Telomere Length Is Associated with Disability Progression in Multiple Sclerosis

Krysko, Kristen M.; Henry, Roland G.; Cree, Bruce A.C.; Lin, Jue; Caillier, Stacy J.; Santaniello, Adam; Zhao, Chao; Gomez, Refujia; Bevan, Carolyn; Smith, Donald W.; Stern, W.; Kirkish, Gina; Oksenberg, Jorge R.; Graves, Jennifer

doi:10.1002/ana.25592

Cited by 55 publications

(75 citation statements)

References 44 publications

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“…For instance, a negative association of LTL and BMI, which has been repeatedly reported in the literature [51], was noted in the data but did not reach significance (F-test p=0.190). In line with the findings by Krysko et al [30], we did not observe an association between LTL and DMT at baseline in the RRMS group (p=0.713). However, more potent therapies for MS have been approved in the past years [8].…”

Section: Discussionsupporting

confidence: 92%

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Leukocyte telomere length in patients with multiple sclerosis and its association with clinical phenotypes

Hecker

Fitzner

Jaeger

et al. 2020

Preprint

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Aging is a significant factor influencing the course of multiple sclerosis (MS). Accelerated telomere attrition is an indicator of premature biological aging and a potential contributor to various chronic diseases, including neurological disorders. However, there is currently a lack of studies focusing on telomere lengths in patients with MS.We measured the average leukocyte telomere length (LTL) in biobanked DNA samples of 40 relapsing-remitting MS patients (RRMS), 20 primary progressive MS patients (PPMS) and 60 healthy controls using a multiplex quantitative polymerase chain reaction method. Changes in LTL over a period of >10 years were evaluated in a subset of 10 patients. Association analyses of baseline LTL with the long-term clinical profiles of the patients were performed using inferential statistical tests and regression models adjusted for age and sex.The cross-sectional analysis revealed that the RRMS group was characterized by a significantly shorter relative LTL, on average, as compared to the PPMS group and controls. Shorter telomeres at baseline were also associated with a higher conversion rate from RRMS to secondary progressive MS (SPMS) in the 10-year follow-up. The LTL decrease over time was similar in RRMS patients and PPMS patients in the longitudinal analysis.Our data suggest a possible contributory role of accelerated telomere shortening in the pathobiology of MS. The interplay between disease-related immune system alterations, immunosenescence and telomere dynamics deserves further investigation. New insights into the mechanisms of disease might be obtained, e.g., by exploring the distribution of telomere lengths in specific blood cell populations.Research in contextEvidence before this studyThere is a growing research interest in the relationship between age and the pathophysiology and clinical presentation of multiple sclerosis (MS). Telomere shortening is a hallmark of biological aging. However, the role of telomeres in this chronic immune-mediated neurodegenerative disease has not yet been widely studied. Two research groups provided evidence that the telomeres of immune cells in the peripheral blood are shorter in patients with MS than in healthy subjects.Added value of this studyWe found that leukocytes from patients with relapsing-remitting MS (RRMS) are characterized by relatively short telomere lengths (TL). On average, we observed 18% shorter TL in the RRMS patient cohort (n=40) than in the age- and sex-matched healthy control cohort (n=60). We further analyzed the association of TL and long-term clinical outcomes. RRMS patients with shorter TL had a higher rate of converting to secondary progressive MS over a 10-year follow-up period.Implications of all the available evidenceAs we and others have shown, TL are generally shorter in MS patients and associated with disease progression, independent of age. These findings suggest a link between biological aging and the heterogeneous clinical course of MS patients. It currently remains unclear whether shortened telomeres in MS are a cause or a consequence of the pathophysiological processes. Further studies with larger patient cohorts and different cell populations will be needed to expand our knowledge of age-related disease mechanisms and the use of TL as a biomarker in MS.

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Section: Discussionsupporting

confidence: 92%

“…In our study, RRMS patients with relatively short telomeres had a higher risk of conversion to SPMS in the following 10 years. This inverse relationship was also reported by Krysko et al [30], although it was not significant in their study. Larger cohorts are necessary to verify this observation.…”

Section: Discussionsupporting

confidence: 81%

Leukocyte telomere length in patients with multiple sclerosis and its association with clinical phenotypes

Hecker

Fitzner

Jaeger

et al. 2020

Preprint

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“…Subsequently, 18 studies were discarded because they did not contain an analysis of MS patient samples (III), and finally, 21 studies were rejected because they were not concerned with measuring TL (IV). In consequence, we included 7 studies in our systematic review [50][51][52][53][54][55][56] (Supplemental Table 1). Four of these studies also provided sufficient data to be pooled into a meta-analysis [51,52,55,56].…”

Section: Search Results Study Selection and Overviewmentioning

confidence: 99%

Systematic Review of Studies on Telomere Lengths in Patients with Multiple Sclerosis

Bühring

Hecker

Fitzner

et al. 2020

Preprint

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BACKGROUNDTelomeres are protective cap structures at the end of chromosomes that are essential for maintening genomic stability. Accelerated telomere shortening is related to premature cellular senescence. Shortened telomere lengths (TL) have been implicated in the pathogenesis of various chronic immune-mediated and neurological diseases.OBJECTIVEWe aimed to systematically review the current literature on the association of TL as a measure of biological age and multiple sclerosis (MS).METHODSA comprehensive literature search was conducted to identify original studies that presented data on TL in samples from MS patients. Quantitative and qualitative information was extracted from the articles to summarize and compare the studies.RESULTSA total of 51 articles were screened, and 7 of them were included in this review. In 6 studies, average TL were analyzed in peripheral blood cells, whereas in one study, bone marrow-derived cells were used. Four of the studies reported significantly shorter leukocyte TL in at least one MS subtype in comparison to healthy controls (p=0.003 in meta-analysis). Shorter telomeres in MS patients were found to be associated, independently of age, with greater disability, lower brain volume, increased relapse rate and more rapid conversion from relapsing to progressive MS. However, it remains unclear how telomere attrition in MS may be linked to oxidative stress, inflammation and age-related disease processes.CONCLUSIONSDespite few studies in this field, there is substantial evidence on the association of TL and MS. Variability in TL appears to reflect heterogeneity in clinical presentation and course. Further investigations in large and well-characterized cohorts are warranted. More detailed studies on TL of individual chromosomes in specific cell types may help to gain new insights into the pathomechanisms of MS.HighlightsThe relationship between aging and the pathophysiology and course of MS is not fully understoodWe have identified seven studies that analyzed telomere lengths (TL) in patients with MSOur meta-analysis revealed significantly shorter leukocyte TL in MS patients compared to healthy controlsThere is evidence that individual variability in biological aging reflects clinical heterogeneity in MSThe potential use of TL as a biomarker of age-related disease mechanisms deserves further investigation

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“…For example, the brains of progressive MS donors show a significant axonal loss in both the demyelinated and normal cortices [14], extensive subpial grey matter demyelination [10], injury to excitatory projection neurons [15], diffuse neuroaxonal metabolic abnormalities [16] and diffuse microglial activation [17]. The underlying mechanisms of these diffuse CNS pathologies in progressive MS are complex but may include transneuronal degeneration due to the destruction of efferent/afferent projections [18], B cell-rich meningeal inflammation [19], the accumulation of peripheral immune cells in the choroid plexus stroma [20], chronically active and slowly expanding lesions with smoldering inflammation [21], accelerated biological aging [22], or complement activation [23]. Different aspects of the described progressive MS pathologies can be visualized by different imaging techniques, including positron emission tomography (PET) imaging, advanced magnetic resonance imaging (MRI), brain volume measurement, optical coherence tomography (OCT), diffusion tensor imaging (DTI), or myelin water imaging (MWI) [24][25][26][27][28].…”

Section: General Aspects Of Ms Pathology and The Relevance Of Glial Cmentioning

confidence: 99%

Does Siponimod Exert Direct Effects in the Central Nervous System?

Kipp

2020

Cells

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The modulation of the sphingosine 1-phosphate receptor is an approved treatment for relapsing multiple sclerosis because of its anti-inflammatory effect of retaining lymphocytes in lymph nodes. Different sphingosine 1-phosphate receptor subtypes are expressed in the brain and spinal cord, and their pharmacological effects may improve disease development and neuropathology. Siponimod (BAF312) is a novel sphingosine 1-phosphate receptor modulator that has recently been approved for the treatment of active secondary progressive multiple sclerosis (MS). In this review article, we summarize recent evidence suggesting that the active role of siponimod in patients with progressive MS may be due to direct interaction with central nervous system cells. Additionally, we tried to summarize our current understanding of the function of siponimod and discuss the effects observed in the case of MS.

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Telomere Length Is Associated with Disability Progression in Multiple Sclerosis

Cited by 55 publications

References 44 publications

Leukocyte telomere length in patients with multiple sclerosis and its association with clinical phenotypes

Leukocyte telomere length in patients with multiple sclerosis and its association with clinical phenotypes

Systematic Review of Studies on Telomere Lengths in Patients with Multiple Sclerosis

Does Siponimod Exert Direct Effects in the Central Nervous System?

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