Disability in multiple sclerosis is related to normal appearing brain tissue MTR histogram abnormalities.

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.

OBJECTIVESTo assess (a) whether the changes in the normal appearing brain tissue (NABT), as revealed by magnetisation transfer (MT) histogram analysis, correlates with cognitive dysfunction in patients with multiple sclerosis...

Magnetization transfer ratio (MTR) histograms have the potential to characterize subtle diffuse changes in multiple sclerosis (MS) and other white matter disease. A new method is described which gives improved correlation with the Expanded Disability Status Scale (EDSS). Classification of individual subjects into normal and MS subgroups is shown. Principal component analysis (PCA) and multiple discriminant analysis (MDA) are shown to give results superior to methods of MTR histogram analysis using traditional features such as peak height and peak location. Scatterplots confirm the improved separation between groups achieved using the MDA score. The histogram analysis provides a comparison of two classification approaches, based on PCA and MDA, to recognize differences between normal controls and the four different subgroups of MS disease (and all MS patients). Multiple linear regression of these PCs vs. EDSS established an MR-based measure of disease. Using a central 60-mm slab of brain tissue, the success rate of binary classification between control and MS subgroups using MDA was 75-95%, depending on which two groups were being compared. Multiple regression analysis of EDSS with the first three PCs as independent variables was significant (r = 0.83 for secondary progressive MS, and r = 0.80 for all MS patients).

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.

Predictive value of different conventional and non-conventional MRI-parameters for specific domains of cognitive function in multiple sclerosis

In a retrospective multicentre cohort study, we explored the association between brain atrophy and multiple sclerosis (MS) disability using different MRI scanners and protocols at multiple sites. Relapse-onset MS patients were included if they had two clinical MRIs 12 months apart and ≥2 Expanded Disability Status Scale (EDSS) scores. Percentage brain volume change (PBVC), percentage grey matter change (PGMC), fluid-attenuated inversion recovery (FLAIR) lesion volume change, whole brain volume (BV), grey matter volume (GMV), FLAIR lesion volume and T1 hypointense lesion volume were assessed by icobrain. Disability was measured by EDSS scores and 6-month confirmed disability progression (CDP). Of the 260 relapse-onset MS patients included, 204 (78%) MRI pairs were performed in the same scanner and 56 (22%) pairs were from different scanners. 93% of patients were on treatment and mean PBVC was -0.26% (±0.52). During the median follow-up of 2.8 years from the second MRI, median EDSS change was 0.0 and 12% patients experienced 6-month CDP. Cross-sectional BV and GMV at the later MRI showed a trend for association with CDP (HR 0.99; 95% CI 0.98 to 1.00; p=0.06). Only BV at the later MRI was associated with EDSS score (β -0.03, SE 0.01, p<0.001) and the rate of EDSS change over time (β -0.001, SE 0.0003, p=0.02). There was no association between longitudinal PBVC or PGMC and CDP or EDSS (p>0.05). In this highly treated MS cohort with low disability accrual, only cross-sectional BV showed an association with future EDSS scores, while no MRI metric predicted 6-month CDP. These findings highlight the limitations of current clinical MRI measures in predicting disability worsening in real-world settings.

The correlation between T2 lesion load (LL) detected on conventional MR sequences and disability assessed by the Expanded Disability Status Scale (EDSS) in multiple sclerosis (MS) is, at best, moderate. The present study was performed to determine whether the correlation between disability and LL is improved by (i) use of the more sensitive three-dimensional fast fluid-attenuated inversion recovery (3D-fast FLAIR) sequence; (ii) application of the newly devised MS functional composite (MSFC) score. Forty-one patients with clinically definite or probable MS were studied. All had been followed prospectively for 14 years since their first symptom. EDSS and MSFC score were assessed. Imaging was performed with 3D-fFLAIR, fast spin-echo (FSE), and T1 weighted SE sequences. 3D-fFLAIR detected a 34% higher LL than FSE, but did not improve the correlation between T2 LL and EDSS (r = 0.51 and r = 0.53); the correlation was stronger with T1 LL (r = 0.57). The MSFC score did not significantly correlate with T2 LL or T1 LL. The robust correlation in this cohort between T2 LL and EDSS may reflect the homogeneous disease duration and the wide spread of disability. This correlation was not improved by the increased detection of T2 lesions with the 3D-fFLAIR sequence. The stronger correlation between T1 LL with EDSS is consistent with the finding that this subgroup of lesions represent areas of more severe tissue damage. The MSFC score did not improve the clinico-radiological paradox that is found in MS, despite including information on cognitive function.

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.

Disability in progressive MS is associated with T2 lesion changes

In established multiple sclerosis, magnetization transfer ratio (MTR) histograms reveal abnormalities of normal-appearing white matter (NAWM) and grey matter (NAGM). The aim of this study was to investigate for such abnormalities in a large cohort of patients presenting with clinically isolated syndromes suggestive of multiple sclerosis. Magnetization transfer imaging was performed on 100 patients (67 women, 33 men, median age 32 years) a mean of 19 weeks (SD 3.8, range 12-33 weeks) after symptom onset with a clinically isolated syndrome and in 50 healthy controls (34 women, 16 men, median age 32.5 years). SPM99 software was used to generate segmented NAWM and NAGM MTR maps. The volumes of T2 lesions, white matter and grey matter were calculated. Eighty-one patients were followed up clinically and with conventional MRI after 3 years (n = 61) or until they developed multiple sclerosis if this occurred sooner (n = 20). Multiple regression analysis was used to investigate differences between patients and controls with age, gender and volume measures as covariates to control for potential confounding effects. The MTR histograms for both NAWM and NAGM showed a reduction in the mean (NAWM, 38.14 versus 38.33, P = 0.001; NAGM 32.29 versus 32.50, P = 0.009; units in pu) and peak location, with a left shift in the histogram. Mean NAWM and NAGM MTR were also reduced in the patients who developed clinically definite multiple sclerosis and multiple sclerosis according to the McDonald criteria but not in the 24 patients with normal T2-weighted brain magnetic resonance imaging (MRI). MTR abnormalities occur in the NAWM and NAGM at the earliest clinical stages of multiple sclerosis.

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.

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.

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...

Background: Remote assessment of neurological disability in people with multiple sclerosis (MS) could improve access to clinical care and efficiency of clinical research. Objective: To develop and validate a telemedicine-based MS disability examination that does not require an in-home examiner. Methods: Adults with MS were recruited after a standardized in-person Expanded Disability Status Scale (EDSS) evaluation, and within 1 week underwent a blinded televideo-enabled EDSS examination with a different clinician. EDSS and tele-EDSS scores were compared. Results: Overall, 41 adults participated (mean (standard deviation (SD)) age: 47.0 years (11.6); median EDSS: 2 (range: 0–7)); 37 required no in-home assistance for the tele-EDSS evaluation (e.g. help positioning camera). Mean difference between EDSS and tele-EDSS was 0.34 (95% confidence interval (CI): 0.07–0.61). For 88% of evaluations, tele-EDSS and EDSS scores were within 1 point (similar to reported in-person inter-rater differences). Unweighted kappa for agreement within 0.5 point was 0.72. Correlation for individual functional systems (FS) ranged from modest (vision: 0.37) to high (bowel/bladder: 0.79). Overall correlation between EDSS and tele-EDSS was 0.89 (p < 0.0001); and 0.98 (p < 0.0001) at EDSS range: 4–7. Conclusion: In this proof of principle study, disability evaluation in mild to moderate MS is feasible using telemedicine without an aide at the patient’s location.

OBJECTIVEMagnetisation transfer imaging (MTI) provides information about brain damage with increased pathological specificity over conventional MRI and detects subtle abnormalities in the normal appearing brain tissue, which go undetected with...