Dataset Information

Deep gray matter volume loss drives disability worsening in multiple sclerosis.

ABSTRACT: 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.

SUBMITTER: Eshaghi A

PROVIDER: S-EPMC5838522 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Deep gray matter volume loss drives disability worsening in multiple sclerosis.

Eshaghi Arman A Prados Ferran F Brownlee Wallace J WJ Altmann Daniel R DR Tur Carmen C Cardoso M Jorge MJ De Angelis Floriana F van de Pavert Steven H SH Cawley Niamh N De Stefano Nicola N De Stefano Nicola N Stromillo M Laura ML Battaglini Marco M Ruggieri Serena S Gasperini Claudio C Filippi Massimo M Rocca Maria A MA Rovira Alex A Sastre-Garriga Jaume J Vrenken Hugo H Leurs Cyra E CE Killestein Joep J Pirpamer Lukas L Enzinger Christian C Ourselin Sebastien S Wheeler-Kingshott Claudia A M Gandini CAMG Chard Declan D Thompson Alan J AJ Alexander Daniel C DC Barkhof Frederik F Ciccarelli Olga O

Annals of neurology 20180206 2

<h4>Objective</h4>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.<h4>Methods</h4>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-progres ...[more]

PMID: 29331092

Similar Datasets

Project description:ImportanceMultiple sclerosis (MS) is characterized by progressive gray matter (GM) atrophy that strongly correlates with clinical disability. However, whether localized GM atrophy correlates with specific disabilities in patients with MS remains unknown.ObjectiveTo understand the association between localized GM atrophy and clinical disability in a biology-driven analysis of MS.Design, setting, and participantsIn this cross-sectional study, magnetic resonance images were acquired from 133 women with relapsing-remitting MS and analyzed using voxel-based morphometry and volumetry. A regression analysis was used to determine whether voxelwise GM atrophy was associated with specific clinical deficits. Data were collected from June 28, 2007, to January 9, 2014.Main outcomes and measuresVoxelwise correlation of GM change with clinical outcome measures (Expanded Disability Status Scale and Multiple Sclerosis Functional Composite scores).ResultsAmong the 133 female patients (mean [SD] age, 37.4 [7.5] years), worse performance on the Multiple Sclerosis Functional Composite correlated with voxelwise GM volume loss in the middle cingulate cortex (P < .001) and a cluster in the precentral gyrus bilaterally (P = .004). In addition, worse performance on the Paced Auditory Serial Addition Test correlated with volume loss in the auditory and premotor cortices (P < .001), whereas worse performance on the 9-Hole Peg Test correlated with GM volume loss in Brodmann area 44 (Broca area; P = .02). Finally, voxelwise GM loss in the right paracentral lobulus correlated with bowel and bladder disability (P = .03). Thus, deficits in specific clinical test results were directly associated with localized GM loss in clinically eloquent locations.Conclusions and relevanceThese biology-driven data indicate that specific disabilities in MS are associated with voxelwise GM loss in distinct locations. This approach may be used to develop disability-specific biomarkers for use in future clinical trials of neuroprotective treatments in MS.

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:In multiple sclerosis (MS), upper cervical cord gray matter (GM) atrophy correlates more strongly with disability than does brain or cord white matter (WM) atrophy. The corresponding relationships in the thoracic cord are unknown owing to technical difficulties in assessing GM and WM compartments by conventional magnetic resonance imaging techniques.To investigate the associations between MS disability and disease type with lower thoracic cord GM and WM areas using phase-sensitive inversion recovery magnetic resonance imaging at 3 T, as well as to compare these relationships with those obtained at upper cervical levels.Between July 2013 and March 2014, a total of 142 patients with MS (aged 25-75 years; 86 women) and 20 healthy control individuals were included in this cross-sectional observational study conducted at an academic university hospital.Total cord areas (TCAs), GM areas, and WM areas at the disc levels C2/C3, C3/C4, T8/9, and T9/10. Area differences between groups were assessed, with age and sex as covariates.Patients with relapsing MS (RMS) had smaller thoracic cord GM areas than did age- and sex-matched control individuals (mean differences [coefficient of variation (COV)]: 0.98 mm2 [9.2%]; P?=?.003 at T8/T9 and 0.93 mm2 [8.0%]; P?=?.01 at T9/T10); however, there were no significant differences in either the WM area or TCA. Patients with progressive MS showed smaller GM areas (mean differences [COV]: 1.02 mm2 [10.6%]; P?<?.001 at T8/T9 and 1.37 mm2 [13.2%]; P?<?.001 at T9/T10) and TCAs (mean differences [COV]: 3.66 mm2 [9.0%]; P?<?.001 at T8/T9 and 3.04 mm2 [7.2%]; P?=?.004 at T9/T10) compared with patients with RMS. All measurements (GM, WM, and TCA) were inversely correlated with Expanded Disability Status Scale score. Thoracic cord GM areas were correlated with lower limb function. In multivariable models (which also included cord WM areas and T2 lesion number, brain WM volumes, brain T1 and fluid-attenuated inversion recovery lesion loads, age, sex, and disease duration), cervical cord GM areas had the strongest correlation with Expanded Disability Status Scale score followed by thoracic cord GM area and brain GM volume.Thoracic cord GM atrophy can be detected in vivo in the absence of WM atrophy in RMS. This atrophy is more pronounced in progressive MS than RMS and correlates with disability and lower limb function. Our results indicate that remarkable cord GM atrophy is present at multiple cervical and lower thoracic levels and, therefore, may reflect widespread cord GM degeneration.

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.

Dataset Information

Deep gray matter volume loss drives disability worsening in multiple sclerosis.

Publications

Deep gray matter volume loss drives disability worsening in multiple sclerosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets