Relationship of grey and white matter abnormalities with distance from the surface of the brain in multiple sclerosis

Pardini, Matteo; Sudre, Carole H.; Prados, Ferrán; Yaldizli, Özgür; Sethi, Varun; Muhlert, Nils; Samson, R; Pavert, Steven H van de; Cardoso, M. Jorge; Ourselin, Sébastien; Wheeler-Kingshott, C; Miller, David H.; Chard, Declan

doi:10.1136/jnnp-2016-313979

Cited by 54 publications

(79 citation statements)

References 28 publications

(35 reference statements)

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“…Pathology studies of the subpial cortical injury describe demyelination, neuronal loss, microglial activation, and a relative paucity of inflammatory cells, as well as a pattern of damage that follows a "surface‐in" gradient . These observations are supported by recent magnetization transfer ratio (MTR) imaging studies in MS reporting a graded surface‐in abnormality starting at the brain–cerebrospinal fluid (CSF) interfaces of both the cortical surface and the ventricular surfaces . Together with the correlation between the severity of subpial cortical damage and the degree of meningeal inflammation, these findings have raised the hypothesis that soluble factors, potentially released by immune cells in the meninges, diffuse into the CSF and into the superficial brain layers such as the subpial cortical tissue, contributing to the observed gradient of pathological changes …”

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confidence: 82%

A surface‐in gradient of thalamic damage evolves in pediatric multiple sclerosis

Fadda

Brown

Magliozzi

et al. 2019

Annals of Neurology

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Objective Central nervous system pathology in multiple sclerosis includes both focal inflammatory perivascular injury and injury to superficial structures, including the subpial region of the cortex, which reportedly exhibits a gradient of damage from the surface inward. We assessed how early in the multiple sclerosis course a "surface‐in" process of injury suggesting progressive biology may begin. Methods We focused on the thalamus, which notably has both a cerebrospinal fluid (CSF) interface and a white matter interface. Thalamic volume trajectories were assessed in a prospectively followed cohort of children from initial presentation with either multiple sclerosis or monophasic acquired demyelination, and healthy controls. Voxelwise volume changes were calculated using deformation‐based morphometry, and analyzed in relation to distance from the CSF interface by mixed effects modeling and semiparametric smoothing methods. Results Twenty‐seven children with multiple sclerosis and 73 children with monophasic demyelination were prospectively followed with yearly brain scans (mean follow‐up = 4.6 years, standard deviation = 1.9). A total of 282 healthy children with serial scans were included as controls. Relative to healthy controls, children with multiple sclerosis and children with monophasic demyelination demonstrated volume loss in thalamic regions adjacent to the white matter. However, only children with multiple sclerosis exhibited an additional surface‐in gradient of thalamic injury on the ventricular side, which was already notable in the first year of clinical disease (asymptote estimate = 3.01, 95% confidence interval [CI] = 1.44–4.58, p = 0.0002) and worsened over time (asymptote:time estimate = 0.33, 95% CI = 0.12–0.54, p = 0.0021). Interpretation Our results suggest that a multiple sclerosis disease‐specific surface‐in process of damage can manifest at the earliest stages of the disease. ANN NEUROL 2019;85:340–351.

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mentioning

confidence: 82%

A surface‐in gradient of thalamic damage evolves in pediatric multiple sclerosis

Fadda

Brown

Magliozzi

et al. 2019

Annals of Neurology

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“…When we looked at baseline predictors of disability accumulation, without any longitudinal imaging measure in the model, only the DGM predicted future EDSS progression. The hazard ratio (95% CI, p value) for time-to-EDSS progression was 0.73 (95% CI, 0.65, 0.82; p < 0.0001), which suggests that, for every SD (Z-score) decrease in the DGM volume at baseline, the risk of presenting a shorter time to EDSS worsening during the follow-up increased by 27% (95% CI, [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. The hazard ratio remained similar when we analyzed relapse-onset and PPMS patients separately (0.72 and 0.73, respectively).…”

Section: Association Between Edss and Gm Lossmentioning

confidence: 99%

“…32 GIF uses an atlas propagation and label fusion strategy to calculate the voxel probabilities of GM, white matter, and CSF 31 ; this method has been previously used in MS and other neurodegenerative disorders. 33,34 The template library had 95 MRI brain scans (HCs and patients with AD) with neuroanatomic labels (http://www.neuromorphometrics.com/). This atlas, which is similar to the Mindboggle atlas, was developed to improve the consistency and clarity of the Desikan-Killiany protocol.…”

Section: Image Analysismentioning

confidence: 99%

Deep gray matter volume loss drives disability worsening in multiple sclerosis

Eshaghi

Prados

Brownlee

et al. 2018

Annals of Neurology

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ObjectiveGray 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.MethodsWe 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.ResultsSPMS 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).InterpretationThis 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

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“…For example, magnetization transfer (MT) images (8), and "myelin maps" derived from the ratio of conventional T1-and T2-weighted images (T1w/T2w) (9), are sensitive to the proportion of fatty brain tissue represented by each voxel which, according to histological studies on animal models, is related to myelin content (10)(11)(12)(13). MT maps have been used as markers of myelination, in white matter and in cortex (14) in healthy subjects (15) and in demyelinating disorders such as multiple sclerosis (16)(17)(18). Schizophrenia has been associated with reduced MT in frontal, temporal and insular cortex (19)(20)(21)(22)(23)(24)(25)(26) and the cortical expression of schizophrenia-related genes was (negatively) correlated with T1w/T2w maps (27).…”

Section: Introductionmentioning

confidence: 99%

Schizotypy-related magnetization of cortex in healthy adolescence is co-located with expression of schizophrenia-related genes

Romero-García

Seidlitz

Whitaker

et al. 2018

Preprint

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= 249 words (max 250 words) Main text = 3997 words (max 4000 words). References = 72 Figures = 4 Table = 1 Intra-cortical magnetization and patterning of schizophrenia-related genes 2 Abstract Background Genetic risk is thought to drive clinical variation on a spectrum of schizophrenia-like traits but the underlying changes in brain structure that mechanistically link genomic variation to schizotypal experience and behaviour are unclear. MethodsWe assessed schizotypy using a self-reported questionnaire, and measured magnetization transfer (MT), as a putative micro-structural MRI marker of intra-cortical myelination, in 68 brain regions, in 248 healthy young people (aged 14-25 years). We used normative adult brain gene expression data, and partial least squares (PLS) analysis, to find the weighted gene expression pattern that was most co-located with the cortical map of schizotypy-related magnetization (SRM). ResultsMagnetization was significantly correlated with schizotypy in bilateral posterior cingulate cortex and precuneus (and for disorganized schizotypy also in medial prefrontal cortex; all FDR-corrected P < 0.05), which are regions of the default mode network specialized for social and memory functions. The genes most positively weighted on the whole genome expression map co-located with SRM were enriched for genes that were significantly downregulated in two prior case-control histological studies of brain gene expression in schizophrenia. Conversely, the most negatively weighted genes were enriched for genes that were transcriptionally up-regulated in schizophrenia. Positively weighted (downregulated) genes were enriched for neuronal, specifically inter-neuronal, affiliations and coded a network of proteins comprising a few highly interactive "hubs" such as parvalbumin and calmodulin. ConclusionsMicrostructural MRI maps of intracortical magnetization can be linked to both the behavioural traits of schizotypy and to prior histological data on dysregulated gene expression in schizophrenia. previous version of this paper was posted on bioRxiv: https://www.biorxiv.org/content/10.1101/487108v1 DATA and CODE SHARING DataRegional magnetisation transfer (MT) for 68 cortical regions, schizotypy scores, age, gender, socio-economic status, scanning site, total brain volume and Euler values, for N=248, are available at: https://github.com/RafaelRomeroGarcia/Schizotypy_MT_geneExp. CodeCortical parcellation of gene expression maps to estimate regional mean gene expression (62): (https://github.com/RafaelRomeroGarcia/geneExpression_Repository) Generate null-models that preserve the spatial contiguity of cortical regions for permutation testing (31): https://github.com/frantisekvasa/rotate_parcellation PLS analysis and bootstrapping to estimate PLS weights (15): https://github.com/KirstieJane/NSPN_WhitakerVertes_PNAS2016/tree/master/SCRIPTS Generate Figure S1 from raw Gandal (5) and Fromer (49) datasets: https://github.com/RafaelRomeroGarcia/Schizotypy_MT_geneExpMapping regional values to the cortical surface for visuali...

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Relationship of grey and white matter abnormalities with distance from the surface of the brain in multiple sclerosis

Cited by 54 publications

References 28 publications

A surface‐in gradient of thalamic damage evolves in pediatric multiple sclerosis

A surface‐in gradient of thalamic damage evolves in pediatric multiple sclerosis

Deep gray matter volume loss drives disability worsening in multiple sclerosis

Schizotypy-related magnetization of cortex in healthy adolescence is co-located with expression of schizophrenia-related genes

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