scholarly journals Stress Signal ULBP4, an NKG2D Ligand, Is Upregulated in Multiple Sclerosis and Shapes CD8+ T-Cell Behaviors

2021 ◽  
Vol 9 (1) ◽  
pp. e1119
Author(s):  
Ana Carmena Moratalla ◽  
Yves Carpentier Solorio ◽  
Florent Lemaitre ◽  
Negar Farzam-kia ◽  
Annie Levert ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Lymphocytes ◽  
Gray Matter ◽  
Primary Cultures ◽  
Postmortem Brain ◽  
In Vitro Assays ◽  
Soluble Form ◽  
Healthy Controls ◽  
Human Astrocytes ◽  
The Impact

Background and ObjectivesWe posit the involvement of the natural killer group 2D (NKG2D) pathway in multiple sclerosis (MS) pathology via the presence of specific NKG2D ligands (NKG2DLs). We aim to evaluate the expression of NKG2DLs in the CNS and CSF of patients with MS and to identify cellular stressors inducing the expression of UL16-binding protein 4 (ULBP4), the only detectable NKG2DL. Finally, we evaluate the impact of ULBP4 on functions such as cytokine production and motility by CD8+ T lymphocytes, a subset largely expressing NKG2D, the cognate receptor.MethodsHuman postmortem brain samples and CSF from patients with MS and controls were used to evaluate NKG2DL expression. In vitro assays using primary cultures of human astrocytes and neurons were performed to identify stressors inducing ULBP4 expression. Human CD8+ T lymphocytes from MS donors and age/sex-matched healthy controls were isolated to evaluate the functional impact of soluble ULBP4.ResultsWe detected mRNA coding for the 8 identified human NKG2DLs in brain samples from patients with MS and controls, but only ULBP4 protein expression was detectable by Western blot. ULBP4 levels were greater in patients with MS, particularly in active and chronic active lesions and normal-appearing white matter, compared with normal-appearing gray matter from MS donors and white and gray matter from controls. Soluble ULBP4 was also detected in CSF of patients with MS and controls, but a smaller shed/soluble form of 25 kDa was significantly elevated in CSF from female patients with MS compared with controls and male patients with MS. Our data indicate that soluble ULBP4 affects various functions of CD8+ T lymphocytes. First, it enhanced the production of the proinflammatory cytokines GM-CSF and interferon-γ (IFNγ). Second, it increased CD8+ T lymphocyte motility and favored a kinapse-like behavior when cultured in the presence of human astrocytes. CD8+ T lymphocytes from patients with MS were especially altered by the presence of soluble ULBP4 compared with healthy controls.DiscussionOur study provides new evidence for the involvement of NKG2D and its ligand ULBP4 in MS pathology. Our results point to ULBP4 as a viable target to specifically block 1 component of the NKG2D pathway without altering immune surveillance involving other NKG2DL.

Association of Age at Onset With Gray Matter Volume and White Matter Microstructural Abnormalities in People With Multiple Sclerosis

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012869
Author(s):  
Raffaello Bonacchi ◽  
Alessandro Meani ◽  
Elisabetta Pagani ◽  
Olga Marchesi ◽  
Andrea Falini ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Gray Matter ◽  
Linear Models ◽  
Gray Matter Volume ◽  
Age At Onset ◽  
Healthy Controls ◽  
Compensatory Mechanisms ◽  
Cross Sectional ◽  
Matter Volume

Objective:To investigate whether age at onset influences brain gray matter volume (GMV) and white matter (WM) microstructural abnormalities in adult multiple sclerosis (MS) patients, given its influence on clinical phenotype and disease course.Method:In this hypothesis-driven cross-sectional study, we enrolled 67 pediatric-onset MS (POMS) patients and 143 sex- and disease duration (DD)-matched randomly-selected adult-onset MS (AOMS) patients, together with 208 healthy controls. All subjects underwent neurological evaluation and 3T MRI acquisition. MRI variables were standardized based on healthy controls, to remove effects of age and sex. Associations with DD in POMS and AOMS patients were studied with linear models. Time to reach clinical and MRI milestones was assessed with product-limit approach.Results:At DD=1 year, GMV and WM fractional anisotropy (FA) were abnormal in AOMS but not in POMS patients. Significant interaction of age at onset (POMS vs AOMS) into the association with DD was found for GMV and WM FA. The crossing point of regression lines in POMS and AOMS patients was at 20 years of DD for GMV and 14 for WM FA. For POMS and AOMS patients, median DD was 29 and 19 years to reach Expanded Disability Status Scale=3 (p<0.001), 31 and 26 years to reach abnormal Paced Auditory Serial Addition Task-3 (p=0.01), 24 and 18 years to reach abnormal GMV (p=0.04), and 19 and 17 years to reach abnormal WM FA (p=0.36).Conclusions:Younger patients are initially resilient to MS-related damage. Then, compensatory mechanisms start failing with loss of WM integrity, followed by GM atrophy and finally disability.

Cognitive reserve moderates the impact of subcortical gray matter atrophy on neuropsychological status in multiple sclerosis

2015 ◽  
Vol 22 (1) ◽  
pp. 36-42 ◽  
Author(s):  
Claire M Modica ◽  
Niels Bergsland ◽  
Michael G Dwyer ◽  
Deepa P Ramasamy ◽  
Ellen Carl ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cognitive Decline ◽  
Cognitive Processing ◽  
Gray Matter ◽  
Cognitive Reserve ◽  
Cognitive Outcome ◽  
Brain Reserve ◽  
The Impact ◽  
Normal Controls

Background: Cognitive decline is characterized in multiple sclerosis (MS), but the rate and severity vary. The reserve hypothesis proposes that baseline neurological differences impact cognitive outcome in neurodegenerative disease. Objective: To elucidate how brain reserve and cognitive reserve influence subcortical gray matter (SCGM) atrophy and cognitive decline in MS over 3 years. Methods: Seventy-one MS patients and 23 normal controls underwent magnetic resonance imaging and cognitive assessment at baseline and 3-year follow-up. The influence of reserve on cognitive processing speed (CPS) and memory was examined. Results: SCGM volume and cognitive scores were lower in MS than normal controls ( P⩽0.001). Accounting for baseline, comparison of follow-up means yielded a difference between groups in SCGM volume ( P<0.001) but not cognition (NS). Cognitive reserve ( P=0.005), but not brain reserve, contributed to CPS, with only low cognitive reserve MS subjects showing decline in CPS ( P=0.029). SCGM change predicted CPS outcome in MS with low cognitive reserve ( P=0.002) but not high cognitive reserve. There were no effects in the domain of memory. Conclusions: SCGM atrophy occurs in normal controls, but significantly more so in MS. While CPS did not change in normal controls, low cognitive reserve was associated with CPS decline in MS. High cognitive reserve protect MS patients from cognitive decline related to SCGM atrophy.

The Impact of MRI T1 Hypointense Brain Lesions on Cerebral Deep Gray Matter Volume Measures in Multiple Sclerosis

2019 ◽  
Author(s):  
Korhan Buyukturkoglu ◽  
Enricomaria Mormina ◽  
Philip L. Jager ◽  
Claire S. Riley ◽  
Victoria M. Leavitt
Keyword(s):  
Multiple Sclerosis ◽  
Gray Matter ◽  
Gray Matter Volume ◽  
Brain Lesions ◽  
Matter Volume ◽  
Deep Gray Matter ◽  
The Impact

scholarly journals Long-range connections are more severely damaged and relevant for cognition in multiple sclerosis

Brain ◽  
2019 ◽  
Vol 143 (1) ◽  
pp. 150-160 ◽  
Author(s):  
Kim A Meijer ◽  
Martijn D Steenwijk ◽  
Linda Douw ◽  
Menno M Schoonheim ◽  
Jeroen J G Geurts
Keyword(s):  
Multiple Sclerosis ◽  
Functional Connectivity ◽  
Fractional Anisotropy ◽  
Long Range ◽  
Short Range ◽  
Brain Regions ◽  
Healthy Controls ◽  
Network Efficiency ◽  
Structural Network ◽  
The Impact

Abstract An efficient network such as the human brain features a combination of global integration of information, driven by long-range connections, and local processing involving short-range connections. Whether these connections are equally damaged in multiple sclerosis is unknown, as is their relevance for cognitive impairment and brain function. Therefore, we cross-sectionally investigated the association between damage to short- and long-range connections with structural network efficiency, the functional connectome and cognition. From the Amsterdam multiple sclerosis cohort, 133 patients (age = 54.2 ± 9.6) with long-standing multiple sclerosis and 48 healthy controls (age = 50.8 ± 7.0) with neuropsychological testing and MRI were included. Structural connectivity was estimated from diffusion tensor images using probabilistic tractography (MRtrix 3.0) between pairs of brain regions. Structural connections were divided into short- (length &lt; quartile 1) and long-range (length &gt; quartile 3) connections, based on the mean distribution of tract lengths in healthy controls. To determine the severity of damage within these connections, (i) fractional anisotropy as a measure for integrity; (ii) total number of fibres; and (iii) percentage of tract affected by lesions were computed for each connecting tract and averaged for short- and long-range connections separately. To investigate the impact of damage in these connections for structural network efficiency, global efficiency was computed. Additionally, resting-state functional connectivity was computed between each pair of brain regions, after artefact removal with FMRIB’s ICA-based X-noiseifier. The functional connectivity similarity index was computed by correlating individual functional connectivity matrices with an average healthy control connectivity matrix. Our results showed that the structural network had a reduced efficiency and integrity in multiple sclerosis relative to healthy controls (both P &lt; 0.05). The long-range connections showed the largest reduction in fractional anisotropy (z = −1.03, P &lt; 0.001) and total number of fibres (z = −0.44, P &lt; 0.01), whereas in the short-range connections only fractional anisotropy was affected (z = −0.34, P = 0.03). Long-range connections also demonstrated a higher percentage of tract affected by lesions than short-range connections, independent of tract length (P &lt; 0.001). Damage to long-range connections was more strongly related to structural network efficiency and cognition (fractional anisotropy: r = 0.329 and r = 0.447. number of fibres r = 0.321 and r = 0.278. and percentage of lesions: r = −0.219; r = −0.426, respectively) than damage to short-range connections. Only damage to long-distance connections correlated with a more abnormal functional network (fractional anisotropy: r = 0.226). Our findings indicate that long-range connections are more severely affected by multiple sclerosis-specific damage than short-range connections. Moreover compared to short-range connections, damage to long-range connections better explains network efficiency and cognition.

scholarly journals Word-finding difficulty is a prevalent disease-related deficit in early multiple sclerosis

2019 ◽  
Vol 26 (13) ◽  
pp. 1752-1764 ◽  
Author(s):  
Rachel Brandstadter ◽  
Michelle Fabian ◽  
Victoria M Leavitt ◽  
Stephen Krieger ◽  
Anusha Yeshokumar ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Gray Matter ◽  
Objective Assessment ◽  
Lesion Volume ◽  
Healthy Controls ◽  
Patient Report ◽  
Word Finding ◽  
Cognitive Complaint ◽  
Two Samples ◽  
Patient Reported

Background: Persons with multiple sclerosis (MS) commonly report word-finding difficulty clinically, yet this language deficit remains underexplored. Objective: To investigate the prevalence and nature of word-finding difficulty in persons with early MS on three levels: patient report, cognitive substrates, and neuroimaging. Methods: Two samples of early MS patients ( n = 185 and n = 55; ⩽5 years diagnosed) and healthy controls ( n = 50) reported frequency/severity of cognitive deficits and underwent objective assessment with tasks of rapid automatized naming (RAN), measuring lexical access speed, memory, word generation, and cognitive efficiency. High-resolution brain magnetic resonance imaging (MRI) derived measurements of regional cortical thickness, global and deep gray matter volume, and T2 lesion volume. Relationships among patient-reported word-finding difficulty, cognitive performance, and neural correlates were examined. Results: Word-finding difficulty was the most common cognitive complaint of MS patients and the only complaint reported more by patients than healthy controls. Only RAN performance discriminated MS patients with subjective word-finding deficits from those without subjective complaints and from healthy controls. Thinner left parietal cortical gray matter independently predicted impaired RAN performance, driven primarily by the left precuneus. Conclusion: Three levels of evidence (patient-report, objective behavior, regional gray matter) support word-finding difficulty as a prevalent, measurable, disease-related deficit in early MS linked to left parietal cortical thinning.

Iron content of the pulvinar nucleus of the thalamus is increased in adolescent multiple sclerosis

2012 ◽  
Vol 19 (5) ◽  
pp. 567-576 ◽  
Author(s):  
Jesper Hagemeier ◽  
E Ann Yeh ◽  
Mari Heininen Brown ◽  
Niels Bergsland ◽  
Michael G Dwyer ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Gray Matter ◽  
Iron Content ◽  
Neurological Disorders ◽  
Normal Phase ◽  
Susceptibility Weighted Imaging ◽  
Healthy Controls ◽  
Volume Measurements ◽  
Deep Gray Matter ◽  
Age And Sex

Objective: The objective of this paper is to assess abnormal phase values, indicative of increased iron content, using susceptibility-weighted imaging (SWI)-filtered phase of the subcortical deep gray matter (SDGM) in adolescent multiple sclerosis (MS) and other neurological disorders (OND) patients, and in healthy controls (HC). Methods: Twenty adolescent MS and eight adolescent OND patients and 21 age- and sex-matched HC were scanned on a 3T GE scanner. Mean phase of abnormal phase tissue (MP-APT), MP-APT volume, normal phase tissue volume (NPTV) and normalized volume measurements were obtained for total SDGM, as well as specific structures separately. Results: Significantly increased MP-APT (28.2%, p<.001) and MP-APT volume (82.7%, p<.001), and decreased NPTV (−23.3%, p<.001) and normalized volume (−15.5%, p<.001) in the pulvinar nucleus of the thalamus was found in MS patients compared to HC. MP-APT in MS patients was also increased in total SDGM ( p=.012) and thalamus ( p=.044). Compared to OND patients, MS patients had increased MP-APT volume in the pulvinar nucleus of the thalamus ( p=.044) and caudate ( p=.045). Increased MP-APT of the SDGM structures were associated with increased T2 and T1 lesion burden and brain atrophy in MS patients. Conclusion: Adolescent MS patients showed increased iron content in the SDGM compared to OND patients and HC.

scholarly journals Deep Gray Matter Iron Content in Neuromyelitis Optica and Multiple Sclerosis

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Adam Pudlac ◽  
Andrea Burgetova ◽  
Petr Dusek ◽  
Petra Nytrova ◽  
Manuela Vaneckova ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Magnetic Susceptibility ◽  
Substantia Nigra ◽  
Neuromyelitis Optica ◽  
Gray Matter ◽  
Iron Homeostasis ◽  
Iron Concentration ◽  
Clinical Severity ◽  
Healthy Controls ◽  
Deep Gray Matter

Background. Neuromyelitis optica (NMO) and multiple sclerosis (MS) are often presenting with overlapping symptoms. The aim of this study was to determine whether and how NMO and MS differ regarding cerebral iron deposits in deep gray matter (DGM) and the correlation between iron deposition and clinical severity as well as to regional atrophy of the DGM. Methods. We analyzed 20 patients with NMO, 40 patients with a relapsing-remitting (RR) form of MS, and 20 healthy controls with 1.5T MRI. Quantitative susceptibility mapping (QSM) was performed to estimate iron concentration in the DGM. Results. Patients with NMO have higher magnetic susceptibility values in the substantia nigra compared to healthy controls. RRMS patients have lower magnetic susceptibility values in the thalamus compared to healthy controls and NMO patients. Atrophy of the thalamus, pulvinar, and putamen is significant both in RRMS compared to NMO patients and healthy controls. A correlation was found between the disability score (EDSS) and magnetic susceptibility in the putamen in RRMS. Conclusions. This study confirms that a disturbed cerebral iron homeostasis in patients with NMO occurs in different structures than in patients with RRMS. Increased magnetic susceptibility in substantia nigra in NMO and decreased magnetic susceptibility within the thalamus in RRMS were the only significant differences in the study sample. We could confirm that iron concentration in the thalami is decreased in RRMS compared to that in the HC group. Positive association was found between putaminal iron and EDSS in RRMS.

Cognitive functions in multiple sclerosis: impact of gray matter integrity

2013 ◽  
Vol 20 (4) ◽  
pp. 424-432 ◽  
Author(s):  
Sara Llufriu ◽  
Eloy Martinez-Heras ◽  
Juan Fortea ◽  
Yolanda Blanco ◽  
Joan Berenguer ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cognitive Performance ◽  
Gray Matter ◽  
Cognitive Functions ◽  
Diffusion Tensor ◽  
Lesion Volume ◽  
Memory And Attention ◽  
Diffusion Tensor Images ◽  
Explained Variance ◽  
The Impact

Objectives: Our aim was to investigate the impact of gray matter (GM) integrity on cognitive performance in multiple sclerosis (MS), and its relationship with white matter (WM) integrity and presence of lesions. Methods: Sixty-seven patients with MS and 26 healthy controls underwent voxel-based analysis of diffusion tensor images (DTI) in GM and tract-based spatial statistics (TBSS) from WM to identify the regional correlations between cognitive functions and integrity. Lesion probability mapping (LPM) was generated for correlation analysis with cognition. Multiple linear regression analyses were used to identify the imaging measures associated with cognitive scores. Results: Compared with controls, patients showed abnormal DTI indices in several GM regions and in most WM tracts. Impairment in DTI indices in specific GM regions was associated with worse performance of distinct cognitive functions. Those regions showed anatomical correspondence with cognitively relevant tracts in TBSS and LPM. The combination of regional GM and WM DTI and lesion volume accounted for 36–51% of the variance of memory and attention scores. Regional GM DTI explained less than 5% of that variance. Conclusion: GM and WM integrity of specific networks influences cognitive performance in MS. However, GM damage assessed by DTI only adds a small increment to the explained variance by WM in predicting cognitive functioning.

scholarly journals Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis

2018 ◽  
Vol 25 (5) ◽  
pp. 661-668 ◽  
Author(s):  
Christiane Graetz ◽  
Adriane Gröger ◽  
Felix Luessi ◽  
Anke Salmen ◽  
Daniela Zöller ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Body Mass Index ◽  
Disease Severity ◽  
Body Mass ◽  
Gray Matter ◽  
Structural Mri ◽  
Individual Variability ◽  
Nucleotide Polymorphisms ◽  
Brain Parenchymal ◽  
The Impact

Background: The course of multiple sclerosis (MS) shows substantial inter-individual variability. The underlying determinants of disease severity likely involve genetic and environmental factors. Objective: The aim of this study was to assess the impact of APOE and HLA polymorphisms as well as smoking and body mass index (BMI) in the very early MS course. Methods: Untreated patients ( n = 263) with a recent diagnosis of relapsing-remitting (RR) MS or clinically isolated syndrome underwent standardized magnetic resonance imaging (MRI). Genotyping was performed for single-nucleotide polymorphisms (SNPs) rs3135388 tagging the HLA-DRB1*15:01 haplotype and rs7412 (Ɛ2) and rs429358 (Ɛ4) in APOE. Linear regression analyses were applied based on the three SNPs, smoking and BMI as exposures and MRI surrogate markers for disease severity as outcomes. Results: Current smoking was associated with reduced gray matter fraction, lower brain parenchymal fraction and increased cerebrospinal fluid fraction in comparison to non-smoking, whereas no effect was observed on white matter fraction. BMI and the SNPs in HLA and APOE were not associated with structural MRI parameters. Conclusions: Smoking may have an unfavorable effect on the gray matter fraction as a potential measure of MS severity already in early MS. These findings may impact patients’ counseling upon initial diagnosis of MS.

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