Gray Matter Pathology Research Articles

Effect of switching from daily injections of 20mg glatiramer acetate to 40mg three times a week on gray and white matter pathology in subjects with relapsing multiple sclerosis over 33 months (P2.398)

Effect of switching from daily injections of 20mg glatiramer acetate to 40mg three times a week on gray and white matter pathology in subjects with relapsing multiple sclerosis over 33 months (P2.398)

Effect of dimethyl fumarate on gray and white matter pathology in subjects with relapsing multiple sclerosis over 24 months (P5.352)

Effect of dimethyl fumarate on gray and white matter pathology in subjects with relapsing multiple sclerosis over 24 months (P5.352)

Neuroinflammatory component of gray matter pathology in multiple sclerosis: a combined 7T and 11C-PBR28 MR-PET imaging study (P4.371)

Neuroinflammatory component of gray matter pathology in multiple sclerosis: a combined 7T and 11C-PBR28 MR-PET imaging study (P4.371)

Gray Matter Atrophy Is Primarily Related to Demyelination of Lesions in Multiple Sclerosis: A Diffusion Tensor Imaging MRI Study.

Objective: Cortical pathology, periventricular demyelination, and lesion formation in multiple sclerosis (MS) are related (Hypothesis 1). Factors in the cerebrospinal fluid close to these compartments could possibly drive the parallel processes. Alternatively, the cortical atrophy could be caused by remote axonal transection (Hypothesis 2). Since MRI can differentiate between demyelination and axon loss, we used this imaging modality to investigate the correlation between the pattern of diffusion parameter changes in the periventricular- and deep white matter and the gray matter atrophy.Methods: High-resolution T1-weighted, FLAIR, and diffusion MRI images were acquired in 52 RRMS patients and 50 healthy, age-matched controls. We used EDSS to estimate the clinical disability. We used Tract Based Spatial Statistics to compare diffusion parameters (fractional anisotropy, mean, axial, and radial diffusivity) between groups. We evaluated global brain, white, and gray matter atrophy with SIENAX. Averaged, standard diffusion parameters were calculated in four compartment: periventricular lesioned and normal appearing white matter, non-periventricular lesioned and normal appearing white matter. PLS regression was used to identify which diffusion parameter and in which compartment best predicts the brain atrophy and clinical disability.Results: In our diffusion tensor imaging study compared to controls we found extensive alterations of fractional anisotropy, mean and radial diffusivity and smaller changes of axial diffusivity (maximal p > 0.0002) in patients that suggested demyelination in the lesioned and in the normal appearing white matter. We found significant reduction in total brain, total white, and gray matter (patients: 718.764 ± 14.968, 323.237 ± 7.246, 395.527 ± 8.050 cm3, controls: 791.772 ± 22.692, 355.350 ± 10.929, 436.422 ± 12.011 cm3; mean ± SE), (p < 0.015; p < 0.0001; p < 0.009; respectively) of patients compared to controls. The PLS analysis revealed a combination of demyelination-like diffusion parameters (higher mean and radial diffusivity in patients) in the lesions and in the non-lesioned periventricular white matter, which best predicted the gray matter atrophy (p < 0.001). Similarly, EDSS was best predicted by the radial diffusivity of the lesions and the non-lesioned periventricular white matter, but axial diffusivity of the periventricular lesions also contributed significantly (p < 0.0001).Interpretation: Our investigation showed that gray matter atrophy and white matter demyelination are related in MS but white matter axonal loss does not significantly contribute to the gray matter pathology.

White matter pathology in sporadic frontotemporal lobar degeneration with TDP-43 proteinopathy.

To characterize white matter pathology in frontotemporal lobar degeneration (FTLD) with TDP-43 proteinopathy (FTLD-TDP) and its relationship to gray matter pathology. Fiber tracts from frontal and temporal lobes of 10 sporadic cases of FTLD and 8 controls. Density and spatial patterns of vacuolation, glial cell nuclei, and glial inclusions (GI) were studied in 4 fiber tracts from each case. Densities of vacuoles but not glial cells were greater in FTLD-TDP than controls. No GI were observed in controls, while in FTLD-TDP, greatest densities of GI were observed in the cortex of early-onset cases. Vacuoles, glial cell nuclei, and GI were distributed in clusters which were regularly distributed across the tract. Densities of vacuoles in white matter were positively correlated with those in adjacent gray matter, and correlations were also present between GI in white matter and TDP-43-immunoreactive pathology in gray matter. (1) Degeneration of white matter in sporadic FTLD-TDP was characterized by increased vacuolation and GI, (2) pathological changes were topographically distributed, which suggests propagation of pathological TDP-43 in specific groups of fibers, and (3) both white matter pathology and gray matter pathology need to be considered to quantify the pathological "load" in FTLD-TDP. .

MiR-142-3p Is a Key Regulator of IL-1β-Dependent Synaptopathy in Neuroinflammation

MicroRNAs (miRNA) play an important role in post-transcriptional gene regulation of several physiological and pathological processes. In multiple sclerosis (MS), a chronic inflammatory and degenerative disease of the CNS, and in its mouse model, the experimental autoimmune encephalomyelitis (EAE), miRNA dysregulation has been mainly related to immune system dysfunction and white matter (WM) pathology. However, little is known about their role in gray matter pathology. Here, we explored miRNA involvement in the inflammation-driven alterations of synaptic structure and function, collectively known as synaptopathy, a neuropathological process contributing to excitotoxic neurodegeneration in MS/EAE. Particularly, we observed that miR-142-3p is increased in the CSF of patients with active MS and in EAE brains. We propose miR-142-3p as a molecular mediator of the IL-1β-dependent downregulation of the glial glutamate-aspartate transporter (GLAST), which causes an enhancement of the glutamatergic transmission in the EAE cerebellum. The synaptic abnormalities mediated by IL-1β and the clinical and neuropathological manifestations of EAE disappeared in <i>miR-142</i> knock-out mice. Furthermore, we observed that <i>in vivo</i> miR-142-3p inhibition, either by a preventive and local treatment or by a therapeutic and systemic strategy, abolished IL-1β- and GLAST-dependent synaptopathy in EAE wild-type mice. Consistently, miR-142-3p was responsible for the glutamatergic synaptic alterations caused by CSF of patients with MS, and CSF levels of miR-142-3p correlated with prospective MS disease progression. Our findings highlight miR-142-3p as key molecular player in IL-1β-mediated synaptic dysfunction, possibly leading to excitotoxic damage in both EAE and MS diseases. Inhibition of miR-142-3p could be neuroprotective in MS. <b>SIGNIFICANCE STATEMENT</b> Current studies suggest the role of glutamate excitotoxicity in the development and progression of multiple sclerosis (MS) and of its mouse model experimental autoimmune encephalomyelitis (EAE). The molecular mechanisms linking inflammation and synaptic alterations in MS/EAE are still unknown. Here, we identified miR-142-3p as a determinant molecular actor in inflammation-dependent synaptopathy typical of both MS and EAE. miR-142-3p was upregulated in the CSF of MS patients and in EAE cerebellum. Inhibition of miR-142-3p, locally in EAE brain and in a MS chimeric <i>ex vivo</i> model, recovered glutamatergic synaptic enhancement typical of EAE/MS. We proved that miR-142-3p promoted the IL-1β-dependent glutamate dysfunction by targeting glutamate-aspartate transporter (GLAST), a crucial glial transporter involved in glutamate homeostasis. Finally, we suggest miR-142-3p as a negative prognostic factor in patients with relapsing-remitting multiple sclerosis.

BAFF Index and CXCL13 levels in the cerebrospinal fluid associate respectively with intrathecal IgG synthesis and cortical atrophy in multiple sclerosis at clinical onset

BackgroundB lymphocytes are thought to play a relevant role in multiple sclerosis (MS) pathology. The in vivo analysis of intrathecally produced B cell-related cytokines may help to clarify the mechanisms of B cell recruitment and immunoglobulin production within the central nervous system (CNS) in MS.MethodsPaired cerebrospinal fluid (CSF) and serum specimens from 40 clinically isolated syndrome suggestive of MS or early-onset relapsing-remitting MS patients (CIS/eRRMS) and 17 healthy controls (HC) were analyzed for the intrathecal synthesis of IgG (quantitative formulae and IgG oligoclonal bands, IgGOB), CXCL13, BAFF, and IL-21. 3D-FLAIR, 3D-DIR, and 3D-T1 MRI sequences were applied to evaluate white matter (WM) and gray matter (GM) lesions and global cortical thickness (gCTh).ResultsCompared to HC, CIS/eRRMS having IgGOB (IgGOB+, 26 patients) had higher intrathecal IgG indexes (p < 0.01), lower values of BAFF Index (11.9 ± 6.1 vs 17.5 ± 5.2, p < 0.01), and higher CSF CXCL13 levels (27.7 ± 33.5 vs 0.9 ± 1.5, p < 0.005). In these patients, BAFF Index but not CSF CXCL13 levels inversely correlated with the intrathecal IgG synthesis (r > 0.5 and p < 0.05 for all correlations). CSF leukocyte counts were significantly higher in IgGOB+ compared to IgGOB− (p < 0.05) and HC (p < 0.01), and correlated to CSF CXCL13 concentrations (r 0.77, p < 0.001).The gCTh was significantly lower in patients with higher CSF CXCL13 levels (2.41 ± 0.1 vs 2.49 ± 0.1 mm, p < 0.05), while no difference in MRI parameters of WM and GM pathology was observed between IgGOB+ and IgGOB−.ConclusionsThe intrathecal IgG synthesis inversely correlated with BAFF Index and showed no correlation with CSF CXCL13. These findings seem to indicate that intrathecally synthesized IgG are produced by long-term PCs that have entered the CNS from the peripheral blood, rather than produced by PCs developed in the meningeal follicle-like structures (FLS). In this study, CXCL13 identifies a subgroup of MS patients characterized by higher leukocyte counts in the CSF and early evidence of cortical thinning, further suggesting a role for this chemokine as a possible marker of disease severity.

MiR-142-3p Is a Key Regulator of IL-1β-Dependent Synaptopathy in Neuroinflammation.

Current studies suggest the role of glutamate excitotoxicity in the development and progression of multiple sclerosis (MS) and of its mouse model experimental autoimmune encephalomyelitis (EAE). The molecular mechanisms linking inflammation and synaptic alterations in MS/EAE are still unknown. Here, we identified miR-142-3p as a determinant molecular actor in inflammation-dependent synaptopathy typical of both MS and EAE. miR-142-3p was upregulated in the CSF of MS patients and in EAE cerebellum. Inhibition of miR-142-3p, locally in EAE brain and in a MS chimeric ex vivo model, recovered glutamatergic synaptic enhancement typical of EAE/MS. We proved that miR-142-3p promoted the IL-1β-dependent glutamate dysfunction by targeting glutamate-aspartate transporter (GLAST), a crucial glial transporter involved in glutamate homeostasis. Finally, we suggest miR-142-3p as a negative prognostic factor in patients with relapsing-remitting multiple sclerosis.

Measurement of Cortical Thickness and Volume of Subcortical Structures in Multiple Sclerosis: Agreement between 2D Spin-Echo and 3D MPRAGE T1-Weighted Images.

Gray matter pathology is known to occur in multiple sclerosis and is related to disease outcomes. FreeSurfer and the FMRIB Integrated Registration and Segmentation Tool (FIRST) have been developed for measuring cortical and subcortical gray matter in 3D-gradient-echo T1-weighted images. Unfortunately, most historical MS cohorts do not have 3D-gradient-echo, but 2D-spin-echo images instead. We aimed to evaluate whether cortical thickness and the volume of subcortical structures measured with FreeSurfer and FIRST could be reliably measured in 2D-spin-echo images and to investigate the strength and direction of clinicoradiologic correlations. Thirty-eight patients with MS and 2D-spin-echo and 3D-gradient-echo T1-weighted images obtained at the same time were analyzed by using FreeSurfer and FIRST. The intraclass correlation coefficient between the estimates was obtained. Correlation coefficients were used to investigate clinicoradiologic associations. Subcortical volumes obtained with both FreeSurfer and FIRST showed good agreement between 2D-spin-echo and 3D-gradient-echo images, with 68.8%-76.2% of the structures having either a substantial or almost perfect agreement. Nevertheless, with FIRST with 2D-spin-echo, 18% of patients had mis-segmentation. Cortical thickness had the lowest intraclass correlation coefficient values, with only 1 structure (1.4%) having substantial agreement. Disease duration and the Expanded Disability Status Scale showed a moderate correlation with most of the subcortical structures measured with 3D-gradient-echo images, but some correlations lost significance with 2D-spin-echo images, especially with FIRST. Cortical thickness estimates with FreeSurfer on 2D-spin-echo images are inaccurate. Subcortical volume estimates obtained with FreeSurfer and FIRST on 2D-spin-echo images seem to be reliable, with acceptable clinicoradiologic correlations for FreeSurfer.

Neuroinflammatory component of gray matter pathology in multiple sclerosis.

In multiple sclerosis (MS), using simultaneous magnetic resonance-positron emission tomography (MR-PET) imaging with 11 C-PBR28, we quantified expression of the 18kDa translocator protein (TSPO), a marker of activated microglia/macrophages, in cortex, cortical lesions, deep gray matter (GM), white matter (WM) lesions, and normal-appearing WM (NAWM) to investigate the in vivo pathological and clinical relevance of neuroinflammation. Fifteen secondary-progressive MS (SPMS) patients, 12 relapsing-remitting MS (RRMS) patients, and 14 matched healthy controls underwent 11 C-PBR28 MR-PET. MS subjects underwent 7T T2*-weighted imaging for cortical lesion segmentation, and neurological and cognitive evaluation. 11 C-PBR28 binding was measured using normalized 60- to 90-minute standardized uptake values and volume of distribution ratios. Relative to controls, MS subjects exhibited abnormally high 11 C-PBR28 binding across the brain, the greatest increases being in cortex and cortical lesions, thalamus, hippocampus, and NAWM. MS WM lesions showed relatively modest TSPO increases. With the exception of cortical lesions, where TSPO expression was similar, 11 C-PBR28 uptake across the brain was greater in SPMS than in RRMS. In MS, increased 11 C-PBR28 binding in cortex, deep GM, and NAWM correlated with neurological disability and impaired cognitive performance; cortical thinning correlated with increased thalamic TSPO levels. In MS, neuroinflammation is present in the cortex, cortical lesions, deep GM, and NAWM, is closely linked to poor clinical outcome, and is at least partly linked to neurodegeneration. Distinct inflammatory-mediated factors may underlie accumulation of cortical and WM lesions. Quantification of TSPO levels in MS could prove to be a sensitive tool for evaluating in vivo the inflammatory component of GM pathology, particularly in cortical lesions. Ann Neurol 2016;80:776-790.

Using ventricular modeling to robustly probe significant deep gray matter pathologies: Application to cerebral palsy.

Understanding the relationships between the structure and function of the brain largely relies on the qualitative assessment of Magnetic Resonance Images (MRIs) by expert clinicians. Automated analysis systems can support these assessments by providing quantitative measures of brain injury. However, the assessment of deep gray matter structures, which are critical to motor and executive function, remains difficult as a result of large anatomical injuries commonly observed in children with Cerebral Palsy (CP). Hence, this article proposes a robust surrogate marker of the extent of deep gray matter injury based on impingement due to local ventricular enlargement on surrounding anatomy. Local enlargement was computed using a statistical shape model of the lateral ventricles constructed from 44 healthy subjects. Measures of injury on 95 age-matched CP patients were used to train a regression model to predict six clinical measures of function. The robustness of identifying ventricular enlargement was demonstrated by an area under the curve of 0.91 when tested against a dichotomised expert clinical assessment. The measures also showed strong and significant relationships for multiple clinical scores, including: motor function (r2 = 0.62, P < 0.005), executive function (r2 = 0.55, P < 0.005), and communication (r2 = 0.50, P < 0.005), especially compared to using volumes obtained from standard anatomical segmentation approaches. The lack of reliance on accurate anatomical segmentations and its resulting robustness to large anatomical variations is a key feature of the proposed automated approach. This coupled with its strong correlation with clinically meaningful scores, signifies the potential utility to repeatedly assess MRIs for clinicians diagnosing children with CP. Hum Brain Mapp 37:3795-3809, 2016. © 2016 Wiley Periodicals, Inc.

Increased diffusivity in gray matter in recent onset schizophrenia is associated with clinical symptoms and social cognition

IntroductionDiffusion weighted MRI (dMRI) is a method sensitive to pathological changes affecting tissue microstructure. Most dMRI studies in schizophrenia, however, have focused solely on white matter. There is a possibility, however, that subtle changes in diffusivity exist in gray matter (GM). Accordingly, we investigated diffusivity in GM in patients with recent onset schizophrenia. MethodsWe enrolled 45 patients and 21 age and sex-matched healthy controls. All subjects were evaluated using the short form of the Wechsler Adult Intelligence Scale, the Positive and Negative Syndrome Scale (PANSS), and the video based social cognition scale. DMRI and T1W images were acquired on a 3 Tesla magnet, and mean Fractional Anisotropy (FA), Trace (TR) and volume were calculated for each of the 68 cortical GM Regions of Interest parcellated using FreeSurfer. ResultsThere was no significant difference of FA and GM volume between groups after Bonferroni correction. For the dMRI measures, however, patients evinced increased TR in the left bank of the superior temporal sulcus, the right inferior parietal, the right inferior temporal, and the right middle temporal gyri. In addition, higher TR in the right middle temporal gyrus and the right inferior temporal gyrus, respectively, was associated with decreased social function and higher PANSS score in patients with schizophrenia. ConclusionThis study demonstrates high sensitivity of dMRI to subtle pathology in GM in recent onset schizophrenia, as well as an association between increased diffusivity in temporal GM regions and abnormalities in social cognition and exacerbation of psychiatric symptoms.

Response to the commentary of Yates RL and DeLuca GC on the study: HLA-DRB1*1501 associations with magnetic resonance imaging measures of grey matter pathology in multiple sclerosis

Response to the commentary of Yates RL and DeLuca GC on the study: HLA-DRB1*1501 associations with magnetic resonance imaging measures of grey matter pathology in multiple sclerosis

Comment: HLA-DRB1*1501 associations with magnetic resonance imaging measures of grey matter pathology in multiple sclerosis

Comment: HLA-DRB1*1501 associations with magnetic resonance imaging measures of grey matter pathology in multiple sclerosis

High-resolution T1-relaxation time mapping displays subtle, clinically relevant, gray matter damage in long-standing multiple sclerosis

Background: Gray matter (GM) pathology has high clinical relevance in multiple sclerosis (MS), but conventional magnetic resonance imaging (MRI) is insufficiently sensitive to visualize the rather subtle damage. Objective: To investigate whether high spatial resolution T1-relaxation time (T1-RT) measurements can detect changes in the normal-appearing GM of patients with long-standing MS and whether these changes are associated with physical and cognitive impairment. Methods: High spatial resolution (1.05 × 1.05 × 1.2 mm3) T1-RT measurements were performed at 3 T in 156 long-standing MS patients and 54 healthy controls. T1-RT histogram parameters in several regions were analyzed to investigate group differences. Stepwise linear regression analyses were used to assess the relation of T1-RT with physical and cognitive impairment. Results: In both thalamus and cortex, T1-RT histogram skewness was higher in patients than controls. In the cortex, this was driven by the frontal and temporal lobes. No differences were found in other GM histogram parameters. Cortical skewness, thalamus volume, and average white matter (WM) lesion T1-RT emerged as the strongest predictors for cognitive performance (adjusted R2 = 0.39). Conclusion: Subtle GM damage was present in the cortex and thalamus of MS patients, as indicated by increased T1-RT skewness. Increased cortical skewness emerged as an independent predictor of cognitive dysfunction.

The role of global and regional gray matter volume decrease in multiple sclerosis.

Disability in multiple sclerosis (MS) patients is associated with white matter (WM) and gray matter (GM) pathology, and both processes contribute differently over the disease course. Total and regional GM volume loss can be imaged via voxel-based morphometry (VBM). Here, we retrospectively analyzed a group of 213 MS patients [163 relapsing remitting (RR) and 50 secondary progressive (SP)] using semi-automated white matter (WM) lesion mapping and voxel-based morphometry (VBM). Our aim was to assess the association of increasing disability with decreasing total and regional GM volume. As expected, total GM volume and WM lesion load were associated with patients disability, measured with the Expanded Disability Status Scale (EDSS). The more impaired the patients, the greater the statistical association to the total GM volume. Regional volume loss in the cerebellar gray matter was associated with increasing EDSS and WM lesion volume. Furthermore, SPMS patients had significantly more gray matter volume loss in the cerebellum and the hippocampus compared to RRMS patients. Our results confirm histopathological studies emphasizing the important role of the cerebellum and the hippocampus in MS patients' disability.

Measurement and maintenance of reserve in multiple sclerosis.

Cognitive dysfunction is highly prevalent, disabling, and poorly managed in persons with multiple sclerosis (MS). However, not all persons with MS present with cognitive impairment despite having grey and white matter pathology. To explain such an observation, much attention has been drawn to other factors, namely the concept of reserve (i.e., protection against clinical manifestations of neurological damage). There is a growing body of evidence supporting brain reserve and cognitive reserve for mitigating the deleterious effects of MS pathology on cognition in MS. Measurement and maintenance of reserve is paramount. The current review addresses measures of brain and cognitive reserve, separately, that have been adopted in MS research. These measures are largely based on genetics and premorbid behavior. We propose that reserve may not be limited to premorbid factors that are not highly amenable to change. Rather, reserve can be built and maintained over time based on ongoing participation in cognitively stimulating activities. We conclude with recommendations for future research on reserve in MS samples. This will provide keen insight into potential applications for building reserve and ultimately improving the well-being of those with MS across multiple domains.

Effect of Teriflunomide (Aubagio®) on Gray Matter Pathology in Multiple Sclerosis (P3.062)

Effect of Teriflunomide (Aubagio®) on Gray Matter Pathology in Multiple Sclerosis (P3.062)

HLA-DRB*1501 associations with magnetic resonance imaging measures of grey matter pathology in multiple sclerosis

BackgroundThe HLA-DRB*1501 haplotype influences the risk of developing multiple sclerosis (MS), but it is not known how it affects grey matter pathology. AimTo assess HLA-DRB*1501 effects on magnetic resonance imaging (MRI) cortical grey matter pathology. MethodsWhole and lesional cortical grey matter volumes, lesional and normal-appearing grey matter magnetization transfer ratio were measured in 85 people with MS and 36 healthy control subjects. HLA-DRB*1501 haplotype was determined by genotyping (rs3135388). ResultsNo significant differences were observed in MRI measures between the HLA-DRB*1501 subgroups. ConclusionsThe HLA-DRB*1501 haplotype is not strongly associated with MRI-visible grey matter pathology.

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.