetic resonance imaging (MRI) of the multiple sclerosis spinal cord is limited by low specificity regarding the underlying pathological processes, and new MRI metrics assessing microscopic damage are required. We aim to show for the first time that neurite orientation dispersion (i.e., variability in axon/dendrite orientations) is a new biomarker that uncovers previously undetected layers of complexity of multiple sclerosis spinal cord pathology. Also, we validate against histology a clinically viable MRI technique for dispersion measurement (neurite orientation dispersion and density imaging, NODDI), to demonstrate the strong potential of the new marker.MethodsWe related quantitative metrics from histology and MRI in four post mortem spinal cord specimens (two controls; two progressive multiple sclerosis cases). The samples were scanned at high field, obtaining maps of neurite density and orientation dispersion from NODDI and routine diffusion tensor imaging (DTI) indices. Histological procedures provided markers of astrocyte, microglia, myelin and neurofilament density, as well as neurite dispersion.ResultsWe report from both NODDI and histology a trend toward lower neurite dispersion in demyelinated lesions, indicative of reduced neurite architecture complexity. Also, we provide unequivocal evidence that NODDI‐derived dispersion matches its histological counterpart (P < 0.001), while DTI metrics are less specific and influenced by several biophysical substrates.InterpretationNeurite orientation dispersion detects a previously undescribed and potentially relevant layer of microstructural complexity of multiple sclerosis spinal cord pathology. Clinically feasible techniques such as NODDI may play a key role in clinical trial and practice settings, as they provide histologically meaningful dispersion indices.

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“…For example, an increase in astrocytes and activated microglia appears to outweigh the decrease in oligodendrocytes in plaques, 107 which may offset prolonged relaxation times due to increased free water. In fact, a number of investigations reported a significantly reduced MTR in otherwise normal-appearing WM and GM, 92,106,[108][109][110][111][112][113][114] a close correlation between the MTR and clinical disability, 114 -117 and a potential prognostic value of magnetization transfer MR imaging. 114,118 -120 More recent studies suggest that iron-laden/activated microglia 71,121 and/or aggregates typical of small bleeding 71 cause focally increased T 2 relaxation rates and/or reduced MTR 92 within normal-appearing WM.…”

Section: Inflammationmentioning

confidence: 99%

<i>In Vivo</i> Brain MR Imaging at Subnanoliter Resolution: Contrast and Histology

2016

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This article provides an overview of in vivo magnetic resonance (MR) imaging contrasts obtained for mammalian brain in relation to histological knowledge. Emphasis is paid to the (1) significance of high spatial resolution for the optimization of T 1 , T 2 , and magnetization transfer contrast, (2) use of exogenous extra-and intracellular contrast agents for validating endogenous contrast sources, and (3) histological structures and biochemical compounds underlying these contrasts and (4) their relevance to neuroradiology. Comparisons between MR imaging at subnanoliter resolution and histological data indicate that (a) myelin sheaths, (b) nerve cells, and (c) the neuropil are most responsible for observed MR imaging contrasts, while (a) diamagnetic macromolecules, (b) intracellular paramagnetic ions, and (c) extracellular free water, respectively, emerge as the dominant factors. Enhanced relaxation rates due to paramagnetic ions, such as iron and manganese, have been observed for oligodendrocytes, astrocytes, microglia, and blood cells in the brain as well as for nerve cells. Taken together, a plethora of observations suggests that the delineation of specific structures in high-resolution MR imaging of mammalian brain and the absence of corresponding contrasts in MR imaging of the human brain do not necessarily indicate differences between species but may be explained by partial volume effects. Second, paramagnetic ions are required in active cells in vivo which may reduce the magnetization transfer ratio in the brain through accelerated T 1 recovery. Third, reductions of the magnetization transfer ratio may be more sensitive to a particular pathological condition, such as astrocytosis, microglial activation, inflammation, and demyelination, than changes in relaxation. This is because the simultaneous occurrence of increased paramagnetic ions (i.e., shorter relaxation times) and increased free water (i.e., longer relaxation times) may cancel T 1 or T 2 effects, whereas both processes reduce the magnetization transfer ratio.

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Multiple sclerosis normal‐appearing white matter: Pathology–imaging correlations

Cited by 258 publications

References 45 publications

Adenosine A2A Receptors in Secondary Progressive Multiple Sclerosis: A [11C]TMSX Brain PET Study

Adenosine A2A Receptors in Secondary Progressive Multiple Sclerosis: A [11C]TMSX Brain PET Study

Neurite dispersion: a new marker of multiple sclerosis spinal cord pathology?

<i>In Vivo</i> Brain MR Imaging at Subnanoliter Resolution: Contrast and Histology

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