Networks of microstructural damage predict disability in multiple sclerosis

Background: Network-based measures are emerging MRI markers in multiple sclerosis (MS). We aimed to identify networks of white (WM) and grey matter (GM) damage that predict disability progression and cognitive worsening using data-driven methods. // Methods: We analysed data from 1836 participants with different MS phenotypes (843 in a discovery cohort and 842 in a replication cohort). We calculated standardised T1-weighted/T2-weighted (sT1w/T2w) ratio maps in brain GM and WM, and applied spatial independent component analysis to identify networks of covarying microstructural damage. Clinical outcomes were Expanded Disability Status Scale worsening confirmed at 24 weeks (24-week confirmed disability progression (CDP)) and time to cognitive worsening assessed by the Symbol Digit Modalities Test (SDMT). We used Cox proportional hazard models to calculate predictive value of network measures. // Results: We identified 8 WM and 7 GM sT1w/T2w networks (of regional covariation in sT1w/T2w measures) in both cohorts. Network loading represents the degree of covariation in regional T1/T2 ratio within a given network. The loading factor in the anterior corona radiata and temporo-parieto-frontal components were associated with higher risks of developing CDP both in the discovery (HR=0.85, p<0.05 and HR=0.83, p<0.05, respectively) and replication cohorts (HR=0.84, p<0.05 and HR=0.80, p<0.005, respectively). The decreasing or increasing loading factor in the arcuate fasciculus, corpus callosum, deep GM, cortico-cerebellar patterns and lesion load were associated with a higher risk of developing SDMT worsening both in the discovery (HR=0.82, p<0.01; HR=0.87, p<0.05; HR=0.75, p<0.001; HR=0.86, p<0.05 and HR=1.27, p<0.0001) and replication cohorts (HR=0.82, p<0.005; HR=0.73, p<0.0001; HR=0.80, p<0.005; HR=0.85, p<0.01 and HR=1.26, p<0.0001). // Conclusions: GM and WM networks of microstructural changes predict disability and cognitive worsening in MS. Our approach may be used to identify patients at greater risk of disability worsening and stratify cohorts in treatment trials

Image analysis for the assessment of stereotactic radiosurgery

This thesis describes an image-based system for analyzing dose distributions produced during treatment planning of stereotactic radiosurgery. A review of stereotaxy and radiosurgery, particularly for the treatment of arteriovenous malformations (AVMs), is presented. The stereotactic apparatus and linear accelerator-based irradiation techniques used at McGill University are described in some detail.The image-dose analysis software, running on a UNIX workstation, is presented, including software utilities for the evaluation of radiosurgery treatment plans based on magnetic resonance (MR) images. The importance of dose-volume histograms (DVHs) in the assessment of treatment plans is discussed, and the software developed to generate DVHs is described.A technique for the experimental verification of calculated three-dimensional (3D) dose distributions is presented. This computerized approach is based on stereotactic principles and uses a plastic phantom and radiotherapy verification film as the dosimeter. The results indicate that, with some improvements, this is a viable technique for the experimental validation of stereotactic 3D treatment planning software

Imaging of repeated episodes of demyelination and remyelination in multiple sclerosis

AbstractMultiple sclerosis (MS) is characterized by the formation of demyelinating lesions in the white matter (WM). However, the timecourse of the evolution of healthy white matter into fully demyelinated lesions in MS is not well understood. We use a recently proposed technique to examine magnetization transfer ratio (MTR) timecourses in lesions segmented from MTR images in patients with relapsing–remitting MS (RRMS) and secondary progressive MS (SPMS). In both groups we found MTR lesions forming both in previously normal appearing WM (de novo lesions) as well as in previously lesional tissue that appears to be experiencing a second round of inflammatory demyelination (repeat lesions). Both de novo and repeat lesions exhibited significant, but incomplete MTR recovery, suggesting partial remyelination; post-lesion MTR values in de novo lesions were similar to pre-lesion values in repeat lesions. Both de novo and repeat lesions were found in subjects in relapsing–remitting and secondary progressive stages of MS, and repeat lesions appeared relatively more common in the secondary progressive phase. These observations support the hypothesis that entirely demyelinated lesions found on histopathology are the result of multiple episodes of demyelination and incomplete remyelination, and may have implications for MS treatment development efforts aimed at neuroprotection and enhancing remyelination

Magnetization transfer ratio recovery in new lesions decreases during adolescence in pediatric-onset multiple sclerosis patients

Children and adolescents diagnosed with multiple sclerosis rarely accrue physical disability early in their disease. This could be explained by greater remyelination in children, a capacity that may be lost in adolescence or early adulthood. Magnetization transfer ratio (MTR) MRI can be used to quantify changes in myelin in MS. We used serial MTR imaging and longitudinal random effects analysis to quantify recovery of MTR in acute lesions and to evaluate MTR changes in normal-appearing tissue in 19 adolescent MS patients. Our objective was to determine whether younger adolescents have a greater capacity for remyelination and whether this decreases as patients approach adulthood. We detected a significant decrease in MTR recovery between ages 16 and 20 years (p = 0.023), with older subjects approaching typical recovery levels for adult-onset MS. MTR recovery in acute MS lesions decreases with age in adolescents, suggesting loss of remyelination capacity. This may be related to the conclusion of primary myelination or other developmental factors

Correlation between brain volume change and T2 relaxation time induced by dehydration and rehydration: Implications for monitoring atrophy in clinical studies

Brain volume change measured from magnetic resonance imaging (MRI) provides a widely used and useful in vivo measure of irreversible tissue loss. These measurements, however, can be influenced by reversible factors such as shifts in brain water content. Given the strong effect of water on T2 relaxation, we investigated whether an estimate of T2 relaxation time would correlate with brain volume changes induced by physiologically manipulating hydration status. We used a clinically feasible estimate of T2 (“pseudo-T2”) computed from a dual turbo spin-echo MRI sequence and correlated pseudo-T2 changes to percent brain volume changes in 12 healthy subjects after dehydration overnight (16-hour thirsting) and rehydration (drinking 1.5 L of water). We found that the brain volume significantly increased between the dehydrated and rehydrated states (mean brain volume change = 0.36%, p = 0.0001) but did not change significantly during the dehydration interval (mean brain volume change = 0.04%, p = 0.57). The changes in brain volume and pseudo-T2 significantly correlated with each other, with marginal and conditional correlations (R2) of 0.44 and 0.65, respectively. Our results show that pseudo-T2 may be used in conjunction with the measures of brain volume to distinguish reversible water fluctuations and irreversible brain tissue loss (atrophy) and to investigate disease mechanisms related to neuro-inflammation, e.g., in multiple sclerosis, where edema-related water fluctuations may occur with disease activity and anti-inflammatory treatment

Delineation of cortical pathology in multiple sclerosis using multi-surface magnetization transfer ratio imaging

The purpose of our study was to evaluate the utility of measurements of cortical surface magnetization transfer ratio (csMTR) on the inner, mid and outer cortical boundaries as clinically accessible biomarkers of cortical gray matter pathology in multiple sclerosis (MS). Twenty-five MS patients and 12 matched controls were recruited from the MS Clinic of the Montreal Neurological Institute. Anatomical and magnetization transfer ratio (MTR) images were acquired using 3 Tesla MRI at baseline and two-year time-points. MTR maps were smoothed along meshes representing the inner, mid and outer neocortical boundaries. To evaluate csMTR reductions suggestive of sub-pial demyelination in MS patients, a mixed model analysis was carried out at both the individual vertex level and in anatomically parcellated brain regions. Our results demonstrate that focal areas of csMTR reduction are most prevalent along the outer cortical surface in the superior temporal and posterior cingulate cortices, as well as in the cuneus and precentral gyrus. Additionally, age regression analysis identified that reductions of csMTR in MS patients increase with age but appear to hit a plateau in the outer caudal anterior cingulate, as well as in the precentral and postcentral cortex. After correction for the naturally occurring gradient in cortical MTR, the difference in csMTR between the inner and outer cortex in focal areas in the brains of MS patients correlated with clinical disability. Overall, our findings support multi-surface analysis of csMTR as a sensitive marker of cortical sub-pial abnormality indicative of demyelination in MS patients

Review of automatic segmentation methods of multiple sclerosis white matter lesions on conventional magnetic resonance imaging

Magnetic resonance (MR) imaging is often used to characterize and quantify multiple sclerosis (MS) lesions in the brain and spinal cord. The number and volume of lesions have been used to evaluate MS disease burden, to track the progression of the disease and to evaluate the effect of new pharmaceuticals in clinical trials. Accurate identification of MS lesions in MR images is extremely difficult due to variability in lesion location, size and shape in addition to anatomical variability between subjects. Since manual segmentation requires expert knowledge, is time consuming and is subject to intra- and inter-expert variability, many methods have been proposed to automatically segment lesions. The objective of this study was to carry out a systematic review of the literature to evaluate the state of the art in automated multiple sclerosis lesion segmentation

Quantitative determination of regional lesion volume and distribution in children and adults with relapsing-remitting multiple sclerosis.

Onset of MS occurs during childhood in about 5% of cases. It is unclear whether very young age at MS onset, when the nervous system is still myelinating, affects MS lesion accrual or regional distribution.To compare the frequency, volume and distribution of T2 and T1 lesions in children and adults with relapsing-remitting multiple sclerosis (RRMS).Lesions were segmented on T2- and T1-weighted MRI images from 29 children and 29 adults with RRMS, matched for disease duration.All subjects exhibited T2-weighted brain lesions. Children had higher whole-brain T2-weighted-lesion-volume (T2LV) compared to adults (mean (SD) in cm(3): 12.76(2.7) vs. 10.03(3.4), p<0.0013). The supratentorial-T2LV was similar in children and adults (8.45(1.7) vs. 7.94(1.7), mean (SD), p = 0.2582), but adults were more likely to have supratentorial lesions (96.5% vs. 68.9%, p<0.012). Children were more likely to have infratentorial-T2-weighted lesions (75.9% vs. 43.4%, p<0.03), specifically in the brainstem (62.1% vs. 26.7%, p<0.019) and the pons (48.3% vs. 17.24%, p<0.024), had higher infratentorial-T2-weighted-lesion counts (4.1(5.6) vs. 1.45(2.3), p<0.021), a greater infratentorial-T2LV (4.31(2.7) vs. 2.08(2.4), p<0.0013), and a greater infratentorial-T1-weighted-lesion-volume (T1LV) (3.7(2.5) vs. 1.08(1.9), p<0.0007). Whole-brain-T1LV was higher in children (9.3(2.5) vs. 6.43(2.1), p>0.001). Adult MS patients had higher supratentorial-T1LV (5.5(0.92) vs. 6.41(2.1), mean (SD), p<0.034), whereas children were more likely to have infratentorial-T1-weighted lesions (58.6% vs. 23.3%, p<0.015).Onset of MS during childhood is associated with a higher volume of brain lesions in the first few years of disease relative to adults. Children with MS are more likely than adults to have T2 and T1 lesions in the infratentorial white matter, raising the possibility of preferential immune targeting of more mature myelin. Children with MS have a lower supratentorial T1 lesion burden, possibly reflecting more effective remyelination and repair in brain regions that are still engaged in active primary myelination

Jacobian integration method increases the statistical power to measure gray matter atrophy in multiple sclerosis

Gray matter atrophy provides important insights into neurodegeneration in multiple sclerosis (MS) and can be used as a marker of neuroprotection in clinical trials. Jacobian integration is a method for measuring volume change that uses integration of the local Jacobian determinants of the nonlinear deformation field registering two images, and is a promising tool for measuring gray matter atrophy. Our main objective was to compare the statistical power of the Jacobian integration method to commonly used methods in terms of the sample size required to detect a treatment effect on gray matter atrophy. We used multi-center longitudinal data from relapsing–remitting MS patients and evaluated combinations of cross-sectional and longitudinal pre-processing with SIENAX/FSL, SPM, and FreeSurfer, as well as the Jacobian integration method. The Jacobian integration method outperformed these other commonly used methods, reducing the required sample size by a factor of 4–5. The results demonstrate the advantage of using the Jacobian integration method to assess neuroprotection in MS clinical trials