Diffusely Abnormal White Matter, T2 Burden of Disease, and Brain Volume in Relapsing-Remitting Multiple Sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) diffusely abnormal white matter (DAWM) is a mildly hyperintense magnetic resonance imaging abnormality distinct from typical lesions. Our goal was to investigate the prevalence and natural history of DAWM in a large cohort (n = 348) of relapsing-remitting MS (RRMS) patients. METHODS: The presence of DAWM and relationship to changes in T2 burden of disease (BOD), brain volume (brain fractional ratio, BFR), and disability (Expanded Disability Status Scale, EDSS) were investigated at baseline and year 7-8 (long-term follow-up, LTF). RESULTS: DAWM was present in 25.3% (88 of 348) of patients at baseline. At LTF, DAWM was unchanged in 69.3% (61 of 88), decreased in 28.4% (25 of 88), and increased in 2.3% (2 of 88) of patients. Baseline BOD and change in BOD did not significantly differ between patients with and without DAWM. DAWM was associated with greater reduction in BFR at LTF (P = .038). DAWM and DAWM change did not predict EDSS or EDSS progression. CONCLUSIONS: DAWM is present in a quarter of RRMS patients, and rarely increases or develops de novo. DAWM predicts brain atrophy but does not predict physical disability. Because of its posterior periventricular location, further investigation is warranted to evaluate its relationship to other measures of disability, including visual spatial processing and cognitive function.

Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis.

BACKGROUND: On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also known as a clinically isolated syndrome) to multiple sclerosis. METHODS: During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on T2-weighted MRI, cumulative number of new lesions enhanced on T1-weighted MRI ["enhancing lesions"], and cumulative combined number of unique lesions [new enhancing lesions on T1-weighted MRI plus new and newly enlarged lesions on T2-weighted MRI]). RESULTS: A total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 to 43.9; P=0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P=0.01); the unadjusted risk difference was not significant at the 24-month secondary outcome time point (P=0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo. CONCLUSIONS: The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887 .).

Low-fat, plant-based diet in multiple sclerosis: A randomized controlled trial.

BACKGROUND: The role that dietary interventions can play in multiple sclerosis (MS) management is of huge interest amongst patients and researchers but data evaluating this is limited. Possible effects of a very-low-fat, plant-based dietary intervention on MS related progression and disease activity as measured by brain imaging and MS related symptoms have not been evaluated in a randomized-controlled trial. Despite use of disease modifying therapies (DMT), poor quality of life (QOL) in MS patients can be a significant problem with fatigue being one of the common disabling symptoms. Effective treatment options for fatigue remain limited. Emerging evidence suggests diet and vascular risk factors including obesity and hyperlipidemia may influence MS disease progression and improve QOL. OBJECTIVES: To evaluate adherence, safety and effects of a very-low-fat, plant-based diet (Diet) on brain MRI, clinical [MS relapses and disability, body mass index (BMI)] and metabolic (blood lipids and insulin) outcomes, QOL [Short Form-36 (SF-36)], and fatigue [Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS)], in relapsing-remitting MS (RRMS). METHODS: This was a randomized-controlled, assessor-blinded, one-year long study with 61 participants assigned to either Diet (N=32) or wait-listed (Control, N=29) group. RESULTS: The mean age (years) [Control-40.9±8.48; Diet-40.8±8.86] and the mean disease duration (years) [Control -5.3±3.86; Diet-5.33±3.63] were comparable between the two groups. There was a slight difference between the two study groups in the baseline mean expanded disability status scale (EDSS) score [Control-2.22±0.90; Diet-2.72±1.05]. Eight subjects withdrew (Diet, N=6; Control, N=2). Adherence to the study diet based on monthly Food Frequency Questionnaire (FFQ) was excellent with the diet group showing significant difference in the total fat caloric intake compared to the control group [total fat intake/total calories averaged ~15% (Diet) versus ~40% (Control)]. The two groups showed no differences in brain MRI outcomes, number of MS relapses or disability at 12 months. The diet group showed improvements at six months in low-density lipoprotein cholesterol (Δ=-11.99mg/dL; p=0.031), total cholesterol (Δ=-13.18mg/dL; p=0.027) and insulin (Δ=-2.82mg/dL; p=0.0067), mean monthly reductions in BMI (Rate=-1.125kg/m2 per month; p<0.001) and fatigue [FSS (Rate=-0.0639 points/month; p=0.0010); MFIS (Rate=-0.233 points/month; p=0.0011)] during the 12-month period. CONCLUSIONS: While a very-low fat, plant-based diet was well adhered to and tolerated, it resulted in no significant improvement on brain MRI, relapse rate or disability as assessed by EDSS scores in subjects with RRMS over one year. The diet group however showed significant improvements in measures of fatigue, BMI and metabolic biomarkers. The study was powered to detect only very large effects on MRI activity so smaller but clinically meaningful effects cannot be excluded. The diet intervention resulted in a beneficial effect on the self-reported outcome of fatigue but these results should be interpreted cautiously as a wait-list control group may not completely control for a placebo effect and there was a baseline imbalance on fatigue scores between the groups. If maintained, the improved lipid profile and BMI could yield long-term vascular health benefits. Longer studies with larger sample sizes are needed to better understand the long-term health benefits of this diet.

Personalized activity index, a new safety monitoring tool for multiple sclerosis clinical trials.

BACKGROUND: An abnormal increase of contrast-enhancing lesion (CEL) counts on frequent MRIs is interpreted as a signal of potential worsening in multiple sclerosis (MS) clinical trials. We demonstrate the utility of the MR personalized activity index (MR-pax) to identify such increases. METHODS: We analyzed a previous Phase II study in relapsing patients (n = 167) with MRIs at screening, baseline and months 1-6. We performed five consecutive reviews at 90-day intervals. At each review, we evaluate the MR-pax for each patient and also identify those who meet the rule-of-five (an ad-hoc guideline currently in use). To evaluate its clinical relevance, we assess the relation between having a small MR-pax (≤0.05; indicating an unexpected CEL increase) and relapse status in the 12 weeks post-review. RESULTS: Of the 399 patient reviews, 35 cases met the rule-of-five; 35 had an MR-pax ≤ 0.05; 18 met both criteria. The proportions experiencing clinical relapse are 63% among those meeting the rule-of-five, 61% among those with MR-pax ≤0.05, and 83% for those meeting both criteria, more than double the rate of those meeting neither criterion (40%). CONCLUSION: A guideline combining this new personalized index and the existing threshold-based criterion is able to better identify patients with a higher risk of experiencing relapses.

Further investigation of safety monitoring guidelines based on magnetic resonance imaging lesion activity in multiple sclerosis clinical trials.

We assess two modified guidelines for monitoring patient safety in multiple sclerosis (MS) trials. These guidelines flag patients with an increase in contrast enhancing lesion (CEL) count above a threshold over the CEL level 1-2 months earlier. We compare the new guidelines to the original guideline where the threshold is set according to the baseline by applying the guidelines to two previous studies. The odds ratios of a subsequent clinical relapse associated with meeting the CEL threshold based on the modified guidelines are similar to those based on the original guideline. There is a need for patient and cohort specific monitoring procedures.

Improving the clinical correlation of multiple sclerosis black hole volume change by paired-scan analysis.

The change in T 1-hypointense lesion ("black hole") volume is an important marker of pathological progression in multiple sclerosis (MS). Black hole boundaries often have low contrast and are difficult to determine accurately and most (semi-)automated segmentation methods first compute the T 2-hyperintense lesions, which are a superset of the black holes and are typically more distinct, to form a search space for the T 1w lesions. Two main potential sources of measurement noise in longitudinal black hole volume computation are partial volume and variability in the T 2w lesion segmentation. A paired analysis approach is proposed herein that uses registration to equalize partial volume and lesion mask processing to combine T 2w lesion segmentations across time. The scans of 247 MS patients are used to compare a selected black hole computation method with an enhanced version incorporating paired analysis, using rank correlation to a clinical variable (MS functional composite) as the primary outcome measure. The comparison is done at nine different levels of intensity as a previous study suggests that darker black holes may yield stronger correlations. The results demonstrate that paired analysis can strongly improve longitudinal correlation (from -0.148 to -0.303 in this sample) and may produce segmentations that are more sensitive to clinically relevant changes.

Optimizing the use of radiologist seed points for improved multiple sclerosis lesion segmentation.

Many current methods for multiple sclerosis (MS) lesion segmentation require radiologist seed points as input, but do not necessarily allow the expert to work in an intuitive or efficient way. Ironically, most methods also assume that the points are placed optimally. This paper examines how seed points can be processed with intuitive heuristics, which provide improved segmentation accuracy while facilitating quick and natural point placement. Using a large set of MRIs from an MS clinical trial, two radiologists are asked to seed the lesions while unaware that the points would be fed into a classifier, based on Parzen windows, that automatically delineates each marked lesion. To evaluate the impact of the new heuristics, an interactive region-growing method is used to provide ground truth and the Dice coefficient (DC) and Spearman's rank correlation are used as the primary measures of agreement. A stratified analysis is performed to determine the effect on scans with low-, medium-, and high lesion loads. Compared to the unenhanced classifier, the heuristics dramatically improve the DC (+32.91 pt.) and correlation (+0.50) for the scans with low lesion loads, and also improve the DC (+14.55 pt.) and correlation (+0.15) for the scans with medium lesion loads, while having aminimal effect for the scans with high lesion loads, which are already segmented accurately by Parzen windows.With the heuristics, the DC is close to 80% and the correlation is above 0.9 for all three load categories.

Detection and measurement of coverage loss in interleaved multi-acquisition brain MRIs due to motion-induced inter-slice misalignment.

In MRI scans that are acquired in a slice-by-slice manner, patient motion during scanning can cause adjacent slices to overlap, resulting in duplicate coverage in some areas and missing coverage in others. Scans in which multiple slices are acquired simultaneously and interleaved with other sets of slices are particularly vulnerable because a single movement can result in the misalignment and overlap of many slices. Despite the fact that considerable data losses can occur even with few visible artifacts, this problem has received very little attention from MRI researchers. The primary goals of this paper are: (1) to raise awareness of the problem in the MRI community and (2) to present an efficient multiscale algorithm that accurately quantifies the amount of data loss. Validation of the algorithm's accuracy is performed on 200 scans with simulated patient motion so that the true amount of data loss is known for each scan. The motion parameters are chosen to simulate scans that have significant data loss (mean missing coverage=14.39% of head volume, SD=6.61%, range=2.76-32.98%) but with few visual indications of the problem. The algorithm is shown to be very accurate, yielding estimates that differ from the true values by a mean of only 1.1% point (SD=0.98pt, range=0.00-6.54pt). The algorithm is also shown to be consistent and robust when tested on a large set of scans from a recent multiple sclerosis clinical trial.

Cognitive impairment no dementia - neuropsychological and neuroimaging characterization of an amnestic subgroup.

BACKGROUND/AIMS: Cognitive impairment no dementia (CIND) describes individuals whose cognitive functioning falls below normal but who do not meet dementia criteria. An important goal within CIND is to identify subgroups that will predictably progress to Alzheimer disease. CIND with amnestic deficits has been associated with high risk of Alzheimer disease but has until now been investigated on a retrospective basis. In this study a prospectively defined amnestic CIND group was characterized on a detailed neuropsychological test battery and on structural magnetic resonance imaging (MRI) measures. METHODS: Amnestic CIND was defined as meeting at least 1 but not all DSM-IV-TR criteria for dementia, scoring > or =1 SD below norms on Rey Auditory Verbal Learning Test delayed recall, having a Clinical Dementia Rating score of 0.5 and a Mini-Mental State Exam score > or =24. This cross-sectional study compared subjects meeting these criteria (n = 25) to age- and education-matched controls (n = 26). The neuropsychological battery included memory and nonmemory measures that were analyzed as continuous variables and dichotomized into impaired (> or =1 SD below controls) versus nonimpaired. MRI scans were evaluated with a global-brain volumetric measure [brain fractional ratio (BFR)] and with visually based medial temporal lobe atrophy (MTA) ratings. RESULTS: Amnestic CIND had neuropsychological impairment in the episodic memory domain and also in nonmemory domains. There were 80% of CIND subjects with multidomain impairment. The most clear-cut nonmemory impairment was in the verbal ability domain, with 64% of subjects affected and a moderate effect size (d = 0.7). On MRI, BFR was lower (74.5 +/- 4.6 vs. 75.5 +/- 4.4) and MTA higher (72 vs. 38% with MTA > or =1) in CIND than in control subjects. BFR correlated with MTA (r = -0.45) and with a composite memory score (r = 0.296). CONCLUSION: A prospective amnestic CIND grouping appears to identify individuals with a multidomain pattern of neuropsychological impairment and with both medial temporal lobe and global brain atrophy.

The use of MRI as an outcome measure in clinical trials.

Because the changes on MRI likely reflect various aspects of the underlying pathology of multiple sclerosis, MRI outcome measures have become an important component of most MS clinical trials, providing objective, supportive evidence for the clinical endpoints. Although there is currently insufficient evidence to support any single or combination of MRI measures as a fully validated surrogate, it is now generally accepted that if the aim of a new therapy is to prevent relapses, new Gd-enhancing and T2 lesions can be considered an appropriate surrogate outcome measure of relapses, and MRI activity outcomes can be recommended as the primary measure of treatment efficacy.