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Article ; Online: Deciphering the shift from benign to active relapsing-remitting multiple sclerosis: Insights into T regulatory cell dysfunction and apoptosis regulation.

Achiron, Anat / Falb, Rina / Menascu, Shay / Magalashvili, David / Mandel, Mathilda / Sonis, Polina / Gurevich, Michael

2024 Volume 194, Page(s) 106475

Abstract: Background: Relapsing-remitting multiple sclerosis (RRMS), a common demyelinating disease among young adults, follows a benign course in 10-15% of cases, where patients experience minimal neurological disability for a decade following disease onset. ... ...

Abstract	Background: Relapsing-remitting multiple sclerosis (RRMS), a common demyelinating disease among young adults, follows a benign course in 10-15% of cases, where patients experience minimal neurological disability for a decade following disease onset. However, there is potential for these benign cases to transition into a clinically active, relapsing state. Objective: To elucidate the biological mechanisms underlying the transition from benign to active RRMS using gene expression analysis. Methods: We employed complementary-DNA microarrays to examine peripheral-blood gene expression patterns in patients with benign MS, defined as having a disease duration exceeding 10 years and an Expanded Disability Status Scale (EDSS) score of ≤3.0. We compared the gene expression pattern between patients who switched to active disease (Switching BMS) with those who maintained a benign state (Permanent-BMS) during an additional 5-year follow-up. Results: We identified two primary mechanisms linked to the transition from benign MS to clinically active disease. The first involves the suppression of regulatory T cell activity, and the second pertains to the dysfunction of nuclear receptor 4 A family-dependent apoptosis. These mechanisms collectively contribute to an augmented autoimmune response and increased disease activity. Conclusions: The intricate gene regulatory networks that operate in switching-BMS are related to suppression of immune tolerance and aberrant apoptosis. These findings may lead to new therapeutic targets to prevent the escalation to active disease.
MeSH term(s)	Young Adult ; Humans ; Multiple Sclerosis, Relapsing-Remitting/drug therapy ; Multiple Sclerosis/metabolism ; T-Lymphocytes, Regulatory ; Apoptosis ; Disease Progression
Language	English
Publishing date	2024-03-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2024.106475
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Article ; Online: Emotional burden among MS patients: associations between specific chronic pain diagnoses and psychological features.

Rivel, Michal / Achiron, Anat / Stern, Yael / Zeilig, Gabi / Defrin, Ruth

Journal of neurology

2023 Volume 271, Issue 2, Page(s) 688–698

Abstract: Central neuropathic pain (CNP) and musculoskeletal pain (MSP) are often comorbid with multiple sclerosis (MS), yet data on the emotional burden entailed by this comorbidity are very limited. We studied whether MS patients with CNP exhibited greater ... ...

Abstract	Central neuropathic pain (CNP) and musculoskeletal pain (MSP) are often comorbid with multiple sclerosis (MS), yet data on the emotional burden entailed by this comorbidity are very limited. We studied whether MS patients with CNP exhibited greater emotional burden and pain severity than those with MSP and whether this emotional burden was attributed to the MS, the chronic pain, or both. Participants were 125 MS patients (55 with CNP; 30 with MSP; 40 MS pain-free) and 30 healthy controls (HCs). Participants completed questionnaires assessing pain interference, pain catastrophizing, depression, anxiety, stress, hypervigilance, and chronic pain. Group comparisons and a two-step cluster analysis were performed, and the association between cluster membership and clinical group membership was evaluated. Chronic pain was stronger and more widespread in the CNP group than in the MSP group. Both pain groups had higher pain interference, pain catastrophizing, and stress compared to MS pain-free and HC groups. All MS groups had greater depression levels compared to HCs, and the CNP group had the highest anxiety level. The "high psychological distress" cluster comprised mainly participants with CNP (57%), and the "minimal psychological distress" cluster comprised mainly the MS pain-free and HC groups. In conclusion, CNP seems to induce greater emotional burden and pain severity than does MSP. Whereas depression may be attributed to MS, and anxiety to CNP, enhanced pain interference, catastrophizing, and stress may be attributed to the comorbidity of MS and chronic pain. Identifying these traits among MS patients and targeting them in management programs may contribute to more effective, individually based care.
MeSH term(s)	Humans ; Chronic Pain/diagnosis ; Chronic Pain/epidemiology ; Anxiety/epidemiology ; Pain Measurement ; Catastrophization ; Multiple Sclerosis/complications ; Multiple Sclerosis/epidemiology
Language	English
Publishing date	2023-10-24
Publishing country	Germany
Document type	Journal Article
ZDB-ID	187050-6
ISSN	1432-1459 ; 0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
ISSN (online)	1432-1459
ISSN	0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
DOI	10.1007/s00415-023-12048-8
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Article ; Online: Age-related blood transcriptional regulators affect disease progression in pediatric multiple sclerosis.

Shavit, Eitan / Menascu, Shay / Achiron, Anat / Gurevich, Michael

Neurobiology of disease

2022 Volume 176, Page(s) 105953

Abstract: Background: Pediatric onset multiple sclerosis patients (POMS) are defined as multiple sclerosis with an onset before the age of 18 years. Compared to adult onset multiple sclerosis (AOMS), POMS has more severe disease activity at onset, but better ... ...

Abstract	Background: Pediatric onset multiple sclerosis patients (POMS) are defined as multiple sclerosis with an onset before the age of 18 years. Compared to adult onset multiple sclerosis (AOMS), POMS has more severe disease activity at onset, but better recovery. Little is known about the molecular mechanism responsible for the differences in the clinical presentations. Methods: Peripheral Blood Mononuclear Cells samples were taken from 22 POMS patients (mean age 14.1 ± 2.4 years, 15 females, 7 male), and 16 AOMS patients, (mean age 30.8 ± 6.1 years,10 females, 6 males), and gene-expression were analyzed using Affymetrix Inc. HU-133-A2 microarrays. Differentially Expressed Genes (DEGs) that significantly distinguished between POMS and AOMS with pvalue <0.05 after false discovery rate correction were evaluated using Partek software. Twenty-one matched age and gender control was applied to clarify age-related changes. Clinical assessment was performed by analysis of expanded disability status scale (EDSS) and brain MRI lesion loads. Gene functional analysis was performed by Ingenuity Pathway Analysis software. Results: Compared to AOMS, POMS had higher EDSS (3.0 IQR 2.0-3.0 and 2.0 IQR 2.0-3.0, p = 0.005), volume of T1 (2.72 mm Conclusion: Our finding of higher transcriptional levels of genes involved in cell cycle, cell migration and B cell proliferation that promoted by transcriptional level of age-associated genes and transcription factors allows better understanding of the more aggressive clinical course that defines the POMS.
MeSH term(s)	Adult ; Child ; Female ; Humans ; Male ; Adolescent ; Young Adult ; Multiple Sclerosis/genetics ; Leukocytes, Mononuclear ; Age of Onset ; Disease Progression ; Magnetic Resonance Imaging
Language	English
Publishing date	2022-12-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2022.105953
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Article ; Online: Mapping brain volume change across time in primary-progressive multiple sclerosis.

Warszawer, Yehuda / Gurevich, Michael / Kerpel, Ariel / Dreyer Alster, Sapir / Nissan, Yael / Shirbint, Emanuel / Hoffmann, Chen / Achiron, Anat

Neuroradiology

2024

Abstract: Purpose: Detection and prediction of the rate of brain volume loss with age is a significant unmet need in patients with primary progressive multiple sclerosis (PPMS). In this study we construct detailed brain volume maps for PPMS patients. These maps ... ...

Abstract	Purpose: Detection and prediction of the rate of brain volume loss with age is a significant unmet need in patients with primary progressive multiple sclerosis (PPMS). In this study we construct detailed brain volume maps for PPMS patients. These maps compare age-related changes in both cortical and sub-cortical regions with those in healthy individuals. Methods: We conducted retrospective analyses of brain volume using T1-weighted Magnetic Resonance Imaging (MRI) scans of a large cohort of PPMS patients and healthy subjects. The volume of brain parenchyma (BP), cortex, white matter (WM), deep gray matter, thalamus, and cerebellum were measured using the robust SynthSeg segmentation tool. Age- and gender-related regression curves were constructed based on data from healthy subjects, with the 95% prediction interval adopted as the normality threshold for each brain region. Results: We analyzed 495 MRI scans from 169 PPMS patients, aged 20-79 years, alongside 563 exams from healthy subjects aged 20-86. Compared to healthy subjects, a higher proportion of PPMS patients showed lower than expected brain volumes in all regions except the cerebellum. The most affected areas were BP, WM, and thalamus. Lower brain volumes correlated with longer disease duration for BP and WM, and higher disability for BP, WM, cortex, and thalamus. Conclusions: Constructing age- and gender-related brain volume maps enabled identifying PPMS patients at a higher risk of brain volume loss. Monitoring these high-risk patients may lead to better treatment decisions and improve patient outcomes.
Language	English
Publishing date	2024-04-13
Publishing country	Germany
Document type	Journal Article
ZDB-ID	123305-1
ISSN	1432-1920 ; 0028-3940
ISSN (online)	1432-1920
ISSN	0028-3940
DOI	10.1007/s00234-024-03354-7
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Article ; Online: Faster progression to multiple sclerosis disability is linked to neuronal pathways associated with neurodegeneration: An ethnicity study.

Harari, Gil / Gurevich, Michael / Dolev, Mark / Zilkha Falb, Rina / Achiron, Anat

PloS one

2023 Volume 18, Issue 2, Page(s) e0280515

Abstract: Although the causes of multiple sclerosis are largely unknown, genetic and environmental components play an important role. Geographic distribution, varying with latitude, reflects both genetic and environmental influences. We conducted a retrospective ... ...

Abstract	Although the causes of multiple sclerosis are largely unknown, genetic and environmental components play an important role. Geographic distribution, varying with latitude, reflects both genetic and environmental influences. We conducted a retrospective exploratory observational study to characterize the disability progression of 2396 Jewish patients with relapsing-remitting multiple sclerosis, followed at the Sheba Multiple Sclerosis Center, Tel-Aviv, Israel; 188 patients who originated in Iraq and 2207 patients who originated in northern Europe. Peripheral blood microarray gene expression analysis was performed in a subgroup of patients to identify molecular pathways associated with faster disability progression. During a follow-up period of 18.8 and 19.8 years, respectively, 51.6% of patients with an Iraqi origin progressed to moderate disability defined as expanded disability status scale (EDSS) score of 3.0 to 5.5, compared to 44.2% of patients with a northern European origin (odds ratio 1.347, 95% CI 1.0-1.815, p = 0.049). An Iraqi origin was associated with increased risk of progression to moderate disability adjusted for sex, disease duration, age at onset, and treatment with immunomodulatory drugs (hazard ratio 1.323; 95% CI, 1.049-1.668, p = 0.02), but not to severe disability defined as EDSS score > = 6.0 (i.e., walking aids are required for a distance of 100 meters, (hazard ratio 1.311; 95% CI, 0.918-1.874, p = 0.136). Gene expression analysis disclosed 98 differentially expressed genes (79 over-expressed and 19 under-expressed) between relapsing-remitting multiple sclerosis patients of Iraqi origin (N = 17) and northern European (N = 34) origin. Interestingly, this gene expression was enriched with genes related to neuronal pathways associated with morphology of axons, branching of neurites, proliferation of neocortical neurons, and formation of myelin sheath, suggesting an augmented process of neurodegeneration in relapsing-remitting multiple sclerosis patients with an Iraqi origin. The study results suggest that relapsing-remitting multiple sclerosis patients with an Iraqi origin progress faster to disability possibly due to an enhanced process of neurodegeneration.
MeSH term(s)	Humans ; Multiple Sclerosis ; Multiple Sclerosis, Relapsing-Remitting/drug therapy ; Retrospective Studies ; Ethnicity ; Neurons ; Disease Progression ; Disability Evaluation
Language	English
Publishing date	2023-02-07
Publishing country	United States
Document type	Observational Study ; Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0280515
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Article ; Online: Optical Coherence Tomography Is Associated With Cognitive Impairment in Multiple Sclerosis.

Dreyer-Alster, Sapir / Gal, Aviva / Achiron, Anat

Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society

2021 Volume 42, Issue 1, Page(s) e14–e21

Abstract: Background: Optical coherence tomography (OCT) is a sensitive method for quantifying retinal neuronal and axonal structures. Reductions in retinal nerve fiber layer (RNFL) and ganglion cell inner plexiform layer (GCIPL) thicknesses have a reported ... ...

Abstract	Background: Optical coherence tomography (OCT) is a sensitive method for quantifying retinal neuronal and axonal structures. Reductions in retinal nerve fiber layer (RNFL) and ganglion cell inner plexiform layer (GCIPL) thicknesses have a reported association with white and grey matter atrophy in multiple sclerosis (MS). We hypothesized that the thinning of intraretinal layer measurements associates with cognitive decline in MS patients with no prior event of optic neuritis (ON). Methods: OCT and NeuroTrax computerized cognitive assessments were performed in 204 relapsing remitting MS patients with no history of ON or other conditions affecting the eye. Data were collected between 2010 and 2020 and retrospectively analyzed. Correlations were examined between cognitive performance and a lower RNFL or GCIPL thickness. A multilinear regression model was generated to assess the significance of these correlations regarding the disability score and disease duration. Results: The 204 study participants had a mean age of 40.52 ± 11.8 years (mean ± SD) and disease duration of 9.80 ± 9.40 years. The mean RNFL thickness in this whole cohort was 82.22 ± 10.85 μm and the global cognitive score was 95.32 ± 12.32. The mean GCIPL thickness measured in a subgroup of 104 patients was 74.27 ± 10.37 μm. The RNFL and GCIPL both correlated with the global cognitive score (r = 0.174, P = 0.013 and r = 0.29, P = 0.03, respectively), and with various cognitive domains. However, the GCIPL showed stronger correlations than RNFL, particularly with executive function (r = 0.29, P = 0.003), attention (r = 0.332, P = 0.001), and the information processing speed (r = 0.25, P = 0.012). These correlations remained significant after correcting for confounders. Conclusion: OCT measurements correlate with cognitive performance in MS patients. OCT can thus be used to evaluate central nervous system neurodegeneration in MS, as reflected by cognitive decline.
MeSH term(s)	Adult ; Cognitive Dysfunction/complications ; Cognitive Dysfunction/etiology ; Humans ; Middle Aged ; Multiple Sclerosis/complications ; Multiple Sclerosis/diagnosis ; Optic Neuritis/complications ; Optic Neuritis/diagnosis ; Retinal Ganglion Cells ; Retrospective Studies ; Tomography, Optical Coherence/methods
Language	English
Publishing date	2021-07-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1189901-3
ISSN	1536-5166 ; 1070-8022
ISSN (online)	1536-5166
ISSN	1070-8022
DOI	10.1097/WNO.0000000000001326
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Article ; Online: Faster progression to multiple sclerosis disability is linked to neuronal pathways associated with neurodegeneration

Gil Harari / Michael Gurevich / Mark Dolev / Rina Zilkha Falb / Anat Achiron

PLoS ONE, Vol 18, Iss 2, p e

An ethnicity study.

2023 Volume 0280515

Abstract	Although the causes of multiple sclerosis are largely unknown, genetic and environmental components play an important role. Geographic distribution, varying with latitude, reflects both genetic and environmental influences. We conducted a retrospective exploratory observational study to characterize the disability progression of 2396 Jewish patients with relapsing-remitting multiple sclerosis, followed at the Sheba Multiple Sclerosis Center, Tel-Aviv, Israel; 188 patients who originated in Iraq and 2207 patients who originated in northern Europe. Peripheral blood microarray gene expression analysis was performed in a subgroup of patients to identify molecular pathways associated with faster disability progression. During a follow-up period of 18.8 and 19.8 years, respectively, 51.6% of patients with an Iraqi origin progressed to moderate disability defined as expanded disability status scale (EDSS) score of 3.0 to 5.5, compared to 44.2% of patients with a northern European origin (odds ratio 1.347, 95% CI 1.0-1.815, p = 0.049). An Iraqi origin was associated with increased risk of progression to moderate disability adjusted for sex, disease duration, age at onset, and treatment with immunomodulatory drugs (hazard ratio 1.323; 95% CI, 1.049-1.668, p = 0.02), but not to severe disability defined as EDSS score > = 6.0 (i.e., walking aids are required for a distance of 100 meters, (hazard ratio 1.311; 95% CI, 0.918-1.874, p = 0.136). Gene expression analysis disclosed 98 differentially expressed genes (79 over-expressed and 19 under-expressed) between relapsing-remitting multiple sclerosis patients of Iraqi origin (N = 17) and northern European (N = 34) origin. Interestingly, this gene expression was enriched with genes related to neuronal pathways associated with morphology of axons, branching of neurites, proliferation of neocortical neurons, and formation of myelin sheath, suggesting an augmented process of neurodegeneration in relapsing-remitting multiple sclerosis patients with an Iraqi origin. The study ...
Keywords	Medicine ; R ; Science ; Q
Subject code	616 ; 610
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Coronavirus 2019 outbreak pathogenesis: Why China and Italy?

Achiron, Anat / Mandel, Mathilda / Sheonefeld, Yehuda

European journal of rheumatology

2020 Volume 7, Issue Suppl 2, Page(s) S99–S101

Abstract: COVID-19 has spread to most countries in the world. However, there are differences in the rate of infection in different countries. Specifically, high incidence was reported in specific areas in China (Wuhan) and Italy (Lombardy). These differences may ... ...

Abstract	COVID-19 has spread to most countries in the world. However, there are differences in the rate of infection in different countries. Specifically, high incidence was reported in specific areas in China (Wuhan) and Italy (Lombardy). These differences may be related to different Human Leucocyte Antigen (HLA) patterns in various geographic areas. We suggest HLA spreading between Italy and China is related to the travels of Marco Polo through the Silk Road as a potential historic explanation to COVID-19 spreading.
Keywords	covid19
Language	English
Publishing date	2020-07-20
Publishing country	Turkey
Document type	Journal Article
ZDB-ID	2873727-1
ISSN	2148-4279 ; 2147-9720
ISSN (online)	2148-4279
ISSN	2147-9720
DOI	10.5152/eurjrheum.2020.2068
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Article ; Online: Multiple facets of the cerebellum in multiple sclerosis.

Kalron, Alon / Achiron, Anat / Allali, Gilles

Journal of neurophysiology

2019 Volume 121, Issue 1, Page(s) 345

MeSH term(s)	Cerebellum ; Cognition ; Humans ; Joints ; Multiple Sclerosis
Language	English
Publishing date	2019-01-25
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	80161-6
ISSN	1522-1598 ; 0022-3077
ISSN (online)	1522-1598
ISSN	0022-3077
DOI	10.1152/jn.00829.2018
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Article: Intravenous immunoglobulin treatment during pregnancy and the post-partum period in women with multiple sclerosis: A prospective analysis.

Menascu, Shay / Siegel-Kirshenbaum, Michal / Dreyer-Alster, Sapir / Warszawer, Yehuda / Magalashvili, David / Dolev, Mark / Mandel, Mathilda / Harari, Gil / Achiron, Anat

Multiple sclerosis journal - experimental, translational and clinical

2023 Volume 9, Issue 1, Page(s) 20552173221151127

Abstract: Background: Relapsing-remitting multiple sclerosis (RRMS) affects predominantly young women within reproductive years. As an increased risk of relapses is known to occur during the post-partum period, it is important to consider treatment options.: ... ...

Abstract	Background: Relapsing-remitting multiple sclerosis (RRMS) affects predominantly young women within reproductive years. As an increased risk of relapses is known to occur during the post-partum period, it is important to consider treatment options. Aim: Evaluate the effects of intravenous immunoglobulins (IVIg) to prevent post-partum relapses. Methods: We prospectively followed 198 pregnant female RRMS patients, 67 treated with IVIg during pregnancy and the three months post-partum, and 131 untreated patients that served as controls. Results: During the pre-gestation year, 41.4% were treated with immunomodulatory drugs, and 28.3% experienced a relapse. During pregnancy and the post-partum period, the number of relapsing patients significantly decreased in the IVIg group (37.3%, 10.4%, 8.9%, respectively, Conclusions: IVIg treatment proved efficient to reduce the rate and severity of relapses during pregnancy and the three-month post-partum.
Language	English
Publishing date	2023-01-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2841884-0
ISSN	2055-2173 ; 2055-2173
ISSN (online)	2055-2173
ISSN	2055-2173
DOI	10.1177/20552173221151127
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