The association between olfactory bulb volume, cognitive dysfunction, physical disability and depression in multiple sclerosis.

BACKGROUND AND PURPOSE: Olfactory bulb atrophy is associated with cognitive dysfunction in Parkinson's and Alzheimer's disease, and with major depression. It has been suggested that olfactory bulb atrophy or dysfunction is therefore a marker of neurodegeneration. Multiple sclerosis (MS) is now also recognized as having a significant neurodegenerative component. Thus, the aim of this study was to investigate associations between physical and cognitive disability, depression and olfactory bulb volume in MS. METHODS: In total, 146 patients with MS (mean age 49.0 ± 10.9 years, disease duration 21.2 ± 9.3 years, median Expanded Disability Status Scale (EDSS) score 3.0 (range 0-7.5), 103 relapsing-remitting, 35 secondary progressive and eight primary progressive MS) underwent a standardized neurological examination, comprehensive neuropsychological testing and magnetic resonance imaging (MRI); data of 27 healthy people served as age- and gender-matched control subjects. The olfactory bulb was semi-automatically segmented on high-resolution three-dimensional T1-weighted MRI. RESULTS: Mean olfactory bulb volume was lower in MS patients than healthy controls (183.9 ± 40.1 vs. 209.2 ± 59.3 µl; P = 0.018 adjusted to intracranial volume). Olfactory bulb volume was similar across clinical disease subtypes and did not correlate with cognitive performance, EDSS scores or total proton density/T2 white matter lesion volume. However, in progressive MS, the mean olfactory bulb volume correlated with depression scores (Spearman's rho = -0.38, P < 0.05) confirmed using a multivariate linear regression analysis including cognitive fatigue scores. This association was not observed in relapsing-remitting MS. CONCLUSION: Olfactory bulb volume was lower in MS than in healthy controls. Olfactory bulb volume does not seem to mirror cognitive impairment in MS; however, it is associated with higher depression scores in progressive MS.

Magnetic resonance imaging correlates of physical disability in relapse onset multiple sclerosis of long disease duration.

BACKGROUND: Understanding long-term disability in multiple sclerosis (MS) is a key goal of research; it is relevant to how we monitor and treat the disease. OBJECTIVES: The Magnetic Imaging in MS (MAGNIMS) collaborative group sought to determine the relationship of brain lesion load, and brain and spinal cord atrophy, with physical disability in patients with long-established MS. METHODS: Patients had a magnetic resonance imaging (MRI) scan of their brain and spinal cord, from which we determined brain grey (GMF) and white matter (WMF) fractional volumes, upper cervical spinal cord cross-sectional area (UCCA) and brain T2-lesion volume (T2LV). We assessed patient disability using the Expanded Disability Status Scale (EDSS). We analysed associations between EDSS and MRI measures, using two regression models (dividing cohort by EDSS into two and four sub-groups). RESULTS: In the binary model, UCCA (p < 0.01) and T2LV (p = 0.02) were independently associated with the requirement of a walking aid. In the four-category model UCCA (p < 0.01), T2LV (p = 0.02) and GMF (p = 0.04) were independently associated with disability. CONCLUSIONS: Long-term physical disability was independently linked with atrophy of the spinal cord and brain T2 lesion load, and less consistently, with brain grey matter atrophy. Combinations of spinal cord and brain MRI measures may be required to capture clinically-relevant information in people with MS of long disease duration.

Feasibility of grey matter and white matter segmentation of the upper cervical cord in vivo: a pilot study with application to magnetisation transfer measurements.

Spinal cord pathology can be functionally very important in neurological disease. Pathological studies have demonstrated the involvement of spinal cord grey matter (GM) and white matter (WM) in several diseases, although the clinical relevance of abnormalities detected histopathologically is difficult to assess without a reliable way to assess cord GM and WM in vivo. In this study, the feasibility of GM and WM segmentation was investigated in the upper cervical spinal cord of 10 healthy subjects, using high-resolution images acquired with a commercially available 3D gradient-echo pulse sequence at 3T. For each healthy subject, tissue-specific (i.e. WM and GM) cross-sectional areas were segmented and total volumes calculated from a 15 mm section acquired at the level of C2-3 intervertebral disc and magnetisation transfer ratio (MTR) values within the extracted volumes were also determined, as an example of GM and WM quantitative measurements in the cervical cord. Mean (± SD) total cord cross-sectional area (TCA) and total cord volume (TCV) of the section studied across 10 healthy subjects were 86.9 (± 7.7) mm(2) and 1302.8 (± 115) mm(3), respectively; mean (±SD) total GM cross-sectional area (TGMA) and total GM volume (TGMV) were 14.6 (± 1.1) mm(2) and 218.3 (± 16.8) mm(3), respectively; mean (± SD) GM volume fraction (GMVF) was 0.17 (± 0.01); mean (± SD) MTR of the total WM volume (WM-MTR) was 51.4 (± 1.5) and mean (± SD) MTR of the total GM volume (GM-MTR) was 49.7 (± 1.6). The mean scan-rescan, intra- and inter-observer % coefficient of variation for measuring the TCA were 0.7%, 0.5% and 0.5% and for measuring the TGMA were 6.5%, 5.4% and 12.7%. The difference between WM-MTR and GM-MTR was found to be statistically significant (p=0.00006). This study has shown that GM and WM segmentation in the cervical cord is possible and the MR imaging protocol and analysis method presented here in healthy controls can be potentially extended to study the cervical cord in disease states, with the option to explore further quantitative measurements alongside MTR.

Linking white matter tracts to associated cortical grey matter: a tract extension methodology.

Quantitative diffusion analysis of white matter (WM) tracts has been utilised in many diseases for determining damage to, and changes in, WM tracts throughout the brain. However, there are limited studies investigating associations between quantitative measures in WM tracts and anatomically linked grey matter (GM), due to the difficulty in determining GM regions connected with a given WM tract. This work describes a straightforward method for extending a WM tract through GM based on geometry. The tract is extended by following a straight line from each point on the tract boundary to the outer boundary of the cortex. A comparison between a multiplanar 2D approach and a 3D method was made. This study also tested an analysis pipeline from tracking WM tracts to quantifying magnetisation transfer ratios (MTR) in the associated cortical GM, and assessed the applicability of the method to healthy control subjects. Tract and associated cortical volumes and MTR values for the cortico-spinal tracts, genu and body of the corpus callosum were extracted; the between-subjects standard deviation was calculated. It was found that a multiplanar 2D approach produced a more anatomically plausible volume of GM than a 3D approach, at the expense of possible overestimation of the GM volume. The between-subjects standard deviation of the tract specific quantitative measurements (from both the WM and GM masks) ranged between 1.2 and 7.3% for the MTR measures, and between 10 and 45% for the absolute volume measures. The results show that the method can be used to produce anatomically plausible extensions of the WM tracts through the GM, and regions defined in this way yield reliable estimates of the MTR from the regions.

Brain lesion location and clinical status 20 years after a diagnosis of clinically isolated syndrome suggestive of multiple sclerosis.

BACKGROUND/OBJECTIVES: The objective of this study was to investigate associations between the spatial distribution of brain lesions and clinical outcomes in a cohort of people followed up 20 years after presentation with a clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS). METHODS: Brain lesion probability maps (LPMs) of T1 and T2 lesions were generated from 74 people who underwent magnetic resonance imaging (MRI) and clinical assessment a mean of 19.9 years following a CIS. One-tailed t-test statistics were used to compare LPMs between the following groups: clinically definite (CD) MS and those who remained with CIS, with an abnormal MRI; people with MS and an Expanded Disability Status Scale (EDSS) ≤3 and >3; people with relapsing-remitting (RR) and secondary progressive (SP) MS. The probability of each voxel being lesional was analysed adjusting for age and gender using a multiple linear regression model. RESULTS: People with CDMS were significantly more likely than those with CIS and abnormal scan 20 years after onset to have T1 and T2 lesions in the corona radiata, optic radiation, and splenium of the corpus callosum (periventricularly) and T2 lesions in the right fronto-occipital fasciculus. People with MS EDSS >3, compared with those with EDSS ≤3, were more likely to have optic radiation and left internal capsule T2 lesions. No significant difference in lesion distribution was noted between RRMS and SPMS. CONCLUSION: This work demonstrates that lesion location characteristics are associated with CDMS and disability after long-term follow-up following a CIS. The lack of lesion spatial distribution differences between RRMS and SPMS suggests focal pathology affects similar regions in both subgroups.

MRI only conversion to multiple sclerosis following a clinically isolated syndrome.

OBJECTIVES: Using current diagnostic criteria, patients who present with a clinically isolated syndrome (CIS) may develop multiple sclerosis (MS) by subsequently exhibiting dissemination in space and time on clinical (clinically definite (CD) MS) or radiological (MRI) grounds. This study investigated the frequency of radiological without clinical conversion to MS after long term follow-up as this has not previously been defined. METHODS: Two cohorts who underwent serial clinical and MRI studies from presentation with a CIS and who were followed-up over a mean of 6 and 20 years were investigated. The distribution and formation of lesions visible on brain MRI were assessed using the revised McDonald criteria (2005). Radiologically defined (RD) MS was determined by fulfilment of the MRI but not the CDMS criteria. RESULTS: 105 people were followed-up for 6 years after a CIS, of whom 51% developed CDMS, 15% RDMS and the remainder were classified as still having had a CIS. 70 people were followed-up at 20 years, of whom 61% and 11% had developed CDMS and RDMS, respectively. CONCLUSION: About 10-15% of CIS patients may develop MS on MRI criteria only, without further clinical events for up to two decades.

Neuromyelitis optica spectrum disorder related tonic spasms responsive to lacosamide.

Paroxysmal tonic spasms [PTS] are common in patients with neuromyelitis optica spectrum disorder (NMOSD).1 2 In patients with demyelinating disease, PTS can significantly reduce the quality of life, limit activities of daily living and the rehabilitative process following an acute relapse 3. As in patients with multiple sclerosis (MS), paroxysmal tonic spasms in NMOSD usually respond well to treatment with carbamazepine.2 However, the optimal treatment in patients where carbamazepine is contraindicated or poorly tolerated is unclear. We describe a patient with NMOSD with severe paroxysmal tonic spasms who did not tolerate carbamazepine but was successfully treated with lacosamide (Vimpat).

Antecedent anti-NMDA receptor encephalitis in two patients with multiple sclerosis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder characterised by psychiatric symptoms, movement disorder and seizures often evolving into a severe encephalopathy. An overlap has recently been recognised between anti-NMDAR encephalitis and inflammatory demyelinating disorders, particularly neuromyelitis optical spectrum disorder (NMOSD). In this case report, we describe two patients with an initial presentation consistent with anti-NMDAR encephalitis who have subsequently developed relapsing-remitting multiple sclerosis (MS) and discuss the literature pertaining to potential overlap between NMDAR encephalitis and inflammatory demyelinating disorders.

Metabolite changes in early relapsing-remitting multiple sclerosis. A two year follow-up study.

Previous in vivo proton magnetic resonance spectroscopic imaging ((1)H-MRSI) studies have found reduced levels of N-acetyl-aspartate (NAA) in multiple sclerosis (MS) lesions, the surrounding normal-appearing white matter (NAWM) and cortical grey matter (CGM), suggesting neuronal and axonal dysfunction and loss. Other metabolites, such as myoinositol (Ins), creatine (Cr), choline (Cho), and glutamate plus glutamine (Glx), can also be quantified by (1)H-MRSI, and studies have indicated that concentrations of these metabolites may also be altered in MS. Relatively little is known about the time course of such metabolite changes. This preliminary study aimed to characterise changes in total NAA (tNAA, the sum of NAA and N-acetyl-aspartyl-glutamate), Cr, Cho, Ins and Glx concentrations in NAWM and in CGM, and their relationship with clinical outcome, in subjects with clinically early relapsing-remitting MS (RRMS). Twenty RRMS subjects and 10 healthy control subjects underwent (1)H-MRSI examinations yearly for two years. Using the LCModel, tNAA, Cr, Cho, Ins and Glx concentrations were estimated both in NAWM and CGM. At baseline, the concentration of tNAA was significantly reduced in the NAWM of the MS patients compared to the control group (-7%, p = 0.003), as well as in the CGM (-8.7%, p = 0.009). NAWM tNAA concentrations tended to recover from baseline, but otherwise tissue metabolite profiles did not significantly change in the MS subjects, or relatively between MS and healthy control subjects. While neuronal and axonal damage is apparent from the early clinical stages of MS, this study suggests that initially it may be partly reversible. Compared with other MR imaging measures, serial (1)H-MRSI may be relatively less sensitive to progressive pathological tissue changes in early RRMS.

Metabolite changes in normal-appearing gray and white matter are linked with disability in early primary progressive multiple sclerosis.

BACKGROUND: Abnormalities in normal-appearing brain tissues may contribute to disability in primary progressive multiple sclerosis (PPMS), where few lesions are seen on conventional imaging. OBJECTIVES: To evaluate the mechanisms underlying disease progression in the early phase of PPMS by measuring metabolite concentrations in normal-appearing white matter (NAWM) and cortical gray matter (CGM) and to assess their relationship with clinical outcomes. DESIGN: Case-control study. SETTING: Tertiary referral hospital. Patients Forty-three consecutive patients within 5 years of onset of PPMS and 44 healthy control subjects. MAIN OUTCOME MEASURES: Concentrations of choline-containing compounds, phosphocreatine, myo-inositol, total N-acetyl-aspartate (tNAA), and glutamate-glutamine were estimated using proton magnetic resonance spectroscopic imaging. Brain parenchymal, white matter and gray matter fractions and proton density and gadolinium-enhancing lesion loads were calculated. The Expanded Disability Status Scale and Multiple Sclerosis Functional Composite scores were recorded. RESULTS: In CGM, concentrations of the tNAA (P<.001) and glutamate-glutamine (P = .005) were lower in patients with PPMS than in controls. In NAWM, myo-inositol levels were higher (P = .002) and tNAA levels were lower (P = .005) in patients with PPMS than in controls. The Expanded Disability Status Scale score correlated with the tNAA concentration in CGM (r = -0.44; P = .03) and with myo-inositol (r = 0.41; P = .01) and glutamate-glutamine concentrations (r = 0.41; P = .01) in NAWM. Proton density lesion load correlated negatively with CGM tNAA concentration and positively with NAWM myo-inositol concentration. CONCLUSION: Metabolite changes, which differ in CGM and NAWM, occur in early PPMS and are linked with disability.

Increasing normal-appearing grey and white matter magnetisation transfer ratio abnormality in early relapsing-remitting multiple sclerosis.

Abnormalities within normal-appearing grey and white matter (NAGM and NAWM) occur early in the clinical course of multiple sclerosis (MS) and can be detected in-vivo using the magnetisation transfer ratio (MTR). To better characterize the rates of change in both tissues and to ascertain when such changes begin, we serially studied a cohort of minimally disabled, early relapsing-remitting MS patients, using NAGM and NAWM MTR histograms. Twenty-three patients with clinically definite early relapsing-remitting MS (mean disease duration at baseline 1.9 years), and 19 healthy controls were studied. A magnetisation transfer imaging sequence was acquired yearly for two years. Twenty-one patients and 10 controls completed followup. NAWM and NAGM MTR histograms were derived and mean MTR calculated. A hierarchical regression analysis, adjusting for brain parenchymal fraction,was used to assess MTR change over time. MS NAWM and NAGM MTR were significantly reduced in comparison with controls at baseline and, in patients, both measures decreased further during follow-up: (-0.10 pu/year, p=0.001 and -0.18 pu/year, p<0.001 respectively). The rate of MTR decrease was significantly greater in NAGM than NAWM (p=0.004). Under the assumption that such changes are linear, backward extrapolation of the observed rates of change suggested that NAWM abnormality began before symptom onset. We conclude that increasing MTR abnormalities in NAWM and NAGM are observed early in the course of relapsing-remitting MS. It is now important to investigate whether these measures are predictive of future disability, and consequently, whether MTR could be used as a surrogate marker in therapeutic trials.

Predicting outcome in clinically isolated syndrome using machine learning.

We aim to determine if machine learning techniques, such as support vector machines (SVMs), can predict the occurrence of a second clinical attack, which leads to the diagnosis of clinically-definite Multiple Sclerosis (CDMS) in patients with a clinically isolated syndrome (CIS), on the basis of single patient's lesion features and clinical/demographic characteristics. Seventy-four patients at onset of CIS were scanned and clinically reviewed after one and three years. CDMS was used as the gold standard against which SVM classification accuracy was tested. Radiological features related to lesional characteristics on conventional MRI were defined a priori and used in combination with clinical/demographic features in an SVM. Forward recursive feature elimination with 100 bootstraps and a leave-one-out cross-validation was used to find the most predictive feature combinations. 30 % and 44 % of patients developed CDMS within one and three years, respectively. The SVMs correctly predicted the presence (or the absence) of CDMS in 71.4 % of patients (sensitivity/specificity: 77 %/66 %) at 1 year, and in 68 % (60 %/76 %) at 3 years on average over all bootstraps. Combinations of features consistently gave a higher accuracy in predicting outcome than any single feature. Machine-learning-based classifications can be used to provide an "individualised" prediction of conversion to MS from subjects' baseline scans and clinical characteristics, with potential to be incorporated into routine clinical practice.

The normal appearing grey matter in primary progressive multiple sclerosis: a magnetisation transfer imaging study.

BACKGROUND: In 10-15 % of patients with multiple sclerosis (MS), the clinical course is characterized by slow progression in disability without relapses (primary progressive (PP) MS). The mechanism of disability in this form of MS is poorly understood. Using magnetization transfer ratio (MTR) imaging, we investigated normal appearing white matter (NAWM) and normal appearing grey matter (NAGM) in PPMS and explored the relationship of MTR measures with disability. METHODS: Thirty patients with PPMS and 30 age matched controls had spin echo based MTR imaging to study lesions and normal appearing tissues. The brain was segmented into NAWM and NAGM using SPM99 with lesions segmented using a semiautomated local thresholding technique. A 75% probability threshold for classification of NAWM and NAGM was used to diminish partial volume effects. From normalized histograms of MTR intensity values, six MTR parameters were measured. Mean lesion MTR and T2 lesion volume were also measured. Disability was assessed using Kurtzke's expanded disability status scale (EDSS). RESULTS: Compared with controls, patients exhibited a significant reduction in mean NAWM (p = 0.001) and NAGM (p = 0.004) MTR. Spearman's rank correlation of EDSS with the six MTR parameters in NAWM and NAGM, mean lesion MTR, and T2 lesion volume, was only significant with mean NAGM MTR (r = -0.41, p = 0.02), the 25th percentile of NAGM MTR intensity (r = -0.37, p = 0.05), and T2 lesion volume (r = 0.39, p = 0.04). Multiple regression analysis of the relationship between EDSS and 4 MR parameters representing each tissue type (mean NAWM MTR, mean NAGM MTR, mean lesion MTR, T2 lesion volume) showed that the association of EDSS with mean NAGM MTR remained significant. CONCLUSIONS: There appear to be significant abnormalities in the NAGM in PP MS. Further investigation of the pathological basis and functional significance of grey matter abnormality in PPMS is warranted.

Accurate GM atrophy quantification in MS using lesion-filling with co-registered 2D lesion masks.

BACKGROUND: In multiple sclerosis (MS), brain atrophy quantification is affected by white matter lesions. LEAP and FSL-lesion_filling, replace lesion voxels with white matter intensities; however, they require precise lesion identification on 3DT1-images. AIM: To determine whether 2DT2 lesion masks co-registered to 3DT1 images, yield grey and white matter volumes comparable to precise lesion masks. METHODS: 2DT2 lesion masks were linearly co-registered to 20 3DT1-images of MS patients, with nearest-neighbor (NNI), and tri-linear interpolation. As gold-standard, lesion masks were manually outlined on 3DT1-images. LEAP and FSL-lesion_filling were applied with each lesion mask. Grey (GM) and white matter (WM) volumes were quantified with FSL-FAST, and deep gray matter (DGM) volumes using FSL-FIRST. Volumes were compared between lesion mask types using paired Wilcoxon tests. RESULTS: Lesion-filling with gold-standard lesion masks compared to native images reduced GM overestimation by 1.93 mL (p < .001) for LEAP, and 1.21 mL (p = .002) for FSL-lesion_filling. Similar effects were achieved with NNI lesion masks from 2DT2. Global WM underestimation was not significantly influenced. GM and WM volumes from NNI, did not differ significantly from gold-standard. GM segmentation differed between lesion masks in the lesion area, and also elsewhere. Using the gold-standard, FSL-FAST quantified as GM on average 0.4% of the lesion area with LEAP and 24.5% with FSL-lesion_filling. Lesion-filling did not influence DGM volumes from FSL-FIRST. DISCUSSION: These results demonstrate that for global GM volumetry, precise lesion masks on 3DT1 images can be replaced by co-registered 2DT2 lesion masks. This makes lesion-filling a feasible method for GM atrophy measurements in MS.

Sulcal and gyral crown cortical grey matter involvement in multiple sclerosis: A magnetisation transfer ratio study.

BACKGROUND: Histopathology has demonstrated extensive cortical grey matter (GM) demyelination in multiple sclerosis (MS), and suggests that sulcal folds may be preferentially affected, particularly in progressive MS. This has not been confirmed in vivo, and it is not known if it is relevant to clinical status. OBJECTIVES: To determine sulcal and gyral crown magnetisation transfer ratio (MTR) in MS cortical GM, and the MTR associations with clinical status. METHODS: We measured sulcal and gyral crown cortical GM MTR values in 61 MS patients and 32 healthy controls. Disability was measured using Expanded Disability Status Scale and Multiple Sclerosis Functional Composite scores. RESULTS: MTR values were reduced in sulcal and gyral crown regions in all MS subtypes, more so in secondary progressive (SP) MS than relapsing remitting (RR) MS, and similarly in primary progressive (PP) MS and RRMS. Sulcal MTR was lower than gyral crown MTR in controls, PPMS and RRMS patients, but not in SPMS. MTR correlated with clinical status in RRMS and SPMS, but not PPMS. CONCLUSIONS: Cortical pathology, as reflected by MTR, is present in all MS subtypes and most pronounced in SPMS. A preferential disease effect on sulcal cortical regions was not observed. Cortical MTR abnormalities appear to be more clinically relevant in relapse-onset rather than progressive-onset MS.

Advances in imaging to support the development of novel therapies for multiple sclerosis.

Multiple sclerosis (MS) is a common neurological disease in North America and Europe. Although most patients develop major locomotor disability over the course of 15-20 years, in approximately one-third of patients the long-term course is favorable, with minimal disability. Although current disease-modifying treatments reduce the relapse rate, their long-term effects are uncertain. MS treatment trials are challenging because of the variable clinical course and typically slow evolution of the disease. Magnetic resonance imaging (MRI) is sensitive in monitoring MS pathology and facilitates evaluation of potential new treatments. MRI measurements of lesion activity have identified new immunomodulatory treatments for preventing relapse. Quantitative measurements of tissue volume and structural integrity, capable of detecting neuroprotection and repair, should facilitate new treatments designed to prevent irreversible disability. Higher-field MR scanners and new positron emission tomography (PET) radioligands are providing new insights into cellular and pathophysiological abnormalities, and should be valuable in future therapeutic trials. Retinal axonal loss measured using optical coherence tomography (OCT) can assess acute neuroprotection in optic neuritis.

Consensus recommendations for MS cortical lesion scoring using double inversion recovery MRI.

BACKGROUND: Different double inversion recovery (DIR) sequences are currently used in multiple sclerosis (MS) research centers to visualize cortical lesions, making it difficult to compare published data. This study aimed to formulate consensus recommendations for scoring cortical lesions in patients with MS, using DIR images acquired in 6 European centers according to local protocols. METHODS: Consensus recommendations were formulated and tested in a multinational meeting. RESULTS: Cortical lesions were defined as focal abnormalities on DIR, hyperintense compared to adjacent normal-appearing gray matter, and were not scored unless ≥ 3 pixels in size, based on at least 1.0 mm(2) in-plane resolution. Besides these 2 obligatory criteria, additional, supportive recommendations concerned a priori artifact definition on DIR, use of additional MRI contrasts to verify suspected lesions, and a constant level of displayed image contrast. Robustness of the recommendations was tested in a small dataset of available, heterogeneous DIR images, provided by the different participating centers. An overall moderate agreement was reached when using the proposed recommendations: more than half of the readers agreed on slightly more than half (54%) of the cortical lesions scored, whereas complete agreement was reached in 19.4% of the lesions (usually larger, mixed white matter/gray matter lesions). CONCLUSIONS: Although not designed as a formal interobserver study, the current study suggests that comparing available literature data on cortical lesions may be problematic, and increased consistency in acquisition protocols may improve scoring agreement. Sensitivity and specificity of the proposed recommendations should now be studied in a more formal, prospective, multicenter setting using similar DIR protocols.

Magnetization transfer ratio abnormalities reflect clinically relevant grey matter damage in multiple sclerosis.

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 T(2)-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.