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Background: This study aimed to establish normal regional Magnetization Transfer Ratio (MTR) values in white and grey matter using 3-Tesla MRI in healthy adult subjects, with a particular focus on cortical and deep brain structures. It also aims to assess the variability of these values and provide a baseline for further pathological studies. Materials and Methods: Seventy healthy volunteers (28 females, 42 males, mean age 28 years) were included. MRI scans were performed using a 3.0 Tesla MRI scanner. Conventional cranial MRI sequences were acquired, followed by Magnetization Transfer Imaging (MTI) with off-resonance pulses. MTR maps were generated from proton density-weighted images obtained with and without magnetization transfer pre-pulses. Measurements were performed in 31 white matter and 9 grey matter regions, with additional assessments of CSF for noise control. Statistical analysis was carried out to compare MTR values across different brain regions. Results: The mean MTR value was significantly higher in white matter (23.9 ± 0.21) compared to grey matter (17.3 ± 0.77). The corpus callosum had the highest MTR values within the white matter, particularly in the splenium, while the thalamus exhibited the highest MTR values in the grey matter. Regional variations were observed, with higher MTR values in the occipital and temporal lobes and lower values in the frontal and parietal lobes. MTR measurements showed excellent intra-observer (ICC > 0.9) and good inter-observer reliability (ICC 0.80–0.90). Conclusions: This study provides detailed MTR mapping of normal brain tissue, highlighting significant regional dif-ferences between white and grey matter. The findings offer valuable baseline data for assessing structural changes in CNS diseases and for evaluating the efficacy of therapeutic interventions. MTR measurements demonstrate high reproducibility, making this technique a reliable tool in clinical and research applications for monitoring pathological alterations in the central nervous system.

ABSTRACTPurposeTo determine whether magnetization transfer imaging (MTI) is able to detect microstructure alterations in the cervical spinal cord (CSC) in relapsing‐remitting multiple sclerosis (RRMS) patients and whether they correlate with clinical disability.Methods and MaterialsFifteen RRMS patients (5 males, 10 females, mean ± standard deviation (SD) age: 47.0 ± 12.9 years, age range: 18–70 years; median Expanded Disability Status Scale (EDSS) score = 2; (range: 0.5–6.5) and 20 healthy controls (10 male, 10 females, mean ± sd age: 40.7 ± 12.4 years) underwent 3T MRI scans using standard MTI sequences. Spinal Cord Toolbox (SCT) was used for image post‐processing. Data were first segmented and then registered to a template and then the magnetization transfer ratio (MTR) was computed over the volume between the 2nd and 5th cervical vertebrae for the total white matter (WM) and for specific WM regions: dorsal column (DC), ventral column (VC), and lateral column (LC). Independent sample t‐tests were used to conduct a comparative analysis of means between the healthy and RRMS groups. The association between MTR measures over different ROIs and EDSS was investigated by the univariate association using Pearson correlation coefficient (r) and a simple linear regression analysis.ResultsMTR values were significantly decreased in all ROIs (p < 0.01) in RRMS versus Healthy participants. There was no significant correlation between MTR and EDSS in all ROIs.ConclusionThis study demonstrates that clinical trials using MTI techniques are feasible and show that quantitative MTI can monitor tissue changes in degenerative WM patients.

Magnetic resonance neurography (MRN) has been used extensively to study pathological conditions affecting the peripheral nervous system (PNS). However, tissue damage is assessed qualitatively with little information regarding the underlying pathophysiological processes involved. Magnetisation transfer ratio (MTR) is a quantitative magnetic resonance imaging method which is sensitive to tissue macromolecular content and may therefore have an important role in the study of pathologies affecting the PNS. This study explored the feasibility of obtaining reliable MTR measurements in the proximal lumbar plexus of healthy volunteers using MRN to identify and segment each lumbar segment (L2–L5) and regions (preganglionic, ganglionic and postganglionic). Reproducibility of the MTR measurements and of the segmentation method were assessed from repeated measurements (scan-rescan), and from the reanalysis of images (intra- and inter-rater assessment), by calculating the coefficient of variation (COV). In all segments combined (L2–L5), mean (± SD) MTR was 30.5 (± 2.4). Scan-rescan, intra- and inter-rater COV values were 3.2%, 4.4% and 5.3%, respectively. One-way analysis of variance revealed a statistically significant difference in MTR between the preganglionic and postganglionic regions in all lumbar segments. This pilot study in healthy volunteers demonstrates the feasibility of obtaining reliable MTR measurements in the proximal lumbar plexus, opening up the possibility of studying a broad spectrum of neurological conditions in vivo.

We obtained magnetization transfer imaging (MTI) scans from individuals with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (1) to investigate the presence, extent, and nature of pathology in white and gray matter outside proton density (PD)-visible lesions; (2) to quantify the degree of tissue damage occurring in lesions seen on PD-weighted scans; and (3) to correlate MTI-derived measures of disease burden with age, physical disability, and cognitive performance. Dual-echo, T1-weighted, and MTI scans of the brain were obtained from 33 individuals with CADASIL and 12 control subjects. Magnetization transfer ratio (MTR) values from PD-visible lesions, normal-appearing white matter (NAWM), and normal-appearing gray matter (NAGM) were measured. Histograms of MTR from the whole brain and normal-appearing brain tissue were also produced. All MTR values from NAWM and NAGM regions studied were significantly lower for individuals with CADASIL than for control subjects, with the exception of those obtained from the NAWM of the infratentorial structures and the NAGM of the occipital cortex. The average MTR from PD lesions in individuals with CADASIL was significantly lower than that from all the NAWM regions. Average MTR and peak location from whole-brain and normal-appearing brain tissue histograms were significantly lower for individuals with CADASIL than for control subjects. MTR values from NAWM were strongly correlated with the extent of macroscopic lesions and their average MTR. Apart from NAGM, average MTR from all other tissues studied significantly decreased with increasing age, physical disability, and cognitive impairment. PD lesions of individuals with CADASIL have variable degrees of tissue damage. Brain tissue outside PD abnormalities is also damaged. This study suggests that the extent and the severity of the brain tissue damage are critical factors in determining clinical status in CADASIL.

Magnetization transfer ratio (MTR) histogram analysis provides a global measure of disease burden in multiple sclerosis (MS). MTR abnormalities in normal appearing brain tissue (NABT) provide quantitative information on the extent of tissue damage undetected by conventional T2-weighted (T2W) magnetic resonance imaging (MRI). 1) To compare the MTR histograms from NABT across a broad spectrum of relapse onset MS patients, including relapsing-remitting (RR) MS (including newly diagnosed and benign subgroups) and secondary progressive (SP) MS. 2) To determine the relationship between clinical disability and NABT MTR histograms. 2D spin echo magnetization transfer imaging was performed on 70 RRMS and 25 SPMS patients and compared with 63 controls. MTR histograms were acquired for NABT after extracting lesions and cerebrospinal fluid (CSF). T2W images were used to measure the brain parenchymal fraction (BPF) and T2 lesion load. MS patients had a disease duration ranging from 0.5 to 37 years and an Expanded Disability Status Scale (EDSS) score ranging from 0 to 8.5. There was a significant decrease in NABT mean MTR (+/- standard deviation) compared with controls (33.07 pu +/- 1.06 versus 34.26 pu +/- 0.47; P < 0.001) with an effect size of 2.56. The reduction in NABT mean MTR varied among patient groups from 4.9% for SPMS, 3% for all RRMS, 2.7% for early RRMS and 2.5% for benign MS, compared with controls. NABT mean MTR correlated significantly with T2 lesion load (r = -0.82) and BPF (r = 0.58). EDSS score correlated with NABT mean MTR (r = -0.43), BPF (r = -0.33) and with T2 lesion load (r = 0.59). Multivariate analysis using NABT MTR peak height, T2 lesion load and BPF combined only accounted for 38% of the variance in the EDSS (r = 0.62; P < 0.001). Disease duration accounted for an additional 14% of variance in the EDSS (r = 0.72; P < 0.001). There is evidence of diffuse abnormalities in NABT in addition to global brain atrophy in relapse onset MS patients, including those with recently diagnosed RRMS and benign MS. The abnormalities are greatest in patients with the more disabling SPMS. Atrophy, NABT and lesion abnormalities are all partly correlated; the processes marked by these MR measures all contribute to disability in MS, providing complementary information relevant to the complex pathological processes that occur in MS.

This study presents automated atlas-based magnetization transfer (MT) measurements of the typically developing pediatric cervical spinal cord (SC). We report normative MT ratio (MTR) values from the whole cervical cord white matter (WM) and WM tracts, examining variations with age, sex, height, and weight. MT scans of 33 healthy females (mean age=12.8) and 22 males (mean age=13.09) were acquired from the cervical SC (C2-C7) using a 3.0T MRI. Data were processed using the SC Toolbox, segmented, and registered to the PAM50 template. Affine and non-rigid transformations co-registered the PAM50 WM atlas to subject-specific space. MTRs were measured for the specific WM tracts (left and right dorsal fasciculus gracilis, dorsal fasciculus cuneatus, and lateral corticospinal tracts [LCST]) and the whole WM. Descriptive statistics, correlation analysis, and unpaired t-tests (p<0.05) assessed relationships with age, height, weight, and sex. Normative MTR measurements were obtained from all regions. The coefficients of variation were low to moderate. No significant differences (p>0.05) were found across all the cervical levels. However, significant sex differences were observed in whole WM (p=0.04) and LCST (p=0.03). MTR values correlated positively with age, with significant correlations at C5 (r=0.3, p false discovery rate=0.04). A decreasing trend in MTR values across levels was found for whole WM (r=-0.2, p<0.001). This study provides an understanding of MTR values in pediatric cervical SC and their variations by sex, age, height, and weight, providing a baseline for comparisons in pediatric SC diseases.

The purpose of this work was to determine the extent of disease and disease severity in the conventional MR normal-appearing gray matter (NAGM) and white matter (NAWM) in patients with relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS) utilizing quantitative magnetization transfer ratio (MTR) histogram analysis. Twenty-seven patients with MS (16 RR, 11 SP) and 16 healthy control subjects were studied. MTR was calculated in the totally segmented GM and WM without T2 lesions in each group. Each of the RR and SP MS patient groups had significantly smaller MTR histogram mean values in NAGM and NAWM than the healthy subjects (p </= 0.0015). SP MS patients had a significantly lower first quartile and MTR histogram peak height for NAGM only (p </= 0.004) when compared with both RR MS patients and healthy subjects. The T2 lesion load had a modest negative correlation with MTR values in both RR and SP MS, but only in NAGM. Separate analysis of GM and WM MTR histograms may allow better detection of subtle damage and better understanding of the natural history of MS disease and ultimately the response to therapeutics.

Background In multiple sclerosis, grey matter (GM) damage appears more clinically relevant than either white matter damage or lesion load. Objective We investigated if normal-appearing white matter (NAWM) and grey matter tissue changes assessed by magnetization transfer ratio were associated with long-term disability. Methods Sixty-nine people were assessed 20 years after presentation with a clinically isolated syndrome (CIS) [28 still CIS, 31 relapsing-remitting multiple sclerosis, 10 secondary progressive multiple sclerosis], along with 19 healthy subjects. Mean magnetization transfer ratio, peak height (PH) and peak location of the normalized magnetization transfer ratio histograms were determined in NAWM and grey matter, as well as, white matter and GM Fraction (GMF) and T2-weighted lesion load. Results Median expanded disability status scale for multiple sclerosis patients was 2.5 (range 1–8). GM-PH, and less so, NAWM mean and peak location, were lower in multiple sclerosis patients (P = 0.009) versus controls, relapsing-remitting multiple sclerosis versus CIS (P = 0.008) and secondary progressive multiple sclerosis versus relapsing-remitting multiple sclerosis (P = 0.002). GM-PH (as well as GMF) correlated with expanded disability status scale (r s = −0.49; P = 0.001) and multiple sclerosis functional score (r s = 0.51; P = 0.001). GM-PH independently predicted disability with similar strength to the associations of GMF with clinical measures. Conclusion Grey matter damage was related to long-term disability in multiple sclerosis cohort with a relatively low median expanded disability status scale. Markers of intrinsic grey matter damage (magnetization transfer ratio) and tissue loss offer clinically relevant information in multiple sclerosis.

MTR and T1 relaxation times are abnormal in MS lesions and NAWM, and may reflect tissue damage such as demyelination and axonal loss. Their relationship and potential to provide complementary information in tissue characterisation is explored. The aim of this study was to document the relationship between magnetisation transfer ratio (MTR) and T1 relaxation time in Multiple Sclerosis (MS) lesions and normal appearing white matter (NAWM) in order to determine whether the combination provides a more comprehensive tissue characterisation than either parameter in isolation. Ten patients with relapsing remitting MS and 10 age matched healthy controls underwent imaging using a protocol which included the measurement of both MTR and T1 relaxation times. The MTR and T1 values were compared statistically using a commonly adopted correlation approach and a mixed-model regression approach. There was a strong correlation between MTR and T1 in MS lesions (r=0.74). The correlation was seen equally in T1 hypointense and isointense lesions. The relationship was much weaker in MS NAWM (r=0.24) and no correlation was found in control white matter (r=0.06). Mixed-model regression analysis confirmed that the relationship between T1 and MTR is strongly dependent upon tissue type (MS lesion, MS NAWM, or control white matter). The relationship between MTR and T1 relaxation time measurements varies markedly between pathological and normal tissue types. In MS, the complementary information obtained from MTR and T1 is most apparent in NAWM. The results emphasise the potential for combinations of MR parameters to improve tissue characterisation, which in turn should improve understanding of disease pathology and treatment monitoring. Multiple Sclerosis (2000) 6 327 - 331

Objective: To determine the effects of intravenous natalizumab and intramuscular interferon beta-1a (IFNβ-1a) on the volume of white-matter (WM) lesions and normal appearing brain tissue (NABT) undergoing voxel-wise (VW) increases in magnetization transfer ratio (MTR) suggestive of remyelination in patients with relapsing multiple sclerosis. Methods: This prospective, open-label, single-blinded study enrolled patients with relapsing–remitting multiple sclerosis (RRMS) and relapsing secondary progressive multiple sclerosis (RSPMS) as well as a group of age/sex-matched healthy controls (n=22). Patients with multiple sclerosis were assigned to receive natalizumab monotherapy (n=77; RRMS/RSPMS) or intramuscular IFNβ-1a (n=26) as either monotherapy (RRMS) or combined with pulsed i.v. methylprednisolone, as needed (RSPMS). The primary endpoint was the two-year change in volume of NABT VWMTR, by quantifying the number of voxels that increased (suggesting remyelination) or decreased (suggesting demyelination) in their MTR value. Results: The volume of tissue undergoing increases in VWMTR was significantly larger in natalizumab compared with IFNβ-1a-treated patients (year 1: p=0.001 in NABT and p<0.006 in WM lesions; year 2: p=0.008 in NABT) and compared with healthy control subjects (year 1: p=0.05 and year 2: p=0.007 in NABT). The larger volume within NABT undergoing decreases in VWMTR was detected in multiple sclerosis patients compared with healthy controls (p<0.001), and in the IFNβ-1a group compared with the natalizumab group (year 1: p=0.05; year 2: p=0.002). One patient on natalizumab died from progressive multifocal leukoencephalopathy eight months after completing the study. Conclusion: Natalizumab may promote remyelination and stabilize demyelination in lesions and NABT in relapsing multiple sclerosis, compared with intramuscular IFNβ-1a.

Background Magnetization transfer ratio (MTR) permits the quantitative estimation of cervical cord tissue damage in patients with multiple sclerosis (MS). Objective To determine whether a single time-point MTR scan of the cervical cord is associated with short-term disease evolution in patients with relapsing-remitting (RR) MS. Methods Using a 1.5-T magnetic resonance imaging (MRI) system with a tailored cervical cord phased array coil, fast short-tau inversion recovery (fast-STIR) and MTR scans were obtained from 14 untreated patients with RRMS at baseline. Cervical cord MTR histograms were derived. Over the 18- month follow-up period, relapse rate was measured and disability assessed by the Expanded Disability Status Scale (EDSS) score. Results Average cervical cord MTR was correlated with relapse rate (r= -0.56, P = 0.037). A moderate correlation (r values ranging from -0.33 to -0.36) between baseline cervical cord MTR metrics and EDSS changes over 18 months was also noted, albeit statistical significance was not reached (P = 0.26 and 0.21, respectively) perhaps because of the relatively small sample size. Conclusions This study suggests that a ‘snapshot’ MT MRI assessment of the cervical cord may detect cervical cord tissue changes associated with short-term disease evolution in RRMS.

The study was undertaken to determine the pathologic basis of subtle abnormalities in magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) parameters observed in normal-appearing white matter (NAWM) in multiple sclerosis brains. Brain tissues were obtained through a rapid postmortem protocol that included in situ magnetic resonance imaging (MRI). Four types of MRI-defined regions of interest (ROIs) were analyzed: (1) regions that were abnormal on all images (T2T1MTR lesions); (2) NAWM regions with slightly abnormal MTR located close to white matter lesions (sa-WM Close); (3) NAWM regions with slightly abnormal MTR located far from lesions (sa-WM Far); and (4) NAWM regions with normal MTR (NAWM). Immunohistochemical analysis for each ROI comprised immunostaining for myelin, axonal markers, activated microglia/macrophages, astrocytes, plasma proteins, and blood vessels. Forty-eight ROIs from 4 secondary progressive MS brains were analyzed. sa-WM Close ROIs were associated with significantly more axonal swellings. There were more enlarged major histocompatibility complex II(+) microglia and macrophages detected in sa-WM Far, sa-WM Close, and T2T1MTR lesions than in NAWM. Across all ROIs, MTR and DTI measures were moderately correlated with myelin density, axonal area, and axonal counts. Excluding T2T1MTR lesions from analysis revealed that MTR and DTI measures in nonlesional white matter (WM) were correlated with activated microglia, but not with axonal or myelin integrity. The pathologic substrates for MRI abnormalities in NAWM vary based on distance from focal WM lesions. Close to WM lesions, axonal pathology and microglial activation may explain subtle MRI changes. Distant from lesions, microglial activation associated with proximity to cortical lesions might underlie MRI abnormalities.

Magnetic resonance fingerprinting in multiple sclerosis

Human prion diseases are fatal neurodegenerative disorders caused by misfolding of the prion protein. There are no useful biomarkers of disease progression. Cerebral cortex spongiform change, one of the classical pathological features of prion disease, resolves in prion-infected transgenic mice following prion protein gene knockout. We investigated the cross-sectional, longitudinal and post-mortem cerebral magnetization transfer ratios as a surrogate for prion disease pathology. Twenty-three prion disease patients with various prion protein gene mutations and 16 controls underwent magnetization transfer ratio and conventional magnetic resonance imaging at 1.5 T. For each subject, whole-brain, white and grey matter magnetization transfer ratio histogram mean, peak height, peak location, and magnetization transfer ratio at 25th, 50th and 75th percentile were computed and correlated with several cognitive, functional and neuropsychological scales. Highly significant associations were found between whole brain magnetization transfer ratio and prion disease (P < 0.01). Additionally, highly significant correlations were found between magnetization transfer ratio histogram parameters and clinical, functional and neuropsychological scores (P < 0.01). Longitudinally, decline in the Clinician's Dementia Rating scale was correlated with decline in magnetization transfer ratio. To investigate the histological correlates of magnetization transfer ratio, formalin-fixed cerebral and cerebellar hemispheres from 19 patients and six controls underwent magnetization transfer ratio imaging at 1.5 T, with mean magnetization transfer ratio calculated from six regions of interest, and findings were followed-up in six variant Creutzfeldt-Jakob disease cases with 9.4 T high-resolution magnetization transfer imaging on frontal cortex blocks, with semi-quantitative histopathological scoring of spongiosis, astrocytosis and prion protein deposition. Post-mortem magnetization transfer ratios was significantly lower in patients than controls in multiple cortical and subcortical regions, but not frontal white matter. Measurements (9.4 T) revealed a significant and specific negative correlation between cortical magnetization transfer ratios and spongiosis (P = 0.02), but not prion protein deposition or gliosis. The magnetic resonance imaging measurement of magnetization transfer ratios may be an in vivo surrogate for spongiform change and has potential utility as a therapeutic biomarker in human prion disease.

In vivo quantification of brain injury in adult Niemann–Pick Disease Type C