Aging and multiple sclerosis

The life expectancy and average age of persons with multiple sclerosis (MS) have increased significantly during the last two decades. The introduction of disease-modifying therapies and a better delineation and understanding of the superimposed comorbidities often diagnosed in MS patients are probably the most important factors accountable for the increase in aging MS population worldwide. Healthcare teams must therefore address the problems arising due to advancing age superimposed on this chronic neurologic disease. In this review, we focus on the physiology of aging, its effects on MS disease course, and the pathological and immunological changes associated with aging and disease progression. Additionally, we discuss the common comorbidities that occur in aging persons with MS that may arise either as a result of the aging process or from relentless chronic MS disease progression as well as the challenges on differentiating the two processes for a more appropriate therapeutic approach.

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Cerebrospinal fluid mtDNA concentration is elevated in multiple sclerosis disease and responds to treatment

Multiple Sclerosis Journal ◽

10.1177/1352458517699874 ◽

2017 ◽

Vol 24 (4) ◽

pp. 472-480 ◽

Cited By ~ 10

Author(s):

Cyra E Leurs ◽

Petar Podlesniy ◽

Ramon Trullas ◽

Lisanne Balk ◽

Martijn D Steenwijk ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Disease Progression ◽

Progressive Multiple Sclerosis ◽

Neurologic Disease ◽

Brain Volumes ◽

Multiple Sclerosis Disease ◽

Relapsing Remitting ◽

Relapsing Remitting Multiple Sclerosis ◽

Digital Polymerase Chain Reaction

Background: Mitochondrial dysfunction is increasingly recognized as an important feature of multiple sclerosis (MS) pathology and may be relevant for clinical disease progression. However, it is unknown whether mitochondrial DNA (mtDNA) levels in the cerebrospinal fluid (CSF) associate with disease progression and therapeutic response. Objectives: To evaluate whether CSF concentrations of mtDNA in MS patients can serve as a marker of ongoing neuropathology and may be helpful to differentiate between MS disease subtypes. To explore the effect of disease-modifying therapies on mtDNA levels in the CSF. Methods: CSF mtDNA was measured using a digital polymerase chain reaction (PCR) CSF mtDNA in two independent MS cohorts. The cohorts included 92 relapsing-remitting multiple sclerosis (RRMS) patients, 40 progressive multiple sclerosis (PMS) patients (27 secondary progressive and 13 primary progressive), 50 various neurologic disease controls, and 5 healthy controls. Results: Patients with PMS showed a significant increase in CSF mtDNA compared to non-inflammatory neurologic disease controls. Patients with higher T2 lesion volumes and lower normalized brain volumes showed increased concentration of mtDNA. Patients treated with fingolimod had significantly lower mtDNA copy levels at follow-up compared to baseline. Conclusion: Our results showed a non-specific elevation of concentration of mtDNA in PMS patients. mtDNA concentrations respond to fingolimod and may be used to monitor biological effect of this treatment.

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Assessing Pharmacists’ Preferences towards Efficacy Attributes of Disease-Modifying Therapies in Relapsing-Remitting Multiple Sclerosis

Pharmacy ◽

10.3390/pharmacy8020061 ◽

2020 ◽

Vol 8 (2) ◽

pp. 61

Author(s):

Iciar Martínez-López ◽

Jorge Maurino ◽

Patricia Sanmartín-Fenollera ◽

Ana Ontañon-Nasarre ◽

Alejandro Santiago-Pérez ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Progression ◽

Critical Role ◽

Cross Sectional ◽

Hospital Pharmacists ◽

Disease Modifying Therapies ◽

Hypothetical Treatment ◽

Related Quality ◽

Health Related ◽

Disease Modifying

Introduction: Hospital pharmacists are increasingly playing a critical role in the care of patients with multiple sclerosis (MS). However, little is known about their preferences and perspectives towards different attributes of disease-modifying therapies (DMTs). The objective of this research was to assess pharmacists´ preferences for DMT efficacy attributes. Methods: A multicenter, non-interventional, cross-sectional, web-based study was conducted. Preventing relapses, delaying disease progression, controlling radiological activity, and preserving health-related quality of life (HRQoL) and cognition were the attributes selected based on a literature review and a focus group with six hospital pharmacists. Conjoint analysis was used to determine preferences in eight hypothetical treatment scenarios, combining different levels of each attribute and ranking them from most to least preferred. Results: Sixty-five hospital pharmacists completed the study (mean age: 43.5 ± 7.8 years, 63.1% female, mean years of professional experience: 16.1 ± 7.4 years). Participants placed the greatest preference on delaying disease progression (35.7%) and preserving HRQoL (21.6%) and cognition (21.6%). Importance was consistent in all groups of pharmacists stratified according to demographic characteristics, experience, research background, and volume of patients seen per year. Conclusions: Understanding which treatment characteristics are meaningful to hospital pharmacists may help to enhance their synergistic role in the multidisciplinary management of patients with MS.

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Treatment Discontinuation and Disease Progression with Injectable Disease-Modifying Therapies

International Journal of MS Care ◽

10.7224/1537-2073.2012-034 ◽

2013 ◽

Vol 15 (4) ◽

pp. 194-201 ◽

Cited By ~ 22

Author(s):

Robert J. Fox ◽

Amber R. Salter ◽

Tuula Tyry ◽

Jennifer Sun ◽

Xiaojun You ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Progression ◽

Clinical Decision Making ◽

Medication Compliance ◽

Clinical Decision ◽

Research Committee ◽

The North ◽

Disease Modifying Therapies ◽

Patient Reported ◽

Disease Modifying

Injectable first-line disease-modifying therapies (DMTs) for multiple sclerosis (MS) are generally prescribed for continuous use. Accordingly, the various factors that influence patient persistence with treatment and that can lead some patients to switch medications or discontinue treatment may affect clinical outcomes. Using data from the North American Research Committee on Multiple Sclerosis (NARCOMS) database, this study evaluated participants' reasons for discontinuation of injectable DMTs as well as the relationship between staying on therapy and sustained patient-reported disease progression and annualized relapse rates. Participants selected their reason(s) for discontinuation from among 16 possible options covering the categories of efficacy, safety, tolerability, and burden, with multiple responses permitted. Both unadjusted data and data adjusted for baseline age, disease duration, disability, and sex were evaluated. Discontinuation profiles varied among DMTs. Participants on intramuscular interferon beta-1a (IM IFNβ-1a) and glatiramer acetate (GA) reported the fewest discontinuations based on safety concerns, although GA was associated with reports of higher burden and lower efficacy than other therapies. Difficulties with tolerability were more often reported as a reason for discontinuing subcutaneous (SC) IFNβ-1a than as a reason for discontinuing IM IFNβ-1a, GA, or SC IFNβ-1b. In the persistent therapy cohort, less patient-reported disability progression was reported with IM IFNβ-1a treatment than with SC IFNβ-1a, IFNβ-1b, or GA. These findings have relevance to clinical decision making and medication compliance in MS patient care.

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Retrospective unbiased plasma lipidomic of progressive multiple sclerosis patients-identifies lipids discriminating those with faster clinical deterioration

Scientific Reports ◽

10.1038/s41598-020-72654-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Mario Amatruda ◽

Maria Petracca ◽

Maureen Wentling ◽

Benjamin Inbar ◽

Kamilah Castro ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Progression ◽

Progressive Multiple Sclerosis ◽

Primary Progressive Multiple Sclerosis ◽

Disease Course ◽

Primary Progressive ◽

T2 Lesions ◽

Relapsing Remitting ◽

One Year ◽

Multiple Sclerosis Patients

Abstract The disease course of patients with a confirmed diagnosis of primary progressive multiple sclerosis (PPMS) is uncertain. In an attempt to identify potential signaling pathways involved in the evolution of the disease, we conducted an exploratory unbiased lipidomic analysis of plasma from non-diseased controls (n = 8) and patients with primary progressive MS (PPMS, n = 19) and either a rapid (PPMS-P, n = 9) or slow (PPMS-NP, n = 10) disease course based on worsening disability and/or MRI-visible appearance of new T2 lesions over a one-year-assessment. Partial least squares-discriminant analysis of the MS/MSALL lipidomic dataset, identified lipids driving the clustering of the groups. Among these lipids, sphingomyelin-d18:1/14:0 and mono-hexosylceramide-d18:1/20:0 were differentially abundant in the plasma of PPMS patients compared to controls and their levels correlated with MRI signs of disease progression. Lyso-phosphatidic acid-18:2 (LPA-18:2) was the only lipid with significantly lower abundance in PPMS patients with a rapidly deteriorating disease course, and its levels inversely correlated with the severity of the neurological deficit. Decreased levels of LPA-18:2 were detected in patients with more rapid disease progression, regardless of therapy and these findings were validated in an independent cohort of secondary progressive (SPMS) patients, but not in a third cohorts of relapsing–remitting (RRMS) patients. Collectively, our analysis suggests that sphingomyelin-d18:1/14:0, mono-hexosylceramide-d18:1/20:0, and LPA-18:2 may represent important targets for future studies aimed at understanding disease progression in MS.

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A Mechanistic, Stochastic Model Helps Understand Multiple Sclerosis Course and Pathogenesis

International Journal of Genomics ◽

10.1155/2013/910321 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 10

Author(s):

Isabella Bordi ◽

Renato Umeton ◽

Vito A. G. Ricigliano ◽

Viviana Annibali ◽

Rosella Mechelli ◽

...

Keyword(s):

Multiple Sclerosis ◽

Complex Traits ◽

Mechanistic Model ◽

Random Perturbations ◽

Disease Course ◽

Disease Etiology ◽

Random Forcing ◽

Disease Modifying Therapies ◽

Disease Threshold ◽

Satisfactory Manner

Heritable and nonheritable factors play a role in multiple sclerosis, but their effect size appears too small, explaining relatively little about disease etiology. Assuming that the factors that trigger the onset of the disease are, to some extent, also those that generate its remissions and relapses, we attempted to model the erratic behaviour of the disease course as observed on a dataset containing the time series of relapses and remissions of 70 patients free of disease-modifying therapies. We show that relapses and remissions follow exponential decaying distributions, excluding periodic recurrences and confirming that relapses manifest randomly in time. It is found that a mechanistic model with a random forcing describes in a satisfactory manner the occurrence of relapses and remissions, and the differences in the length of time spent in each one of the two states. This model may describe how interactions between “soft” etiologic factors occasionally reach the disease threshold thanks to comparably small external random perturbations. The model offers a new context to rethink key problems such as “missing heritability” and “hidden environmental structure” in the etiology of complex traits.

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Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis

Neurology ◽

10.1212/wnl.0000000000005345 ◽

2018 ◽

Vol 90 (17) ◽

pp. 789-800 ◽

Cited By ~ 46

Author(s):

Alexander Rae-Grant ◽

Gregory S. Day ◽

Ruth Ann Marrie ◽

Alejandro Rabinstein ◽

Bruce A.C. Cree ◽

...

Keyword(s):

Multiple Sclerosis ◽

Systematic Review ◽

Disease Progression ◽

Glatiramer Acetate ◽

Full Text ◽

Predictive Biomarkers ◽

Stepped Care ◽

Disease Modifying Therapies ◽

Cochrane Reviews ◽

Disease Modifying

ObjectiveTo review evidence on starting, switching, and stopping disease-modifying therapies (DMTs) for multiple sclerosis (MS) in clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and progressive MS forms.MethodsRelevant, peer-reviewed research articles, systematic reviews, and abstracts were identified (MEDLINE, CENTRAL, EMBASE searched from inception to November 2016). Studies were rated using the therapeutic classification scheme. Prior published Cochrane reviews were also used.ResultsTwenty Cochrane reviews and an additional 73 full-text articles were selected for data extraction through an updated systematic review (completed November 2016). For people with RRMS, many DMTs are superior to placebo (annualized relapses rates [ARRs], new disease activity [new MRI T2 lesion burden], and in-study disease progression) (see summary and full text publications). For people with RRMS who experienced a relapse on interferon-β (IFN-β) or glatiramer acetate, alemtuzumab is more effective than IFN-β-1a 44 μg subcutaneous 3 times per week in reducing the ARR. For people with primary progressive MS, ocrelizumab is probably more effective than placebo (in-study disease progression). DMTs for MS have varying adverse effects. In people with CIS, glatiramer acetate and IFN-β-1a subcutaneous 3 times per week are more effective than placebo in decreasing risk of conversion to MS. Cladribine, immunoglobulins, IFN-β-1a 30 μg intramuscular weekly, IFN-β-1b subcutaneous alternate day, and teriflunomide are probably more effective than placebo in decreasing risk of conversion to MS. Suggestions for future research include studies considering comparative effectiveness, usefulness of high-efficacy treatment vs stepped-care protocols, and research into predictive biomarkers.

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MOLECULAR CROSSROADS OF FRAILTY AND HIV

Journal of Frailty & Aging ◽

10.14283/jfa.2014.7 ◽

2014 ◽

pp. 1-8

Author(s):

O. TAMEZ-RIVERA ◽

P. MARTINEZ-AYALA ◽

A.P. NAVARRETE-REYES ◽

H. AMIEVA ◽

J.A. AVILA-FUNES

Keyword(s):

Older Adults ◽

Human Immunodeficiency Virus ◽

Aging Process ◽

Accelerated Aging ◽

Epidemiological Transition ◽

Number Of Patients ◽

Depth Analysis ◽

Immunodeficiency Virus ◽

The Common ◽

Immunological Changes

An epidemiological transition is occurring regarding Human Immunodeficiency Virus (HIV) infection.This phenomenon, explained by several mechanisms (e.g.: physiologic changes, pharmacologic advances, sexualbehaviors), is demonstrated by a significant increase in the number of patients aged 50 years and older diagnosedwith this infection. The immunological changes observed in HIV-infected patients may prompt the appearance ofan accelerated aging process as well as that of comorbidities and other pathological entities commonly diagnosedin older adults. Frailty is a biologic syndrome characterized by a multi-systemic decrease of the individual’sphysiologic and homeostatic reserves, leading to diminished resistance against stressors and increasedvulnerability. The purpose of this review is to describe the common molecular changes seen in both frailty andHIV-1 infection, offering an in-depth analysis of their pathophysiology and specifying common processes wheretheir pathways meet.

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The course of multiple sclerosis rewritten: a Norwegian population-based study on disease demographics and progression

Journal of Neurology ◽

10.1007/s00415-020-10279-7 ◽

2020 ◽

Author(s):

Cecilia Smith Simonsen ◽

Heidi Øyen Flemmen ◽

Line Broch ◽

Cathrine Brunborg ◽

Pål Berg-Hansen ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Progression ◽

Disease Onset ◽

Population Based ◽

Natural Course ◽

Mixed Effect ◽

Patient Demographics ◽

Disease Modifying Therapies ◽

Norwegian Population ◽

Disease Modifying

Abstract Objectives Over the past few decades, there has been an improvement in the rate of disability progression in multiple sclerosis (MS) patients, and most studies relate this evolvement to the introduction of disease-modifying therapies. However, several other factors have changed over this period, including access to MRI and newer diagnostic criteria. The aim of this study is to investigate changes in the natural course of MS over time in a near-complete and geographically well-defined population from the south-east of Norway. Methods We examined disease progression and demographics over two decades and assessed the effect of disease-modifying therapies using linear mixed-effect models. Results In a cohort of 2097 patients, we found a significant improvement in disability as measured by the Expanded Disability Status Scale (EDSS) stratified by age, and the improvement remained significant after adjusting for time on disease-modifying medications, gender and progressive MS at onset. The time from disease onset to EDSS 6 in the total cohort was 29.8 years (95% CI 28.5–31.1) and was significantly longer in patients diagnosed after 2006 compared to patients diagnosed before. There are significant differences between patient demographics, as well as time to EDSS 6, in the near-complete, geographically well-defined population compared to an additional cohort from the capital Oslo and its suburbs. Conclusion The natural course of MS is improving, but the improvement seen in disease progression has multifaceted explanations. Our study underlines the importance of completeness of data, relevant timeframes and demographics when comparing different MS populations. Studies on incomplete populations should be interpreted with caution.

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