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Changes of deep gray matter magnetic susceptibility over 2 years in multiple sclerosis and healthy control brain.

ABSTRACT: In multiple sclerosis, pathological changes of both tissue iron and myelin occur, yet these factors have not been characterized in a longitudinal fashion using the novel iron- and myelin-sensitive quantitative susceptibility mapping (QSM) MRI technique. We investigated disease-relevant tissue changes associated with myelin loss and iron accumulation in multiple sclerosis deep gray matter (DGM) over two years. One-hundred twenty (120) multiple sclerosis patients and 40 age- and sex-matched healthy controls were included in this prospective study. Written informed consent and local IRB approval were obtained from all participants. Clinical testing and QSM were performed both at baseline and at follow-up. Brain magnetic susceptibility was measured in major DGM structures. Temporal (baseline vs. follow-up) and cross-sectional (multiple sclerosis vs. controls) differences were studied using mixed factorial ANOVA analysis and appropriate t-tests. At either time-point, multiple sclerosis patients had significantly higher susceptibility in the caudate and globus pallidus and lower susceptibility in the thalamus. Over two years, susceptibility increased significantly in the caudate of both controls and multiple sclerosis patients. Inverse thalamic findings among MS patients suggest a multi-phase pathology explained by simultaneous myelin loss and/or iron accumulation followed by iron depletion and/or calcium deposition at later stages.

SUBMITTER: Hagemeier J

PROVIDER: S-EPMC5984575 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Changes of deep gray matter magnetic susceptibility over 2 years in multiple sclerosis and healthy control brain.

Hagemeier Jesper J Zivadinov Robert R Dwyer Michael G MG Polak Paul P Bergsland Niels N Weinstock-Guttman Bianca B Zalis Joshua J Deistung Andreas A Reichenbach Jürgen R JR Schweser Ferdinand F

NeuroImage. Clinical 20170413

In multiple sclerosis, pathological changes of both tissue iron and myelin occur, yet these factors have not been characterized in a longitudinal fashion using the novel iron- and myelin-sensitive quantitative susceptibility mapping (QSM) MRI technique. We investigated disease-relevant tissue changes associated with myelin loss and iron accumulation in multiple sclerosis deep gray matter (DGM) over two years. One-hundred twenty (120) multiple sclerosis patients and 40 age- and sex-matched health ...[more]

PMID: 29868452

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Project description:ObjectiveThis study aimed to investigate longitudinal deep gray matter (DGM) shape changes and their relationship with measures of clinical disability and white matter lesion-load in a large multiple sclerosis (MS) cohort.Materials and methodsA total of 230 MS patients (179 relapsing-remitting, 51 secondary progressive; baseline age 44.5 ± 11.3 years; baseline disease duration 12.99 ± 9.18) underwent annual clinical and MRI examinations over a maximum of 6 years (mean 4.32 ± 2.07 years). The DGM structures were segmented on the T1-weighted images using the "Multiple Automatically Generated Templates" brain algorithm. White matter lesion-load was measured on T2-weighted MRI. Clinical examination included the expanded disability status scale, 9-hole peg test, timed 25-foot walk test, symbol digit modalities test and paced auditory serial addition test. Vertex-wise longitudinal analysis of DGM shapes was performed using linear mixed effect models and evaluated the association between average/temporal changes of DGM shapes with average/temporal changes of clinical measurements, respectively.ResultsA significant shrinkage over time of the bilateral ventrolateral pallidal and the left posterolateral striatal surface was observed, whereas no significant shape changes over time were observed at the bilateral thalamic and right striatal surfaces. Higher average lesion-load was associated with an average inwards displacement of the global thalamic surface with relative sparing on the posterior side (slight left-side predominance), the antero-dorso-lateral striatal surfaces bilaterally (symmetric on both sides) and the antero-lateral pallidal surface (left-side predominance). There was also an association between shrinkage of large lateral DGM surfaces with higher clinical motor and cognitive disease severity. However, there was no correlation between any DGM shape changes over time and measurements of clinical progression or lesion-load changes over time.ConclusionsThis study showed specific shape change of DGM structures occurring over time in relapse-onset MS. Although these shape changes over time were not associated with disease progression, we demonstrated a link between DGM shape and the patients' average disease severity as well as white matter lesion-load.

Project description:Background and purposeModifications of magnetic susceptibility have been consistently demonstrated in the subcortical gray matter of MS patients, but some uncertainties remain concerning the underlying neurobiological processes and their clinical relevance. We applied quantitative susceptibility mapping and longitudinal relaxation rate relaxometry to clarify the relative contribution of atrophy and iron and myelin changes to deep gray matter damage and disability in MS.Materials and methodsQuantitative susceptibility mapping and longitudinal relaxation rate maps were computed for 91 patients and 55 healthy controls from MR images acquired at 3T. Applying an external model, we estimated iron and myelin concentration maps for all subjects. Subsequently, changes of deep gray matter iron and myelin concentration (atrophy-dependent) and content (atrophy-independent) were investigated globally (bulk analysis) and regionally (voxel-based and atlas-based thalamic subnuclei analyses). The clinical impact of the observed MRI modifications was evaluated via regression models.ResultsWe identified reduced thalamic (P < .001) and increased pallidal (P < .001) mean iron concentrations in patients with MS versus controls. Global myelin and iron content in the basal ganglia did not differ between the two groups, while actual iron depletion was present in the thalamus (P < .001). Regionally, patients showed increased iron concentration in the basal ganglia (P ≤ .001) and reduced iron and myelin content in thalamic posterior-medial regions (P ≤ .004), particularly in the pulvinar (P ≤ .001). Disability was predicted by thalamic volume (B = -0.341, P = .02), iron concentration (B = -0.379, P = .005) and content (B = -0.406, P = .009), as well as pulvinar iron (B = -0.415, P = .003) and myelin (B = -0.415, P = .02) content, independent of atrophy.ConclusionsQuantitative MRI suggests an atrophy-related iron increase within the basal ganglia of patients with MS, along with an atrophy-independent reduction of thalamic iron and myelin correlating with disability. Absolute depletions of thalamic iron and myelin may represent sensitive markers of subcortical GM damage, which add to the clinical impact of thalamic atrophy in MS.

Project description:BackgroundCerebral atrophy is common in multiple sclerosis (MS) and selectively involves gray matter (GM). Several fully automated methods are available to measure whole brain and regional deep GM (DGM) atrophy from MRI.ObjectiveTo assess the sensitivity of fully automated MRI segmentation pipelines in detecting brain atrophy in patients with relapsing-remitting (RR) MS and normal controls (NC) over five years.MethodsConsistent 3D T1-weighted sequences were performed on a 3T GE unit in 16 mildly disabled patients with RRMS and 16 age-matched NC at baseline and five years. All patients received disease-modifying immunotherapy on-study. Images were applied to two pipelines to assess whole brain atrophy [brain parenchymal fraction (BPF) from SPM12; percentage brain volume change (PBVC) from SIENA] and two other pipelines (FSL-FIRST; FreeSurfer) to assess DGM atrophy (thalamus, caudate, globus pallidus, putamen). MRI change was compared by two sample t-tests. Expanded Disability Status Scale (EDSS) and timed 25-foot walk (T25FW) change was compared by repeated measures proportional odds models.ResultsUsing FreeSurfer, the MS group had a ~10-fold acceleration in on-study volume loss than NC in the caudate (mean decrease 0.51 vs. 0.05 ml, p = 0.022). In contrast, caudate atrophy was not detected by FSL-FIRST (mean decrease 0.21 vs. 0.12 ml, p = 0.53). None of the other pipelines showed any difference in volume loss between groups, for whole brain or regional DGM atrophy (all p>0.38). The MS group showed on-study stability on EDSS (p = 0.47) but slight worsening of T25FW (p = 0.054).ConclusionsIn this real-world cohort of mildly disabled treated patients with RRMS, we identified ongoing atrophy of the caudate nucleus over five years, despite the lack of any significant whole brain atrophy, compared to healthy controls. The detectability of caudate atrophy was dependent on the MRI segmentation pipeline employed. These findings underscore the increased sensitivity gained when assessing DGM atrophy in monitoring MS.

Project description:BackgroundHistopathological studies in Wilson's disease (WD) have revealed increased copper and iron concentrations in the deep gray matter nuclei. However, the commonly used mean bulk susceptibility only reflects the regional metal concentration rather than the total metal content, and regional atrophy may affect the assessment of mean bulk susceptibility. Our study aimed to quantitatively assess the changes of metal concentration and total metal content in deep gray matter nuclei by quantitative susceptibility mapping to distinguish patients with neurological and hepatic WD from healthy controls.MethodsQuantitative susceptibility maps were obtained from 20 patients with neurological WD, 10 patients with hepatic WD, and 25 healthy controls on a 3T magnetic resonance imaging system. Mean bulk susceptibility, volumes, and total susceptibility of deep gray matter nuclei in different groups were compared using a linear regression model. The area under the curve (AUC) was calculated by receiver characteristic curve to analyze the diagnostic capability of mean bulk susceptibility and total susceptibility.ResultsMean bulk susceptibility and total susceptibility of multiple deep gray matter nuclei in patients with WD were higher than those in healthy controls. Compared with patients with hepatic WD, patients with neurological WD had higher mean bulk susceptibility but similar total susceptibility in the head of the caudate nuclei, globus pallidus, and putamen. Mean bulk susceptibility of putamen demonstrated the best diagnostic capability for patients with neurological WD, the AUC was 1, and the sensitivity and specificity were all equal to 1. Total susceptibility of pontine tegmentum was most significant for the diagnosis of patients with hepatic WD, the AUC was 0.848, and the sensitivity and specificity were 0.7 and 0.96, respectively.ConclusionBrain atrophy may affect the assessment of mean bulk susceptibility in the deep gray matter nuclei of patients with WD, and total susceptibility should be an additional metric for total metal content assessment. Mean bulk susceptibility and total susceptibility of deep gray matter nuclei may be helpful for the early diagnosis of WD.

Project description:OBJECTIVE:Gray matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS. METHODS:We analyzed 3,604 brain high-resolution T1-weighted magnetic resonance imaging scans from 1,417 participants: 1,214 MS patients (253 clinically isolated syndrome [CIS], 708 relapsing-remitting [RRMS], 128 secondary-progressive [SPMS], and 125 primary-progressive [PPMS]), over an average follow-up of 2.41 years (standard deviation [SD] = 1.97), and 203 healthy controls (HCs; average follow-up = 1.83 year; SD = 1.77), attending seven European centers. Disability was assessed with the Expanded Disability Status Scale (EDSS). We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem, and cerebral white matter. Hierarchical mixed models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time-to-EDSS progression. RESULTS:SPMS showed the lowest baseline volumes of cortical GM and DGM. Of all baseline regional volumes, only that of the DGM predicted time-to-EDSS progression (hazard ratio = 0.73; 95% confidence interval, 0.65, 0.82; p < 0.001): for every standard deviation decrease in baseline DGM volume, the risk of presenting a shorter time to EDSS worsening during follow-up increased by 27%. Of all longitudinal measures, DGM showed the fastest annual rate of atrophy, which was faster in SPMS (-1.45%), PPMS (-1.66%), and RRMS (-1.34%) than CIS (-0.88%) and HCs (-0.94%; p < 0.01). The rate of temporal GM atrophy in SPMS (-1.21%) was significantly faster than RRMS (-0.76%), CIS (-0.75%), and HCs (-0.51%). Similarly, the rate of parietal GM atrophy in SPMS (-1.24-%) was faster than CIS (-0.63%) and HCs (-0.23%; all p values <0.05). Only the atrophy rate in DGM in patients was significantly associated with disability accumulation (beta = 0.04; p < 0.001). INTERPRETATION:This large, multicenter and longitudinal study shows that DGM volume loss drives disability accumulation in MS, and that temporal cortical GM shows accelerated atrophy in SPMS than RRMS. The difference in regional GM atrophy development between phenotypes needs to be taken into account when evaluating treatment effect of therapeutic interventions. Ann Neurol 2018;83:210-222.

Dataset Information

Changes of deep gray matter magnetic susceptibility over 2 years in multiple sclerosis and healthy control brain.

Publications

Changes of deep gray matter magnetic susceptibility over 2 years in multiple sclerosis and healthy control brain.

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