Dataset Information

Localised grey matter atrophy in multiple sclerosis is network-based: a coordinate-based meta-analysis.

ABSTRACT:

Aim

To test the network degeneration hypothesis in multiple sclerosis (MS) with a two-stage coordinate-based meta-analysis by: (1) characterising regional selectivity of grey matter (GM) atrophy and (2) testing for functional connectivity involving these regions.

Materials and methods

Meta-analytic sources included 33 journal articles (1,666 MS patients and 1,269 healthy controls) with coordinate-based results from voxel-based morphometry analysis demonstrating GM atrophy. Mass univariate and multivariate coordinate-based meta-analyses were performed to identify a convergent pattern of GM atrophy and determine inter-regional co-activation (as a surrogate of functional connectivity), with anatomical likelihood estimation and functional meta-analytic connectivity modelling, respectively.

Results

Localised GM atrophy was demonstrated in the thalamus, putamen, caudate, sensorimotor cortex, insula, superior temporal gyrus, and cingulate gyrus. This convergent pattern of atrophy displayed significant inter-regional functional co-activations.

Conclusion

In MS, GM atrophy was regionally selective, and these regions were functionally connected. The meta-analytic model-based results of this study are intended to guide future development of quantitative neuroimaging markers for diagnosis, evaluating disease progression, and monitoring treatment response.

SUBMITTER: Chiang FL

PROVIDER: S-EPMC6757337 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

Localised grey matter atrophy in multiple sclerosis is network-based: a coordinate-based meta-analysis.

Chiang F L FL Wang Q Q Yu F F FF Romero R S RS Huang S Y SY Fox P M PM Tantiwongkosi B B Fox P T PT

Clinical radiology 20190814 10

<h4>Aim</h4>To test the network degeneration hypothesis in multiple sclerosis (MS) with a two-stage coordinate-based meta-analysis by: (1) characterising regional selectivity of grey matter (GM) atrophy and (2) testing for functional connectivity involving these regions.<h4>Materials and methods</h4>Meta-analytic sources included 33 journal articles (1,666 MS patients and 1,269 healthy controls) with coordinate-based results from voxel-based morphometry analysis demonstrating GM atrophy. Mass un ...[more]

PMID: 31421864

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Project description:See Stankoff and Louapre (doi:10.1093/brain/awy114) for a scientific commentary on this article.Grey matter atrophy is present from the earliest stages of multiple sclerosis, but its temporal ordering is poorly understood. We aimed to determine the sequence in which grey matter regions become atrophic in multiple sclerosis and its association with disability accumulation. In this longitudinal study, we included 1417 subjects: 253 with clinically isolated syndrome, 708 with relapsing-remitting multiple sclerosis, 128 with secondary-progressive multiple sclerosis, 125 with primary-progressive multiple sclerosis, and 203 healthy control subjects from seven European centres. Subjects underwent repeated MRI (total number of scans 3604); the mean follow-up for patients was 2.41 years (standard deviation = 1.97). Disability was scored using the Expanded Disability Status Scale. We calculated the volume of brain grey matter regions and brainstem using an unbiased within-subject template and used an established data-driven event-based model to determine the sequence of occurrence of atrophy and its uncertainty. We assigned each subject to a specific event-based model stage, based on the number of their atrophic regions. Linear mixed-effects models were used to explore associations between the rate of increase in event-based model stages, and T2 lesion load, disease-modifying treatments, comorbidity, disease duration and disability accumulation. The first regions to become atrophic in patients with clinically isolated syndrome and relapse-onset multiple sclerosis were the posterior cingulate cortex and precuneus, followed by the middle cingulate cortex, brainstem and thalamus. A similar sequence of atrophy was detected in primary-progressive multiple sclerosis with the involvement of the thalamus, cuneus, precuneus, and pallidum, followed by the brainstem and posterior cingulate cortex. The cerebellum, caudate and putamen showed early atrophy in relapse-onset multiple sclerosis and late atrophy in primary-progressive multiple sclerosis. Patients with secondary-progressive multiple sclerosis showed the highest event-based model stage (the highest number of atrophic regions, P < 0.001) at the study entry. All multiple sclerosis phenotypes, but clinically isolated syndrome, showed a faster rate of increase in the event-based model stage than healthy controls. T2 lesion load and disease duration in all patients were associated with increased event-based model stage, but no effects of disease-modifying treatments and comorbidity on event-based model stage were observed. The annualized rate of event-based model stage was associated with the disability accumulation in relapsing-remitting multiple sclerosis, independent of disease duration (P < 0.0001). The data-driven staging of atrophy progression in a large multiple sclerosis sample demonstrates that grey matter atrophy spreads to involve more regions over time. The sequence in which regions become atrophic is reasonably consistent across multiple sclerosis phenotypes. The spread of atrophy was associated with disease duration and with disability accumulation over time in relapsing-remitting multiple sclerosis.

Project description:Grey matter (GM) atrophy occurs early in primary progressive MS (PPMS), but it is unknown whether its progression involves different brain regions at different rates, as is seen in other neurodegenerative diseases. We aimed to investigate the temporal and regional evolution of GM volume loss over 5years and its relationship with disability progression in early PPMS. We studied 36 patients with PPMS within five years from onset and 19 age and gender-matched healthy controls with clinical and imaging assessments at study entry and yearly for 3years and then at 5years. Patients were scored on the expanded disability status scale (EDSS) and MS Functional Composite (MSFC) at each time-point. An unbiased longitudinal voxel-based morphometry approach, based on high-dimensional spatial alignment within-subject, was applied to the serial imaging data. The rate of local (voxel-wise) volume change per year was compared between groups and its relationship with clinical outcomes was assessed. Patients deteriorated significantly during the five years follow-up. Patients showed a greater decline of GM volume (p<0.05, FWE-corrected) bilaterally in the cingulate cortex, thalamus, putamen, precentral gyrus, insula and cerebellum when compared to healthy controls over five years, although the rate of volume loss varied across the brain, and was the fastest in the cingulate cortex. Significant (p<0.05, FWE-corrected) volume loss was detected in the left insula, left precuneus, and right cingulate cortex in patients at three years, as compared to baseline, whilst the bilateral putamen and the left superior temporal gyrus showed volume loss at five years. In patients, there was a relationship between a higher rate of volume loss in the bilateral cingulate cortex and greater clinical disability, as measured by the MSFC, at five years (Pearson's r=0.49, p=0.003). Longitudinal VBM demonstrated that the progression of GM atrophy in PPMS occurs at different rates in different regions across the brain. The involvement of the cingulate cortex occurs early in the disease course, continues at a steady rate throughout the follow-up period and is associated with patient outcome. These findings provide new insights into the characteristics of GM atrophy across the brain in MS, and have potential consequences for the selection of brain atrophy as an outcome measure in neuroprotective clinical trials.

Project description:BackgroundComorbidities including vascular risk factors can be associated with whole and regional brain atrophy in multiple sclerosis (MS). This has been examined in mixed MS cohorts in prospective or observational studies; however, the association between vascular comorbidities (VCM) in secondary progressive MS (SPMS) and brain atrophy has been less well studied. The aim was to investigate the cross-sectional and longitudinal association between VCM, comorbidity burden and brain atrophy in SPMS.MethodsPost hoc analysis of 445 participants from the MS-Secondary Progressive multi-arm trial (MS-SMART)-a multi-arm multicentre phase-2b randomised placebo-controlled trial of three agents in SPMS (NCT01910259). VCM (hypertension, hyperlipidaemia) but also asthma, hypothyroidism and osteoporosis were recorded. Regional and whole brain volume (WBV), and percentage brain volume change were calculated using SIENAX and SIENA, respectively. Multiple linear regression was used to investigate the cross-sectional and longitudinal relationships between VCM, overall comorbidity count and whole brain, grey matter (GM) and white matter (WM) atrophy.ResultsThe cohort was predominantly female (67%), mean age 55 with median EDSS 6.0. In total, 13% and 9% had hypertension and hyperlipidaemia, respectively. In cross-sectional regression models, VCM was associated with decreased cortical GM volume [(hypertension β = -0.30, 95%CI -0.54 to -0.06, p = 0.01) (hyperlipidaemia β = -0.37, 95%CI -0.64 to -0.09, p = 0.008)]; but not WBV. Having ≥2 comorbidities was also associated with decreased cortical GM volume (β = -0.36, 95%CI -0.61 to -0.10, p = 0.007). No relationship was observed between VCM/comorbidity count and whole brain or GM atrophy rate over 96 weeks.ConclusionsPeople with SPMS with VCM or increased overall comorbidity burden showed reduced whole brain and especially cortical grey matter volumes, but no significant impact on subsequent 2-year atrophy rate was detected.

Dataset Information

Localised grey matter atrophy in multiple sclerosis is network-based: a coordinate-based meta-analysis.

Aim

Materials and methods

Results

Conclusion

Publications

Localised grey matter atrophy in multiple sclerosis is network-based: a coordinate-based meta-analysis.

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