Decrease In Magnetization Transfer Ratio Research Articles

Tract-specific magnetization transfer ratio provides insights into the severity of degenerative cervical myelopathy.

Cross-sectional study. This study's goal is to report whether Magnetization Transfer Ratio (MTR) can evaluate the severity of white matter (WM) injury in degenerative cervical myelopathy (DCM). Laureate Institute of Brain Research, USA; Department of Neurosurgery, University of Oklahoma Health Sciences Center, USA. 27 DCM patients were aged-matched with 20 healthy controls (HC) and categorized into treatment groups based on modified Japanese Orthopedic Association (mJOA) severity (11 mild and 16 moderate/severe). Regional and tract MTRs were extracted from the two vertebral levels containing maximum compression within magnetization transfer images. MTR differences between groups were assessed using a one-way ANOVA or Kruskal-Wallis test. The association between MTR and mJOA measures was evaluated using Spearman's correlation. Significant decreases in MTR were found between HC and moderate/severe groups in the overall (p = 0.0065) and ventral (p = 0.0009) WM regions; and ventral corticospinal (p = 0.0101), ventral reticulospinal (p = 0.0084), spinal lemniscus (p = 0.0079), and fasciculus cuneatus (p = 0.0219) tracts. The spinal lemniscus MTR also significantly decreased between HC and mild groups (p = 0.038). Ventral reticulospinal tract MTR correlated with upper (r = 0.439; p = 0.022) and lower (r = 0.386; p = 0.047) limb motor mJOA scores. Significant tract-based MTR changes and correlations align with known DCM symptoms, are demonstrated to be lost at the regional level, and display the inhomogeneous compressive damage occurring within DCM spinal cords.

Fastigial nuclei surgical damage and focal midbrain disruption implicate PAG survival circuits in cerebellar mutism syndrome.

Pediatric postoperative cerebellar mutism syndrome (CMS) is a rare but well-known complication of medulloblastoma (Mb) resection with devastating effects on expressive language, mobility, cognition, and emotional regulation that diminishes quality of life for many Mb survivors. The specific anatomical and neuronal basis of CMS remains obscure. We address this issue by identifying patterns of surgical damage and secondary axonal degeneration in Mb survivors with CMS. Children with Mb deemed high risk for CMS based on intraventricular location of the tumor had T1 images analyzed for location(s) of surgical damage using a specially developed algorithm. We used three complementary methods of spatial analysis to identify surgical damage linked to CMS diagnosis. Magnetization transfer ratio (MTR) images were analyzed for evidence of demyelination in anatomic regions downstream of the cerebellum, indicating neuronal dysfunction. Spatial analyses highlighted damage to the fastigial nuclei and their associated cerebellar cortices as the strongest predictors of CMS. CMS-related MTR decrease was greatest in the ventral periaqueductal gray (PAG) area and highly consistent in the left red nucleus. Our evidence points to disruption of output from the fastigial nuclei as a likely causal trigger for CMS. We propose that core CMS symptoms result from a disruption in the triggering of survival behaviors regulated by the PAG, including the gating of vocalization and volitional movement. The fastigial nuclei provide the densest output to the PAG from the cerebellum, thus sparing these structures may provide a greater likelihood of CMS prevention.

Evaluation of enzymatic proteoglycan loss and collagen degradation in human articular cartilage using ultrashort echo time-based biomarkers: A feasibility study.

The objective of the current study was to investigate the feasibility of quantitative 3D ultrashort echo time (UTE)-based biomarkers in detecting proteoglycan (PG) loss and collagen degradation in human cartilage. A total of 104 cartilage samples were harvested for a trypsin digestion study (n = 44), and a sequential trypsin and collagenase digestion study (n = 60), respectively. Forty-four cartilage samples were randomly divided into a trypsin digestion group (tryp group) and a control group (phosphate-buffered saline [PBS] group) (n = 22 for each group) for the trypsin digestion experiment. The remaining 60 cartilage samples were divided equally into four groups (n = 15 for each group) for sequential trypsin and collagenase digestion, including PBS + Tris (incubated in PBS, then Tris buffer solution), PBS + 30 U col (incubated in PBS, then 30 U/ml collagenase [30 U col] with Tris buffer solution), tryp + 30 U col (incubated in trypsin solution, then 30 U/ml collagenase with Tris buffer solution), and tryp + Tris (incubated in trypsin solution, then Tris buffer solution). The 3D UTE-based MRI biomarkers included T1 , multiecho T2 *, adiabatic T1ρ (AdiabT1ρ ), magnetization transfer ratio (MTR), and modeling of macromolecular proton fraction (MMF). For each cartilage sample, UTE-based biomarkers (T1 , T2 *, AdiabT1ρ , MTR, and MMF) and sample weight were evaluated before and after treatment. PG and hydroxyproline assays were performed. Differences between groups and correlations were assessed. All the evaluated biomarkers were able to differentiate between healthy and degenerated cartilage in the trypsin digestion experiment, but only T1 and AdiabT1ρ were significantly correlated with the PG concentration in the digestion solution (p=0.004 and p= 0.0001, respectively). In the sequential digestion experiment, no significant differences were found for T1 and AdiabT1ρ values between the PBS + Tris and PBS + 30 U col groups (p=0.627 and p= 0.877, respectively), but T1 and AdiabT1ρ values increased significantly in the tryp + Tris (p=0.031 and p= 0.024, respectively) and tryp + 30 U col groups (both p<0.0001). Significant decreases in MMF and MTR were found in the tryp + 30 U col group compared with the PBS + Tris group (p=0.002 and p= 0.001, respectively). It was concluded that AdiabT1ρ and T1 have the potential for detecting PG loss, while MMF and MTR are promising for the detection of collagen degradation in articular cartilage, which could facilitate earlier, noninvasive diagnosis of osteoarthritis.

Efficacy and safety of temelimab in multiple sclerosis: Results of a randomized phase 2b and extension study

Background: The envelope protein of human endogenous retrovirus W (HERV-W-Env) is expressed by macrophages and microglia, mediating axonal damage in chronic active MS lesions. Objective and Methods: This phase 2, double-blind, 48-week trial in relapsing-remitting MS with 48-week extension phase assessed the efficacy and safety of temelimab; a monoclonal antibody neutralizing HERV-W-Env. The primary endpoint was the reduction of cumulative gadolinium-enhancing T1-lesions in brain magnetic resonance imaging (MRI) scans at week 24. Additional endpoints included numbers of T2 and T1-hypointense lesions, magnetization transfer ratio, and brain atrophy. In total, 270 participants were randomized to receive monthly intravenous temelimab (6, 12, or 18 mg/kg) or placebo for 24 weeks; at week 24 placebo-treated participants were re-randomized to treatment groups. Results: The primary endpoint was not met. At week 48, participants treated with 18 mg/kg temelimab had fewer new T1-hypointense lesions (p = 0.014) and showed consistent, however statistically non-significant, reductions in brain atrophy and magnetization transfer ratio decrease, as compared with the placebo/comparator group. These latter two trends were sustained over 96 weeks. No safety issues emerged. Conclusion: Temelimab failed to show an effect on features of acute inflammation but demonstrated preliminary radiological signs of possible anti-neurodegenerative effects. Current data support the development of temelimab for progressive MS. Trial registration: CHANGE-MS: ClinicalTrials.gov: NCT02782858, EudraCT: 2015-004059-29; ANGEL-MS: ClinicalTrials.gov: NCT03239860, EudraCT: 2016-004935-18

Multiparametric in vivo analyses of the brain and spine identify structural and metabolic biomarkers in men with adrenomyeloneuropathy

ObjectiveProgressive myelopathy causes severe handicap in men with adrenomyeloneuropathy (AMN), an X-linked disorder due to ABCD1 pathogenic variants. At present, treatments are symptomatic but disease-modifying therapies are under evaluation. Given the small effect size of clinical scales in AMN, biomarkers with higher effect size are needed. Here we used high-resolution magnetic resonance techniques to identify non-invasive in vivo biomarkers of the brain and spine with high effect sizes. MethodsWe performed a multiparametric imaging and spectroscopy study in 23 male patients with AMN (age: 44 ± 11) and 23 male controls (age: 43 ± 11) of similar age and body-mass index. We combined (i) macrostructural analyses of the spine, using cross-sectional area (CSA) and magnetization transfer ratio (MTR), (ii) microstructural analyses of the spine and the brain, using diffusion tensor and the newly developed fixel-based analysis, and (iii) advanced metabolic analyses of the spine using metabolite cycling coupled to a semi-LASER sequences. ResultsMacrostructural alterations (decrease in CSA and MTR) were observed in patients at all spinal cord levels studied (C1-T2 for CSA and C1-C5 for MTR) (p < 0.001). Microstructural alterations were observed in the spine and brain on diffusion tensor and fixel-based metrics though the latter showed higher effect sizes. Metabolic alterations were observed in patients as a decreased total N-acetylaspartate/myo-inositol ratio (p < 0.001). Overall, MTR showed the highest effect size. ConclusionThis cross-sectional study supports the use of multiparametric techniques that elucidate the structural, microstructural and metabolic alterations in AMN. These outcome measures should be tested longitudinally and in clinical trials.

Contrast-free high-resolution 3D magnetization transfer imaging for simultaneous myocardial scar and cardiac vein visualization

ObjectiveTo develop a three-dimensional (3D) high-resolution free-breathing magnetization transfer ratio (MTR) sequence for contrast-free assessment of myocardial infarct and coronary vein anatomy.Materials and methodsTwo datasets with and without off-resonance magnetization transfer preparation were sequentially acquired to compute MTR. 2D image navigators enabled beat-to-beat translational and bin-to-bin non-rigid motion correction. Two different imaging sequences were explored. MTR scar localization was compared against 3D late gadolinium enhancement (LGE) in a porcine model of myocardial infarction. MTR variability across the left ventricle and vessel sharpness in the coronary veins were evaluated in healthy human subjects.ResultsA decrease in MTR was observed in areas with LGE in all pigs (non-infarct: 25.1 ± 1.7% vs infarct: 16.8 ± 1.9%). The average infarct volume overlap on MTR and LGE was 62.5 ± 19.2%. In humans, mean MTR in myocardium was between 37 and 40%. Spatial variability was between 15 and 20% of the mean value. 3D whole heart MT-prepared datasets enabled coronary vein visualization with up to 8% improved vessel sharpness for non-rigid compared to translational motion correction.DiscussionMTR and LGE showed agreement in infarct detection and localization in a swine model. Free-breathing 3D MTR maps are feasible in humans but high spatial variability was observed. Further clinical studies are warranted.

Alterations in brain white matter contributing to age-related slowing of task switching performance: The role of radial diffusivity and magnetization transfer ratio.

Successfully switching between tasks is critical in many daily activities. Age-related slowing of this switching behavior has been documented extensively, but the underlying neural mechanisms remain unclear. Here, we investigated the contribution of brain white matter changes associated with myelin alterations to age-related slowing of switching performance. Diffusion tensor imaging derived radial diffusivity (RD) and magnetization transfer imaging derived magnetization transfer ratio (MTR) were selected as myelin sensitive measures. These metrics were studied in relation to mixing cost (i.e., the increase in reaction time during task blocks that require task switching) on a local-global switching task in young (n = 24) and older (n = 22) adults. Results showed that higher age was associated with widespread increases in RD and decreases in MTR, indicative of white matter deterioration, possibly due to demyelination. Older adults also showed a higher mixing cost, implying slowing of switching performance. Finally, mediation analyses demonstrated that decreases in MTR of the bilateral superior corona radiata contributed to the observed slowing of switching performance with increasing age. These findings provide evidence for a role of cortico-subcortical white matter changes in task switching performance deterioration with healthy aging. Hum Brain Mapp 37:4084-4098, 2016. © 2016 Wiley Periodicals, Inc.

Radiological-pathological correlation of diffusion tensor and magnetization transfer imaging in a closed head traumatic brain injury model.

Metrics of diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) can detect diffuse axonal injury in traumatic brain injury (TBI). The relationship between the changes in these imaging measures and the underlying pathologies is still relatively unknown. This study investigated the radiological-pathological correlation between these imaging techniques and immunohistochemistry using a closed head rat model of TBI. TBI was performed on female rats followed longitudinally by magnetic resonance imaging (MRI) out to 30 days postinjury, with a subset of animals selected for histopathological analyses. A MRI-based finite element analysis was generated to characterize the pattern of the mechanical insult and estimate the extent of brain injury to direct the pathological correlation with imaging findings. DTI axial diffusivity and fractional anisotropy (FA) were sensitive to axonal integrity, whereas radial diffusivity showed significant correlation to the myelin compactness. FA was correlated with astrogliosis in the gray matter, whereas mean diffusivity was correlated with increased cellularity. Secondary inflammatory responses also partly affected the changes of these DTI metrics. The magnetization transfer ratio (MTR) at 3.5ppm demonstrated a strong correlation with both axon and myelin integrity. Decrease in MTR at 20ppm correlated with the extent of astrogliosis in both gray and white matter. Although conventional T2-weighted MRI did not detect abnormalities following TBI, DTI and MTI afforded complementary insight into the underlying pathologies reflecting varying injury states over time, and thus may substitute for histology to reveal diffusive axonal injury pathologies in vivo. This correlation of MRI and histology furthers understanding of the microscopic pathology underlying DTI and MTI changes in TBI. Ann Neurol 2016;79:907-920.

Spatio-Temporal Patterns of Demyelination and Remyelination in the Cuprizone Mouse Model.

Cuprizone administration in mice provides a reproducible model of demyelination and spontaneous remyelination, and has been useful in understanding important aspects of human disease, including multiple sclerosis. In this study, we apply high spatial resolution quantitative MRI techniques to establish the spatio-temporal patterns of acute demyelination in C57BL/6 mice after 6 weeks of cuprizone administration, and subsequent remyelination after 6 weeks of post-cuprizone recovery. MRI measurements were complemented with Black Gold II stain for myelin and immunohistochemical stains for associated tissue changes. Gene expression was evaluated using the Allen Gene Expression Atlas. Twenty-five C57BL/6 male mice were split into control and cuprizone groups; MRI data were obtained at baseline, after 6 weeks of cuprizone, and 6 weeks post-cuprizone. High-resolution (100μm isotropic) whole-brain coverage magnetization transfer ratio (MTR) parametric maps demonstrated concurrent caudal-to-rostral and medial-to-lateral gradients of MTR decrease within corpus callosum (CC) that correlated well with demyelination assessed histologically. Our results show that demyelination was not limited to the midsagittal line of the corpus callosum, and also that opposing gradients of demyelination occur in the lateral and medial CC. T2-weighted MRI gray/white matter contrast was strong at baseline, weak after 6 weeks of cuprizone treatment, and returned to a limited extent after recovery. MTR decreases during demyelination were observed throughout the brain, most clearly in callosal white matter. Myelin damage and repair appear to be influenced by proximity to oligodendrocyte progenitor cell populations and exhibit an inverse correlation with myelin basic protein gene expression. These findings suggest that susceptibility to injury and ability to repair vary across the brain, and whole-brain analysis is necessary to accurately characterize this model. Whole-brain parametric mapping across time is essential for gaining a real understanding of disease processes in-vivo. MTR increases in healthy mice throughout adolescence and adulthood were observed, illustrating the need for appropriate age-matched controls. Elucidating the unique and site-specific demyelination in the cuprizone model may offer new insights into in mechanisms of both damage and repair in human demyelinating diseases.

Chronic T2 Lesions in Multiple Sclerosis are Heterogeneous Regarding Phase MR Imaging.

Phase imaging provides additional information on multiple sclerosis (MS) lesions and may in combination with mean diffusivity (MD) and magnetization transfer ratio (MTR) help differentiating heterogeneity of MS lesion pathology. Magnetic resonance imaging (MRI) was performed in 23 MS patients including diffusion tensor imaging (DTI), magnetization transfer imaging (MTI), and SWI. Mean values (MTR, MD, and homodyne filtered phase) from 138 chronic MS lesions and normal appearing white matter (NAWM) were obtained and correlations examined. For explorative analysis, a divisive hierarchical clustering algorithm was applied. Phase characteristics were an independent characteristic of chronic T2 lesions, as MTR and MD were not correlated with phase values (R = - 0.23, R = - 0.18). Dependent on MTR, MD, and phase, cluster analysis led to five lesion groups. Of the two groups with phase values close to NAWM, one presented with highest MD and most severe MTR decrease (p = 0.01), the other with slight MD increase and MTR decrease. Two lesion groups with highest phase values (p = 0.01) displayed slightly increased MD and moderate decrease in MTR. Clinical data including EDSS, disease duration, and age did not differ significantly between groups. Increased phase is predominantly detectable in lesions with clear MTR decrease but only moderate MD increase. Phase images seem to represent an independent parameter for MS lesion characterization and may provide additional information on MS lesion heterogeneity.

Cerebral maturation in the early preterm period—A magnetization transfer and diffusion tensor imaging study using voxel-based analysis

The magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) correlates of early brain development were examined in cohort of 18 very preterm neonates (27–31 gestational weeks) presenting with normal radiological findings scanned within 2weeks after birth (28–32 gestational weeks). A combination of non-linear image registration, tissue segmentation, and voxel-wise regression was used to map the age dependent changes in MTR and DTI-derived parameters in 3D across the brain based on the cross-sectional in vivo preterm data. The regression coefficient maps obtained differed between brain regions and between the different quantitative MRI indices. Significant linear increases as well as decreases in MTR and DTI-derived parameters were observed throughout the preterm brain. In particular, the lamination pattern in the cerebral wall was evident on parametric and regression coefficient maps. The frontal white matter area (subplate and intermediate zone) demonstrated a linear decrease in MTR. While the intermediate zone showed an unexpected decrease in fractional anisotropy (FA) with age, with this decrease (and the increase in mean diffusivity (MD)) driven primarily by an increase in radial diffusivity (RD) values, the subplate showed no change in FA (and an increase in MD). The latter was the result of a concomitant similar increase in axial diffusivity (AD) and RD values. Interpreting the in vivo results in terms of available histological data, we present a biophysical model that describes the relation between various microstructural changes measured by complementary quantitative methods available on clinical scanners and a range of maturational processes in brain tissue.

Gender, age‐related, and regional differences of the magnetization transfer ratio of the cortical and subcortical brain gray matter

PurposeTo explore gender, age‐related, and regional differences of magnetization transfer ratio (MTR) of brain cortical and subcortical gray matter (GM).Materials and MethodsIn all, 102 healthy subjects (51 women and 51 men; range 25–84 years) were examined with 3‐mm thick MT images. We assessed MTR in automatically segmented GM structures including frontal, parietal‐insular, temporal, and occipital cortex, caudate, pallidus and putamen, and cerebellar cortex. A general linear model analysis was conducted to ascertain the linear and quadratic relationship among the MTR and gender, age, and anatomical structure.ResultsThe effect of gender was borderline (P = 0.07) in all GM structures (with higher MTR values in men), whereas age showed a significant linear as well as quadratic effect in all cortical and subcortical GM structures (P ≤ 0.001). Quadratic age‐related decrease in MTR began at about 40 years of age. Mean and standard deviation (SD) of MTR had the following decreasing order: thalamus (58.3 + 0.8), pallidus (56.8 ± 1.3), caudate (55.5 ± 1.6) and putamen (54.6 ± 1.1); temporal (56.8 ± 0.9), parietal‐insular (56.8 ± 1.1), frontal (56.5 ± 1.1), occipital (55.4 ± 1.0) and cerebellar (53.2 ± 1.0) cortex. In post‐hoc testing, all regional pairwise differences were statistically significant except pallidus vs. temporal or parietal‐insular cortex, caudate vs. occipital cortex, frontal vs. parietal‐insular or temporal cortex.ConclusionMTR of the cortical and subcortical brain GM structures decreases quadratically after midlife and shows significant regional differences. J. Magn. Reson. Imaging 2014;40:360–366 © 2013 Wiley Periodicals, Inc.

Gender, age-related, and regional differences of the magnetization transfer ratio of the cortical and subcortical brain gray matter.

To explore gender, age-related, and regional differences of magnetization transfer ratio (MTR) of brain cortical and subcortical gray matter (GM). In all, 102 healthy subjects (51 women and 51 men; range 25-84 years) were examined with 3-mm thick MT images. We assessed MTR in automatically segmented GM structures including frontal, parietal-insular, temporal, and occipital cortex, caudate, pallidus and putamen, and cerebellar cortex. A general linear model analysis was conducted to ascertain the linear and quadratic relationship among the MTR and gender, age, and anatomical structure. The effect of gender was borderline (P = 0.07) in all GM structures (with higher MTR values in men), whereas age showed a significant linear as well as quadratic effect in all cortical and subcortical GM structures (P ≤ 0.001). Quadratic age-related decrease in MTR began at about 40 years of age. Mean and standard deviation (SD) of MTR had the following decreasing order: thalamus (58.3 + 0.8), pallidus (56.8 ± 1.3), caudate (55.5 ± 1.6) and putamen (54.6 ± 1.1); temporal (56.8 ± 0.9), parietal-insular (56.8 ± 1.1), frontal (56.5 ± 1.1), occipital (55.4 ± 1.0) and cerebellar (53.2 ± 1.0) cortex. In post-hoc testing, all regional pairwise differences were statistically significant except pallidus vs. temporal or parietal-insular cortex, caudate vs. occipital cortex, frontal vs. parietal-insular or temporal cortex. MTR of the cortical and subcortical brain GM structures decreases quadratically after midlife and shows significant regional differences.

Mapping Cortical Degeneration in ALS with Magnetization Transfer Ratio and Voxel-Based Morphometry

Pathological and imaging data indicate that amyotrophic lateral sclerosis (ALS) is a multisystem disease involving several cerebral cortical areas. Advanced quantitative magnetic resonance imaging (MRI) techniques enable to explore in vivo the volume and microstructure of the cerebral cortex in ALS. We studied with a combined voxel-based morphometry (VBM) and magnetization transfer (MT) imaging approach the capability of MRI to identify the cortical areas affected by neurodegeneration in ALS patients. Eighteen ALS patients and 18 age-matched healthy controls were examined on a 1.5T scanner using a high-resolution 3D T1 weighted spoiled gradient recalled sequence with and without MT saturation pulse. A voxel-based analysis (VBA) was adopted in order to automatically compute the regional atrophy and MT ratio (MTr) changes of the entire cerebral cortex. By using a multimodal image analysis MTr was adjusted for local gray matter (GM) atrophy to investigate if MTr changes can be independent of atrophy of the cerebral cortex. VBA revealed several clusters of combined GM atrophy and MTr decrease in motor-related areas and extra-motor frontotemporal cortex. The multimodal image analysis identified areas of isolated MTr decrease in premotor and extra-motor frontotemporal areas. VBM and MTr are capable to detect the distribution of neurodegenerative alterations in the cortical GM of ALS patients, supporting the hypothesis of a multi-systemic involvement in ALS. MT imaging changes exist beyond volume loss in frontotemporal cortices.

Regional Analysis of the Magnetization Transfer Ratio of the Brain in Mild Alzheimer Disease and Amnestic Mild Cognitive Impairment

Manually drawn VOI-based analysis shows a decrease in magnetization transfer ratio in the hippocampus of patients with Alzheimer disease. We investigated with whole-brain voxelwise analysis the regional changes of the magnetization transfer ratio in patients with mild Alzheimer disease and patients with amnestic mild cognitive impairment. Twenty patients with mild Alzheimer disease, 27 patients with amnestic mild cognitive impairment, and 30 healthy elderly control subjects were examined with high-resolution T1WI and 3-mm-thick magnetization transfer images. Whole-brain voxelwise analysis of magnetization transfer ratio maps was performed by use of Statistical Parametric Mapping 8 software and was supplemented by the analysis of the magnetization transfer ratio in FreeSurfer parcellation-derived VOIs. Voxelwise analysis showed 2 clusters of significantly decreased magnetization transfer ratio in the left hippocampus and amygdala and in the left posterior mesial temporal cortex (fusiform gyrus) of patients with Alzheimer disease as compared with control subjects but no difference between patients with amnestic mild cognitive impairment and either patients with Alzheimer disease or control subjects. VOI analysis showed that the magnetization transfer ratio in the hippocampus and amygdala was significantly lower (bilaterally) in patients with Alzheimer disease when compared with control subjects (ANOVA with Bonferroni correction, at P < .05). Mean magnetization transfer ratio values in the hippocampus and amygdala in patients with amnestic mild cognitive impairment were between those of healthy control subjects and those of patients with mild Alzheimer disease. Support vector machine-based classification demonstrated improved classification performance after inclusion of magnetization transfer ratio-related features, especially between patients with Alzheimer disease versus healthy subjects. Bilateral but asymmetric decrease of magnetization transfer ratio reflecting microstructural changes of the residual GM is present not only in the hippocampus but also in the amygdala in patients with mild Alzheimer disease.

A novel approach with “skeletonised MTR” measures tract‐specific microstructural changes in early primary‐progressive MS

We combined tract-based spatial statistics (TBSS) and magnetization transfer (MT) imaging to assess white matter (WM) tract-specific short-term changes in early primary-progressive multiple sclerosis (PPMS) and their relationships with clinical progression. Twenty-one PPMS patients within 5 years from onset underwent MT and diffusion tensor imaging (DTI) at baseline and after 12 months. Patients' disability was assessed. DTI data were processed to compute fractional anisotropy (FA) and to generate a common WM "skeleton," which represents the tracts that are "common" to all subjects using TBSS. The MT ratio (MTR) was computed from MT data and co-registered with the DTI. The skeletonization procedure derived for FA was applied to each subject's MTR image to obtain a "skeletonised" MTR map for every subject. Permutation tests were used to assess (i) changes in FA, principal diffusivities, and MTR over the follow-up, and (ii) associations between changes in imaging parameters and changes in disability. Patients showed significant decreases in MTR over one year in the corpus callosum (CC), bilateral corticospinal tract (CST), thalamic radiations, and superior and inferior longitudinal fasciculi. These changes were located both within lesions and the normal-appearing WM. No significant longitudinal change in skeletonised FA was found, but radial diffusivity (RD) significantly increased in several regions, including the CST bilaterally and the right inferior longitudinal fasciculus. MTR decreases, RD increases, and axial diffusivity decreases in the CC and CST correlated with a deterioration in the upper limb function. We detected tract-specific multimodal imaging changes that reflect the accrual of microstructural damage and possibly contribute to clinical impairment in PPMS. We propose a novel methodology that can be extended to other diseases to map cross-subject and tract-specific changes in MTR.

Prevalence of Grey Matter Pathology in Early Multiple Sclerosis Assessed by Magnetization Transfer Ratio Imaging

The aim of the study was to assess the prevalence, the distribution and the impact on disability of grey matter (GM) pathology in early multiple sclerosis. Eighty-eight patients with a clinically isolated syndrome with a high risk developing multiple sclerosis were included in the study. Forty-four healthy controls constituted the normative population. An optimized statistical mapping analysis was performed to compare each subject's GM Magnetization Transfer Ratio (MTR) imaging maps with those of the whole group of controls. The statistical threshold of significant GM MTR decrease was determined as the maximum p value (p<0.05 FDR) for which no significant cluster survived when comparing each control to the whole control population. Using this threshold, 51% of patients showed GM abnormalities compared to controls. Locally, 37% of patients presented abnormalities inside the limbic cortex, 34% in the temporal cortex, 32% in the deep grey matter, 30% in the cerebellum, 30% in the frontal cortex, 26% in the occipital cortex and 19% in the parietal cortex. Stepwise regression analysis evidenced significant association (p = 0.002) between EDSS and both GM pathology (p = 0.028) and T2 white matter lesions load (p = 0.019). In the present study, we evidenced that individual analysis of GM MTR map allowed demonstrating that GM pathology is highly heterogeneous across patients at the early stage of MS and partly underlies irreversible disability.

MRI is a sensitive marker of subtle white matter pathology in hypoperfused mice

White matter (WM) abnormalities, possibly resulting from hypoperfusion, are key features of the aging human brain. It is unclear, however, whether in vivo magnetic resonance imaging (MRI) approaches, such as diffusion tensor and magnetization transfer MRI are sufficiently sensitive to detect subtle alterations to WM integrity in mouse models developed to study the aging brain. We therefore investigated the use of diffusion tensor and magnetization transfer MRI to measure structural changes in 4 WM tracts following 1 month of moderate hypoperfusion, which results in diffuse WM pathology in C57Bl/6J mice. Following MRI, brains were processed for evaluation of white and gray matter pathology. Significant reductions in fractional anisotropy were observed in the corpus callosum (p = 0.001) and internal capsule (p = 0.016), and significant decreases in magnetization transfer ratio were observed in the corpus callosum (p = 0.023), fimbria (p = 0.032), internal capsule (p = 0.046) and optic tract (p = 0.047) following hypoperfusion. Hypoperfused mice demonstrated diffuse axonal and myelin pathology which was essentially absent in control mice. Both fractional anisotropy and magnetization transfer ratio correlate with markers of myelin integrity/degradation and not axonal pathology. The study demonstrates that in vivo MRI is a sensitive measure of diffuse, subtle WM changes in the murine brain.

Demyelination of superficial white matter in early Alzheimer's disease: a magnetization transfer imaging study

Assuming selective vulnerability of short association U-fibers in early Alzheimer's disease (AD), we quantified demyelination of the surface white matter (dSWM) with magnetization transfer ratio (MTR) in 15 patients (Clinical Dementia Rating Scale [CDR] 0.5-1; Functional Assessment Staging [FAST]: 3-4) compared with 15 controls. MTRs were computed for 39 areas in each hemisphere. We found a bilateral MTR decrease in the temporal, cingulate, parietal, and prefrontal areas. With linear discriminant analysis, we successfully classified all the participants with 3 variates including the cuneus, parahippocampal, and superior temporal regions of the left hemisphere. The pattern of dSWM changed with the age of AD onset. In early onset patients, we found bilateral posterior demyelination spreading to the temporal areas in the left hemisphere. The late onset patients showed a distributed bilateral pattern with the temporal and cingulate areas strongly affected. A correlation with Mini Mental State Examination (MMSE), Lexis, and memory tests revealed the dSWM impact on cognition. A specific landscape of dSWM in early AD shows the potential of MTR imaging as an in vivo biomarker superior to currently used techniques.

Measuring Demyelination and Remyelination in Acute Multiple Sclerosis Lesion Voxels

To validate the use of the magnetization transfer ratio (MTR) as a practical imaging marker of demyelination and remyelination in acute multiple sclerosis lesions. Case study. University hospital multiple sclerosis clinic. Patients Six patients with relapsing-remitting multiple sclerosis and acute gadolinium-enhancing lesions were studied serially using a quantitative magnetization transfer examination. Changes in the water content and macromolecular content, a marker of myelin content that, unlike MTR, is not affected by changes in water content (edema) associated with acute inflammation, and changes in MTR of lesions. Both the macromolecular content and MTR were lower than normal in acute lesions and recovered over several months. The decrease in macromolecular content relative to contralateral normal-appearing white matter was greater than the decrease in MTR (0.46 vs 0.75 at the time of gadolinium enhancement), likely because edema in the acute lesion increased the T1 relaxation time of water and attenuated the decrease in MTR. Nevertheless, there was still a strong correlation between changes in the relative MTR and macromolecular content (R(2) = 0.70; P < .001). Our data support the use of MTR as a practical marker of demyelination and remyelination, even in acute lesions where decreases in MTR are attenuated because of the effects of edema.