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

BackgroundThe structural integrity of the anterior cingulum has been repeatedly observed to be abnormal in patients with schizophrenia. Reduced glutathione levels, indicating oxidative stress, is associated with reduced structural integrity of cingulum bundle in patients with schizophrenia. Variations in neuregulin-1, a well-established candidate marker for schizophrenia, results in oligodendrocyte dysfunction and defective myelination, and is shown to affect the structural integrity of the anterior cingulum in patients with schizophrenia. While the evidence to date has been obtained using diffusion tensor imaging, abnormal tract-specific changes in myelin content can be more directly inferred by combining multiple modalities of WM imaging such as diffusion tensor (DTI) and magnetization transfer imaging (MTI) in parallel.MethodsWe used ultra-high resolution (7 Tesla) MTI in 17 patients with schizophrenia and 20 controls, to evaluate the macromolecular (predominantly myelin) content of the brain. Immediately after the 7T scanning, we also obtained a 3T diffusion tensor image (DTI) and undertook probabilistic tractography using FSL software (AutoPtx, ProbTrackX) to delineate anterior cingulum bilaterally. Unpaired t tests were used for group comparisons along with estimates of Cohen’s d or Hedge’s g for effect sizes.ResultsPatients had a significant reduction in magnetization transfer ratio (MTR) in right (Cohen’s d=0.91, p=0.007) but not left (d=0.03, p=0.92) cingulum bundle. There was also a trend level reduction in fractional anisotropy of right (d=0.60, p=0.07) but not left (d=0.47, p=0.17) cingulum bundle. We did not find any significant relationship between the 3 major symptom dimensions of schizophrenia (Reality Distortion, Disorganization, Psychomotor Poverty) and Cingulum MTR. Patients with Schneiderian delusions (n=5) showed a significantly reduced MTR of left cingulum compared to patients (n=12) with no Schneiderian delusions (Hedges’ g=1.36, p=0.02).DiscussionOur findings suggest that MTR changes in anterior cingulum, resulting from either dysmyelination or neuroinflammation, is present in clinically stable patients with schizophrenia despite their medicated status. We lacked sufficient power to detect association between MTR changes of cingulum and symptom dimensions. Nevertheless, our results suggest that MTR changes are of higher magnitude than changes in fractional anisotropy, indicating the sensitivity of measuring myelination as a biological marker of white matter aberrations in schizophrenia.

In vivo evaluation of remyelination in rat brain by magnetization transfer imaging

Objectives:To investigate the relationship between magnetization transfer (MT) imaging and tissue macromolecules in high-grade serous ovarian cancer (HGSOC) and whether MT ratio (MTR) changes following neoadjuvant chemotherapy (NACT).Methods:This was a prospective observational study. 12 HGSOC patients were imaged before treatment. MTR was compared to quantified tissue histology and immunohistochemistry. For a subset of patients (n = 5), MT imaging was repeated after NACT. The Shapiro–Wilk test was used to assess for normality of data and Spearman’s rank-order or Pearson’s correlation tests were then used to compare MTR with tissue quantifications. The Wilcoxon signed-rank test was used to assess for changes in MTR after treatment.Results:Treatment-naïve tumour MTR was 21.9 ± 3.1% (mean ± S.D.). MTR had a positive correlation with cellularity, rho = 0.56 (p < 0.05) and a negative correlation with tumour volume, ρ = −0.72 (p = 0.01). MTR did not correlate with the extracellular proteins, collagen IV or laminin (p = 0.40 and p = 0.90). For those patients imaged before and after NACT, an increase in MTR was observed in each case with mean MTR 20.6 ± 3.1% (median 21.1) pre-treatment and 25.6 ± 3.4% (median 26.5) post-treatment (p = 0.06).Conclusion:In treatment-naïve HGSOC, MTR is associated with cellularity, possibly reflecting intracellular macromolecular concentration. MT may also detect the HGSOC response to NACT, however larger studies are required to validate this finding.Advances in knowledge:MTR in HGSOC is influenced by cellularity. This may be applied to assess for cell changes following treatment.

Background and objective: The onset of multiple sclerosis is relapsing remitting or primary progressive. An improved understanding of the causes of early progressive disability in primary progressive multiple sclerosis (PPMS)...

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.

Background:Progression rates in primary progressive multiple sclerosis (PPMS) vary widely and brain magnetisation transfer imaging (MTI) has potential as an early prognostic indicator. We investigated the predictive value of MTI...

The goal of this study was to develop and validate a method for generation of regional magnetization transfer ratio (MTR). We also studied the topography of MTR changes in multiple sclerosis (MS) and in normal controls (NC), and preliminarily examined the clinical usefulness of this method. We examined 45 patients with MS (relapsing remitting [RR] = 28 and secondary progressive[SP] = 17] and 19 NC. Mean disease duration was 14.3 years and median Expanded Disability Status Scale was 3.0. Regions of the brain were determined using semiautomated brain region extraction (SABRE). Twenty-six regional masks were automatically applied to MTR maps that were further split into gray matter (GM) and white matter (WM)compartments. Mean MTR from 12 SABRE regions differed significantly between MS patients and NC. For WM, all regional mean MTRs differed significantly between RR, SP, and NC participants(P < .001). In regression analysis, only 3 regions remained significantly different when corrected for total T2-LV. The regression model predicting disability selected GM mean MTR of the right medial inferior frontal region (P = .031). The study results showed that this regional MTR approach is reproducible, reliable and clinically relevant. MTI changes occur selectively in specific sub-regions.

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.

Multiparametric magnetic resonance imaging analysis of the corticospinal tract in multiple sclerosis.

Magnetization transfer imaging of bone marrow with and without fat suppression.

Background: Tract-based spatial statistics (TBSS) is suitable for the assessment of voxel-wise changes in fiber integrity in WM tracts in the entire brain. Longitudinal TBSS analyses of early multiple sclerosis (MS) using 3 Tesla magnetic resonance imaging (MRI) are not common.Objective: To characterize microstructural WM alterations at initial diagnosis in clinically isolated syndrome (CIS) and early MS at baseline and longitudinally over 2 years.Methods: DTI (Diffusion tensor imaging) at 3 Tesla was used to evaluate 106 therapy-naive patients with CIS or definite MS at baseline and at 1-year (N = 83) and 2-year (N = 43) follow-up compared to healthy controls (HC, N = 49). TBSS was used for voxel-wise analyses of the DTI indices of fractional anisotropy (FA) and radial, mean, and axial diffusivity (RD, MD, AD) for cross-sectional and longitudinal comparisons. Mean values of FA, RD, and cluster voxel numbers were extracted from significant clusters using an atlas-based approach. Correlations with disability (EDSS) were calculated for FA and RD changes related to affected brain regions.Results: Reductions in FA compared to HC were found at baseline in patients with CIS and RRMS and involved most supra- and infratentorial WM tracts. In the cerebellum and cerebral peduncles, these changes negatively correlated with EDSS after 2 years. FA changes in patients with CIS and RRMS evolved in the second year, particularly in the descending projection pathways and the cerebellum, and were significantly associated with EDSS. RD alterations compared to HC were undetectable in patients at baseline but were observed after 1 year and were exacerbated during the second year in all major supratentorial WM tracts, the corpus callosum, and the cerebellum. FA did not change between baseline and year 1 follow-up, but longitudinal investigation between the first and second year revealed combined dynamic FA and RD changes in the corpus callosum and corona radiata.Conclusion: TBSS of diffusion metrics at initial diagnosis and at 2-year follow-up showed microstructural WM pathology and associations between FA reduction and future disability, respectively. Combined longitudinal changes in FA and RD occurred in specific structures, where RD increases likely reflected progressing axonal degeneration. The distinct temporal dynamics of FA and RD, implying constancy during the first year, supports early therapeutic intervention for CIS and RRMS.

Reduction in temporal lobe volume is consistently found in dementia of Alzheimer's type (DAT). However, due to the lack of a consistent association between brain volume and cognitive decline in mild cognitive impairment (MCI), volumetric measures are not a reliable predictor for the progression of the disease. In our study, we hypothesized that changes in the magnetization transfer ratio (MTR) may reflect underlying brain pathology in the absence of quantifiable volumetric changes. Such a measure may be used as a predictor for abnormal cognitive decline in elderly subjects. The study was carried out on 15 normal elderly controls, 11 subjects with DAT, and 12 subjects with MCI. We used MTRs with magnetic resonance imaging (MRI) to detect tissue changes in the four lobes of each hemisphere, and compared that to the volumetric changes in the same regions. Our results indicate that the MTR of both temporal lobes is significantly reduced in subjects with MCI in the absence of significant volumetric changes. In comparison, DAT subjects have significantly reduced temporal lobe volumes and MTR. We conclude that changes in MTR have the potential to mark the progression of MCI to DAT, before volumetric changes are detected on conventional MRI scans.

Fragile X syndrome (FXS) is the most commonly inherited form of intellectual disability ascribed to the autism spectrum disorder. Studies with FXS patients have reported altered white matter volume compared to controls. The Fmr1 knockout (KO) mouse, a model for FXS, showed evidence of delayed myelination during postnatal brain development. In this study, we examined several white matter regions in the male Fmr1 KO mouse brain compared to male wild-type (WT) mice at postnatal days (PND) 18, 21, 30, and 60, which coincide with critical stages of myelination and postnatal brain development. White matter volume, T₂ relaxation time, and magnetization transfer ratio (MTR) were measured using magnetic resonance imaging and myelin content was determined with histological staining of myelin. Differences in the developmental accumulation of white matter and myelin between Fmr1 KO and WT mice were observed in the corpus callosum, external and internal capsules, cerebral peduncle, and fimbria. Alterations were more predominant in the external and internal capsules and fimbria of Fmr1 KO mice, where the MTR was lower at PND 18, then elevated at PND 30, and again lower at PND 60 compared to the corresponding regions in WT mice. The pattern of changes in MTR were similar to those observed in myelin staining and could be related to the altered protein synthesis that is a hallmark of FXS. While no significant changes in white matter volumes and T₂ relaxation time between the Fmr1 KO and WT mice were observed, the altered pattern of myelin staining and MTR, particularly in the external capsule, reflecting the abnormalities associated with myelin content is suggestive of a developmental delay in the white matter of Fmr1 KO mouse brain. These early differences in white matter during critical developmental stages may contribute to altered brain networks in the Fmr1 KO mice.

Background. Despite progress made in understanding functional reorganization patterns underlying recovery in subacute aphasia, the relation between recovery and changes in white matter structure remains unclear. Objective. To investigate changes in dorsal and ventral language white matter tract integrity in relation to naming recovery in subacute poststroke aphasia. Methods. Ten participants with aphasia after left-hemisphere stroke underwent language testing and diffusion tensor imaging twice within 3 months post onset, with a 1-month interval between sessions. Deterministic tractography was used to bilaterally reconstruct the superior longitudinal fasciculus (SLF), inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), middle longitudinal fasciculus (MdLF), and uncinate fasciculus (UF). Per tract, the mean fractional anisotropy (FA) was extracted as a measure of microstructural integrity. Naming accuracy was assessed with the Boston Naming Test (BNT). Correlational analyses were performed to investigate the relationship between changes in FA values and change in BNT score. Results. A strong positive correlation was found between FA change in the right ILF within the ventral stream and change on the BNT (r = 0.91, P < .001). An increase in FA in the right ILF was associated with considerable improvement of naming accuracy (range BNT change score: 12-14), a reduction with limited improvement or slight deterioration. No significant correlations were found between change in naming accuracy and FA change in any of the other right or left ventral and dorsal language tracts. Conclusions. Naming recovery in subacute aphasia is associated with change in the integrity of the right ILF.

Reduced MTR in the corticospinal tract and normal T 2 in amyotrophic lateral sclerosis