Atlas-based assessment of hypomyelination: Quantitative MRI in Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease (PMD) is a rare childhood hypomyelinating leukodystrophy. Quantification of the pronounced myelin deficit and delineation of subtle myelination processes are of high clinical interest. Quantitative magnetic resonance imaging (qMRI) techniques can provide in vivo insights into myelination status, its spatial distribution, and dynamics during brain maturation. They may serve as potential biomarkers to assess the efficacy of myelin-modulating therapies. However, registration techniques for image quantification and statistical comparison of affected pediatric brains, especially those of low or deviant image tissue contrast, with healthy controls are not yet established. This study aimed first to develop and compare postprocessing pipelines for atlas-based quantification of qMRI data in pediatric patients with PMD and evaluate their registration accuracy. Second, to apply an optimized pipeline to investigate spatial myelin deficiency using myelin water imaging (MWI) data from patients with PMD and healthy controls. This retrospective single-center study included five patients with PMD (mean age, 6 years ± 3.8) who underwent conventional brain MRI and diffusion tensor imaging (DTI), with MWI data available for a subset of patients. Three methods of registering PMD images to a pediatric template were investigated. These were based on (a) T1-weighted (T1w) images, (b) fractional anisotropy (FA) maps, and (c) a combination of T1w, T2-weighted, and FA images in a multimodal approach. Registration accuracy was determined by visual inspection and calculated using the structural similarity index method (SSIM). SSIM values for the registration approaches were compared using a t test. Myelin water fraction (MWF) was quantified from MWI data as an assessment of relative myelination. Mean MWF was obtained from two PMDs (mean age, 3.1 years ± 0.3) within four major white matter (WM) pathways of a pediatric atlas and compared to seven healthy controls (mean age, 3 years ± 0.2) using a Mann-Whitney U test. Our results show that visual registration accuracy estimation and computed SSIM were highest for FA-based registration, followed by multimodal, and T1w-based registration (SSIMFA = 0.67 ± 0.04 vs. SSIMmultimodal = 0.60 ± 0.03 vs. SSIMT1 = 0.40 ± 0.14). Mean MWF of patients with PMD within the WM pathways was significantly lower than in healthy controls MWFPMD = 0.0267 ± 0.021 vs. MWFcontrols = 0.1299 ± 0.039. Specifically, MWF was measurable in brain structures known to be myelinated at birth (brainstem) or postnatally (projection fibers) but was scarcely detectable in other brain regions (commissural and association fibers). Taken together, our results indicate that registration accuracy was highest with an FA-based registration pipeline, providing an alternative to conventional T1w-based registration approaches in the case of hypomyelinating leukodystrophies missing normative intrinsic tissue contrasts. The applied atlas-based analysis of MWF data revealed that the extent of spatial myelin deficiency in patients with PMD was most pronounced in commissural and association and to a lesser degree in brainstem and projection pathways.

Exploring in vivo lesion myelination dynamics: Longitudinal Myelin Water Imaging in early Multiple Sclerosis.

BACKGROUND: Multiple Sclerosis (MS) lesions are pathologically heterogeneous and the temporal behavior in terms of growth and myelination status of individual lesions is highly variable, especially in the early phase of the disease. Thus, monitoring the development of individual lesion myelination by using quantitative magnetic resonance myelin water imaging (MWI) could be valuable to capture the variability of disease pathology and get an individual insight into the subclinical disease activity. OBJECTIVE: The goal of this work was (1) to observe the variation and longitudinal change of in vivo lesion myelination by means of MWI and its parameter Myelin Water Fraction (MWF), and, (2) to identify individual lesion myelination patterns in early MS. METHODS: In this study n = 12 patients obtained conventional MRI and quantitative MWI derived from multi-component driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) within four weeks after presenting a clinically isolated syndrome and remained within the study if clinically definitive MS was diagnosed within the 12 months study period. Four MRI sessions were acquired at baseline, 3, 6, and 12 months. The short-term and long-term variability of MWF maps was evaluated by scan-rescan measures and the coefficient of variation was determined in four healthy controls. Tracking of individual lesions was performed using the Automatic Follow-up of Individual Lesions (AFIL) algorithm. Lesion volume and MWF were evaluated for every individual lesion in all patients. Median lesion MWF change was used to define lesion categories as decreasing, varying, increasing and invariant for MWF variation. RESULTS: In total n = 386 T2 lesions were detected with a subset of n = 225 permanent lesions present at all four time-points. Among those, a heterogeneous lesion MWF reduction was found, with the majority of lesions bearing only mild MWF reduction, approximately a third with an intermediate MWF decrease and highest MWF reduction in acute-inflammatory active lesions. A moderate negative correlation was determined between individual lesion volumes and median MWF consistent across all time-points. Permanent lesions featured variable temporal dynamics with the majority of varying MWF (58 %), however decreasing (16 %), increasing (15 %) and invariant (11 %) subgroups could be identified resembling demyelinating activity and post-demyelinating inactivity known from histopathology studies. Inflammatory-active enhancing lesions showed a distinct pattern of MWF reduction followed by partial recovery after 3 months. This was similar in new enhancing lesions and those with a non-enhancing precursor lesion. CONCLUSION: This work provides in vivo evidence for an individual evolution of early demyelinated MS lesions measured by means of MWF imaging. Our results support the hypothesis, that MS lesions undergo multiple demyelination and remyelination episodes in the early acute phase. The in vivo MRI surrogate of myelin turnover bears capacity as a novel biomarker to select and potentially monitor personalized MS treatment.

Exploring individual multiple sclerosis lesion volume change over time: Development of an algorithm for the analyses of longitudinal quantitative MRI measures.

BACKGROUND: Magnetic resonance imaging (MRI) is used to follow-up multiple sclerosis (MS) and evaluate disease progression and therapy response via lesion quantification. However, there is a lack of automated post-processing techniques to quantify individual MS lesion change. OBJECTIVE: The present study developed a secondary post-processing algorithm for MS lesion segmentation routine to quantify individual changes in volume over time. METHODS: An Automatic Follow-up of Individual Lesions (AFIL) algorithm was developed to process time series of pre-segmented binary lesion masks. The resulting consistently labelled lesion masks allowed for the evaluation of individual lesion volumes. Algorithm performance testing was executed in seven early MS patients with four MRI visits, and MS experienced readers verified the accuracy. RESULTS: AFIL distinguished 328 individual MS lesions with a 0.9% error rate to track persistent or new lesions based on expert assessment. A total of 121 new lesions evolved within the observed time period. The proportional courses of 69.1% lesions in the persistent lesion population exhibited varying volume, 16.9% exhibited stable volume, 3.4% exhibiting continuously increasing, and 0.5% exhibited continuously decreasing volume. CONCLUSION: This algorithm tracked individual lesions to automatically create an individual lesion growth profile of MS patients. This approach may allow for characterization of patients based on their individual lesion progression.

Characterization of the antibody isotype response in serum and milk of heifers vaccinated with a Staphylococcus aureus bacterin (Lysigin).

The objective was to characterize the antibody isotype responses to vaccination with a commercial Staphylococcus aureus bacterin in dairy heifers. Twenty-five Holstein-Friesian dairy heifers were assigned at random to one of two groups, vaccinates (n=14) or controls (n=11). Vaccinates received two 5-ml doses of Lysigin 28 d apart in late gestation. Both groups were challenged with a heterologous serotype 5 strain of Staph. aureus by aseptic intramammary infusion on days 6, 7 and 8 of lactation. Samples for serum antibody isotype (IgG, IgG1, IgG2 and IgM) determinations were taken before each vaccination, immediately prior to challenge (6 d post-calving) and at the end of the study (28 d post-calving). Samples for milk antibody isotype determinations were taken immediately prior to challenge and at the end of the study. Antibody isotype sample-to-positive ratios (S:P ratio=(mean test sample OD-mean within-plate negative control OD)/(mean within-plate positive control OD-mean within-plate negative control OD)) were determined in milk and serum using a series of ELISAs coated with different strains of Staph. aureus belonging to capsular polysaccharide (CP) serotype 5 or 8 or surface polysaccharide (SP) serotype 336. Vaccinates had higher mean serum IgG1 and IgG2 S:P ratios than controls against all three strains of Staph. aureus (P < or = 0.023). Vaccinates had higher mean milk IgG S:P ratios than controls against CP8 and SP336 strains of Staph. aureus (P< or = 0.030). Hence, a humoural immune response to the vaccine was detected in serum and milk, but responses varied according to strain and antibody isotype tested.