Myelin and Axonal Damage in Normal-Appearing White Matter in Patients with Moyamoya Disease

Hara, Shoko; Hori, Masaaki; Hagiwara, Akifumi; Tsurushima, Y.; Tanaka, Yoji; Maehara, Taketoshi; Aoki, Shigeki; Nariai, Tadashi

doi:10.3174/ajnr.a6708

Cited by 11 publications

(19 citation statements)

References 36 publications

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“…We revealed the myelin damage in association with gray matter volume loss in the same areas, which demonstrates the complexity of the microstructural changes of the brain parenchyma in chronic ischemic conditions. It has been proposed previously, that myelin damage could be irreversible in MMA (Hara et al, 2020) because it persists even after surgical treatment. On the other hand, an increase in fractional anisotropy values in white matter after revascularization surgery has been shown in another study (Kazumata et al, 2019), which should represent the improvement of the white matter microstructural integrity (remyelination).…”

Section: Discussionmentioning

confidence: 97%

“…The P-values on the graphs are before FDR-correction, adjusted p < 0.05 (A), <0.05 (B). (Hara et al, 2020), the calculation of the water myelin fraction, or WMF (MacKay and Laule, 2016); and the method of the macromolecular proton fraction assessment, or MPF (Yarnykh, 2016). Various methods have been used in patients with moyamoya angiopathy and revealed the myelin damage, diffuse or focal (Kazumata et al, 2019;Hara et al, 2020;Liu et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

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Myelin damage and cortical atrophy in watershed regions in patients with moyamoya angiopathy

et al. 2022

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BackgroundDespite it being known that chronic ischemia results in myelin damage and gray matter atrophy, data regarding patients with moyamoya angiopathy is limited. We hypothesized that chronic ischemia in moyamoya angiopathy leads to myelin damage, especially in anterior watershed regions, as well as cortical atrophy in these areas.Materials and methodsTwenty adult patients with moyamoya angiopathy and 17 age- and sex-matched healthy controls were evaluated using the T1w/T2w mapping method and surface-based MR-morphometry. The T1w/T2w signal intensity ratio, which reflects the white matter integrity, and the cortical thickness, were calculated in watershed regions and compared between the patients and controls. In the patients with moyamoya angiopathy, the correlations between these parameters and the Suzuki stage were also evaluated.ResultsThe regional T1w/T2w ratio values from centrum semiovale in patients with MMA were significantly lower than those in healthy controls (p < 0.05); there was also a downward trend in T1w/T2w ratio values from middle frontal gyrus white matter in patients compared with the controls (p < 0.1). The cortical thickness of the middle frontal gyrus was significantly lower in patients than in healthy controls (p < 0.05). There were negative correlations between the Suzuki stage and the T1w/T2w ratio values from the centrum semiovale and middle frontal white matter.ConclusionT1w/T2w mapping revealed that myelin damage exists in watershed regions in patients with moyamoya angiopathy, in association with cortical atrophy according to MR-morphometry. These changes were correlated with the disease stage.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Myelin damage and cortical atrophy in watershed regions in patients with moyamoya angiopathy

et al. 2022

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“…White matter integrity impairment and cognitive disruption in MMD have been demonstrated in several studies, aberrant functional connectivity is another form of brain damage caused by MMD [ 2 , 7 , 18 , 38 ]. The impaired brain functional and structural connectivity between the SMA and IFG in the left hemisphere provides us a novel perception of the pathophysiology of MMD and might be applied as the hallmark in the evaluation of disease progression and prognosis of MMD in the future.…”

Section: Discussionmentioning

confidence: 99%

Abnormal brain functional and structural connectivity between the left supplementary motor area and inferior frontal gyrus in moyamoya disease

et al. 2022

BMC Neurol

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Background Disruption of brain functional connectivity has been detected after stroke, but whether it also occurs in moyamoya disease (MMD) is unknown. Impaired functional connectivity is always correlated with abnormal white matter fibers. Herein, we used multimodal imaging techniques to explore the changes in brain functional and structural connectivity in MMD patients. Methods We collected structural images, resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging for each subject. Cognitive functions of MMD patients were evaluated using the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Trail Making Test parts A and B (TMT-A/-B). We calculated the functional connectivity for every paired region using 90 regions of interest from the Anatomical Automatic Labeling Atlas and then determined the differences between MMD patients and HCs. We extracted the functional connectivity of paired brain regions with significant differences between the two groups. Correlation analyses were then performed between the functional connectivity and variable cognitive functions. To explore whether the impaired functional connectivity and cognitive performances were attributed to the destruction of white matter fibers, we further analyzed fiber integrity using tractography between paired regions that were correlated with cognition. Results There was lower functional connectivity in MMD patients as compared to HCs between the bilateral inferior frontal gyrus, between the bilateral supramarginal gyrus, between the left supplementary motor area (SMA) and the left orbital part of the inferior frontal gyrus (IFGorb), and between the left SMA and the left middle temporal gyrus (P < 0.01, FDR corrected). The decreased functional connectivity between the left SMA and the left IFGorb was significantly correlated with the MMSE (r = 0.52, P = 0.024), MoCA (r = 0.60, P = 0.006), and TMT-B (r = -0.54, P = 0.048) in MMD patients. White matter fibers were also injured between the SMA and IFGorb in the left hemisphere and were positively correlated with reduced functional connectivity. Conclusions Brain functional and structural connectivity between the supplementary motor area and inferior frontal gyrus in the left hemisphere are damaged in MMD. These findings could be useful in the evaluation of disease progression and prognosis of MMD.

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“…The MR g-ratio has been applied in cross- sectional studies of MS, 30, 34, 70, 71 healthy cohorts, 72 other diseases (e.g. Moyamoya disease 73 , Huntington’s disease 74 ), and childhood development, 75 yet longitudinal analysis of g-ratio in the adult brain has been notably lacking. Our results illustrate that g-ratio may be suited to assessing myelin integrity changes over time.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal microstructural MRI markers of demyelination and neurodegeneration in early relapsing-remitting multiple sclerosis: magnetisation transfer, water diffusion and g-ratio

York

Meijboom

Thrippleton

et al. 2022

Preprint

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IntroductionRelapsing-remitting multiple sclerosis (RRMS) is a chronic, immune-mediated neurodegenerative disease with a highly heterogeneous disease course. Conventional MRI is widely used for diagnosis and disease monitoring but provides limited specific information on MS-related damage. Improved in vivo biomarkers, which are sensitive to subtle changes in RRMS pathology, are needed for early patient stratification and evaluation of neuroprotective and disease modifying therapies (DMTs).Quantitative MRI methods, such as myelin-sensitive magnetisation transfer ratio (MTR) or saturation (MTsat) imaging, axon-sensitive diffusion Neurite Orientation Dispersion and Density Imaging (NODDI) and derived aggregate measures (e.g. MR g-ratio) may provide more specific indices of microstructural damage in RRMS.The aim of this study was to determine the sensitivity of microstructural MRI markers (magnetisation transfer ratio [MTR], MTsat, NODDI isotropic/intraneurite volume fractions, and g-ratio) to myelin and axonal damage in white matter lesions (WML) and normal appearing white matter (NAWM) and their longitudinal change in early RRMS.MethodsSeventy-seven people were recruited to an extended MRI sub-study of Future-MS, a longitudinal study of people with recently diagnosed RRMS. MR imaging and clinical assessment were performed at baseline, prior to initiation of any DMTs, and one year later. Twelve healthy volunteers additionally received the same MR protocol, repeated within two weeks, to determine test-retest agreement. Approval was granted from the local Research Ethics committee and participants provided written informed consent.A 3T MR imaging protocol included structural 3D T1-weighted and T2-weighted FLAIR sequences, magnetisation transfer acquisition (comprising two proton density images with and without a saturation pulse, plus a T1-weighted image), and multishell diffusion-weighted 2D echo-planar imaging.MTR and MTsat were calculated from magnetisation transfer data, and NODDI isotropic and intraneurite volume fractions (ISOVF and ICVF, respectively) from diffusion-weighted data. The g-ratio was calculated from MTsat and NODDI data. WML and NAWM tissue masks were segmented from structural images.Tissue contrast for MTsat and MTR was compared with paired t-tests. Voxelwise distributions of microstructural metrics were examined graphically.Longitudinal change in MR-derived measures in NAWM and WML was assessed with paired t-tests (α=0.05) with follow-up linear mixed models, where significant, to control for confounding factors, with False Discovery Rate (FDR) correction for multiple comparisons.ResultsComplete longitudinal data for MTsat and MTR was available for sixty-two patients, and sixty patients for NODDI and g-ratio.Contrast between NAWM and WML was greater for MTsat than MTR (mean difference = 16.9 [95% CI 15.96 to 17.89], paired t-test: t(74)=34.97, p<0.001). Voxelwise histograms showed a negative linear dependence on the approximation of T1 recovery (T1app) for MTsat, but not MTR, in NAWM and a non-linear association in WML.Simulations and voxelwise histograms demonstrated that g-ratio is inversely related to MTsat and NODDI ISOVF but positively related to NODDI ICVF. MTsat and NODDI ICVF were not associated in control white matter or NAWM but broadly co- correlated in WML.In NAWM, g-ratio and NODDI ICVF increased significantly over one year (mean difference = 0.004 [95% CI 0.001 to 0.007] and 0.002 [0.0002 to 0.004], paired t-test: t(59) = 2.60 and 2.29, p = 0.012 and 0.025 respectively) and MTsat decreased (mean difference = -0.032 [95% CI -0.061 to -0.003], t(61) = -2.19, p = 0.033). Neither MTR nor NODDI ISOVF changed significantly over one year (p=0.94 and p=0.67).After accounting for covariates and adjustment for multiple comparisons, the longitudinal increase in g-ratio and in NODDI ICVF remained significant (linear mixed model: adjusted mean difference = 0.007 and 0.004, t(75.9) = 3.08 and t(90.6) = 3.51, FDR-corrected p = 0.029 and 0.007). The decrease in MTsat did not survive correction for multiple comparisons (FDR-corrected p = 0.11).In WML, paired t-tests revealed increases in MTsat, MTR, NODDI ISOVF and ICVF over one year, but no change in g-ratio. Follow-up linear mixed models, however, showed that only changes in MTsat and NODDI metrics were significant after correction for confounding factors and multiple comparisons.Longitudinal change did not, however, generally exceed healthy control test-retest limits of agreement except for NODDI ISOVF and ICVF in WML.DiscussionHigher tissue contrast for MTsat compared with MTR suggests MTsat is more sensitive to demyelination than widely used MTR. Comparisons of microstructural MRI data distributions indicate that MTsat is better suited to measurement of subtle myelin loss in NAWM compared with MTR.NAWM data distributions suggest that MTsat and NODDI ICVF provide independent measures of myelin and axonal integrity. Simulations show that g-ratio increases as MTsat decreases, but changes in NODDI parameters may complicate interpretation of longitudinal change in g-ratio.The observed increase in g-ratio and MTsat in NAWM is indicative of subtle myelin loss in patients with early RRMS. The unexpected increase observed in NODDI ICVF suggests axonal swelling and/or axonal repair, and may confound g-ratio.Increases in MTsat and NODDI ICVF in WML are also suggestive of tissue repair. WML g-ratio did not change over time, likely due to competing effects of longitudinal MTsat and NODDI changes.Despite significant groupwise effects, detection of longitudinal change at an individual level may be limited by technique test-retest agreement in early RRMS.ConclusionMTsat and g-ratio are promising in vivo biomarkers of myelin integrity in early RRMS, and appear more sensitive than MTR for detecting subtle demyelination. Our findings suggest that MTsat and g-ratio measures may be most sensitive for detecting subtle change in NAWM, as compared with more severely damaged WML where T1 effects and neuroaxonal damage predominate. Complex dependence of g- ratio on NODDI parameters illustrates the limitation of interpreting such aggregate measures in isolation, and independent consideration of myelin-sensitive and axonal neuroimaging markers may ultimately be more informative for longitudinal tracking of neuropathology in RRMS. Technique reproducibility currently limits evaluation in individual patients, and future research is warranted to validate diffusion and MT models across heterogeneous microstructural damage found in MS, for translation into clinical practice and trial platforms.

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Myelin and Axonal Damage in Normal-Appearing White Matter in Patients with Moyamoya Disease

Cited by 11 publications

References 36 publications

Myelin damage and cortical atrophy in watershed regions in patients with moyamoya angiopathy

Myelin damage and cortical atrophy in watershed regions in patients with moyamoya angiopathy

Abnormal brain functional and structural connectivity between the left supplementary motor area and inferior frontal gyrus in moyamoya disease

Longitudinal microstructural MRI markers of demyelination and neurodegeneration in early relapsing-remitting multiple sclerosis: magnetisation transfer, water diffusion and g-ratio

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