Skip to main content

Advertisement

SpringerLink
Log in

Impact of Age on Multiple Sclerosis Disease Activity and Progression

  • Demyelinating Disorders (J. Bernard and M. Cameron, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The purpose of this review is to discuss the interaction between aging, progressive disease course, disability worsening, and treatment strategies in multiple sclerosis (MS).

Recent Findings

The transition from the relapsing-remitting phase to the progressive phase in MS often happens in the fifth decade. In MS, structural central nervous system reserve decreases with aging and MS-associated mechanisms. While clinical and subclinical disease activity decreases with aging, the post-relapse recovery potential decreases with aging as well. Moreover, the efficacy of disease-modifying treatments declines with older age.

Summary

Aging emerges as the ultimate target for prevention of progressive disease course, which is the most important determinant of disability worsening in MS. While none of our current treatment strategies targets the association between aging and progressive disease in MS, future treatment targets will likely consider the neuron-astrocyte complex, microglia, and oligodendrocyte functions impacted by the aging process.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Confavreux C, Aimard G, Devic M. Course and prognosis of multiple sclerosis assessed by the computerized data processing of 349 patients. Brain. 1980;103:281–300.

    Article  CAS  PubMed  Google Scholar 

  2. Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study. 2. Predictive value of the early clinical course. Brain. 1989;112(Pt 6):1419–28.

  3. Runmarker B, Andersen O. Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up. Brain. 1993;116(Pt 1):117–34.

    Article  PubMed  Google Scholar 

  4. Zeydan B, Kantarci OH. Progressive forms of multiple sclerosis: distinct entity or age-dependent phenomena. Neurol Clin. 2018;36:163–71.

    Article  PubMed  Google Scholar 

  5. Kantarci OH. Phases and phenotypes of multiple sclerosis. Continuum (Minneap Minn). 2019;25:636–54.

    Google Scholar 

  6. Confavreux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain. 2006;129:606–16.

    Article  PubMed  Google Scholar 

  7. Koch M, Mostert J, Heersema D, De Keyser J. Progression in multiple sclerosis: further evidence of an age dependent process. J Neurol Sci. 2007;255:35–41.

    Article  CAS  PubMed  Google Scholar 

  8. •• Tutuncu M, Tang J, Zeid NA, et al. Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis. Mult Scler. 2013;19:188–98. Independent of the phenotype in the relapsing-remitting phase, the transition to the progressive phase of MS often happens in the fifth decade.

    Article  PubMed  Google Scholar 

  9. Westlye LT, Walhovd KB, Dale AM, Bjornerud A, Due-Tonnessen P, Engvig A, et al. Life-span changes of the human brain white matter: diffusion tensor imaging (DTI) and volumetry. Cereb Cortex. 2010;20:2055–68.

    Article  PubMed  Google Scholar 

  10. Hasan KM, Kamali A, Abid H, et al. Quantification of the spatiotemporal microstructural organization of the human brain association, projection and commissural pathways across the lifespan using diffusion tensor tractography. Brain Struct Funct. 2010;214:361–73.

  11. • Conway BL, Zeydan B, Uygunoglu U, et al. Age is a critical determinant in recovery from multiple sclerosis relapses. Mult Scler. 2019;25:1754–63. The recovery potential from relapses significantly decreases with aging in MS.

  12. Hayes SM, Salat DH, Forman DE, Sperling RA, Verfaellie M. Cardiorespiratory fitness is associated with white matter integrity in aging. Ann Clin Transl Neurol. 2015;2:688–98.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Stankoff B, Wang Y, Bottlaender M, Aigrot MS, Dolle F, Wu C, et al. Imaging of CNS myelin by positron-emission tomography. Proc Natl Acad Sci U S A. 2006;103:9304–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bodini B, Veronese M, Garcia-Lorenzo D, et al. Dynamic imaging of individual remyelination profiles in multiple sclerosis. Ann Neurol. 2016;79:726–38.

  15. Stankoff B, Freeman L, Aigrot MS, Chardain A, Dollé F, Williams A, et al. Imaging central nervous system myelin by positron emission tomography in multiple sclerosis using [methyl-(1)(1)C]-2-(4′-methylaminophenyl)- 6-hydroxybenzothiazole. Ann Neurol. 2011;69:673–80.

    Article  CAS  PubMed  Google Scholar 

  16. Faria Dde P, Copray S, Sijbesma JW, et al. PET imaging of focal demyelination and remyelination in a rat model of multiple sclerosis: comparison of [11C]MeDAS, [11C]CIC and [11C]PIB. Eur J Nucl Med Mol Imaging. 2014;41:995–1003.

    Article  PubMed  Google Scholar 

  17. Veronese M, Bodini B, Garcia-Lorenzo D, et al. Quantification of [(11)C]PIB PET for imaging myelin in the human brain: a test-retest reproducibility study in high-resolution research tomography. J Cereb Blood Flow Metab. 2015;35:1771–82.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Matias-Guiu JA, Cabrera-Martin MN, Matias-Guiu J, et al. Amyloid PET imaging in multiple sclerosis: an (18)F-florbetaben study. BMC Neurol. 2015;15:243.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Zeydan B, Lowe VJ, Schwarz CG, et al. Pittsburgh compound-B PET white matter imaging and cognitive function in late multiple sclerosis. Mult Scler. 2018;24:739–49.

  20. Zeydan B, Schwarz CG, Lowe VJ, Reid RI, Przybelski SA, Lesnick TG, et al. Investigation of white matter PiB uptake as a marker of white matter integrity. Ann Clin Transl Neurol. 2019;6:678–88.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Zeydan B, Kantarci OH. MS progression is predominantly driven by age-related mechanisms - commentary. Mult Scler. 2019;25:906–8.

    Article  PubMed  Google Scholar 

  22. Azevedo CJ, Overton E, Khadka S, Buckley J, Liu S, Sampat M, et al. Early CNS neurodegeneration in radiologically isolated syndrome. Neurol Neuroimmunol Neuroinflamm. 2015;2:e102.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Azevedo CJ, Cen SY, Khadka S, Liu S, Kornak J, Shi Y, et al. Thalamic atrophy in multiple sclerosis: a magnetic resonance imaging marker of neurodegeneration throughout disease. Ann Neurol. 2018;83:223–34.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Zeydan B, Gu X, Atkinson EJ, Keegan BM, Weinshenker BG, Tillema JM, et al. Cervical spinal cord atrophy: an early marker of progressive MS onset. Neurol Neuroimmunol Neuroinflamm. 2018;5:e435.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Rocca MA, Valsasina P, Meani A, et al. Clinically relevant cranio-caudal patterns of cervical cord atrophy evolution in MS. Neurology. 2019;93:e1852–66.

  26. Paz Soldan MM, Novotna M, Abou Zeid N, Kale N, Tutuncu M, Crusan DJ, et al. Relapses and disability accumulation in progressive multiple sclerosis. Neurology. 2015;84:81–8.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Fox EJ, Markowitz C, Applebee A, Montalban X, Wolinsky JS, Belachew S, et al. Ocrelizumab reduces progression of upper extremity impairment in patients with primary progressive multiple sclerosis: findings from the phase III randomized ORATORIO trial. Mult Scler. 2018;24:1862–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kappos L, Bar-Or A, Cree BAC, Fox RJ, Giovannoni G, Gold R, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391:1263–73.

    Article  CAS  PubMed  Google Scholar 

  29. Pawelec G. Hallmarks of human “immunosenescence”: adaptation or dysregulation? Immun Ageing. 2012;9:15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bolton C, Smith PA. The influence and impact of ageing and immunosenescence (ISC) on adaptive immunity during multiple sclerosis (MS) and the animal counterpart experimental autoimmune encephalomyelitis (EAE). Ageing Res Rev. 2018;41:64–81.

    Article  CAS  PubMed  Google Scholar 

  31. Thewissen M, Linsen L, Somers V, et al. Premature immunosenescence in rheumatoid arthritis and multiple sclerosis patients. Ann N Y Acad Sci. 2005;1051:255–62.

    Article  CAS  PubMed  Google Scholar 

  32. Duszczyszyn DA, Williams JL, Mason H, Lapierre Y, Antel J, Haegert DG. Thymic involution and proliferative T-cell responses in multiple sclerosis. J Neuroimmunol. 2010;221:73–80.

    Article  CAS  PubMed  Google Scholar 

  33. Sonobe Y, Jin S, Wang J, Kawanokuchi J, Takeuchi H, Mizuno T, et al. Chronological changes of CD4(+) and CD8(+) T cell subsets in the experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Tohoku J Exp Med. 2007;213:329–39.

    Article  CAS  PubMed  Google Scholar 

  34. Haegele KF, Stueckle CA, Malin JP, Sindern E. Increase of CD8+ T-effector memory cells in peripheral blood of patients with relapsing-remitting multiple sclerosis compared to healthy controls. J Neuroimmunol. 2007;183:168–74.

    Article  CAS  PubMed  Google Scholar 

  35. Ramos S, Brenu E, Broadley S, et al. Regulatory T, natural killer T and gammadelta T cells in multiple sclerosis and chronic fatigue syndrome/myalgic encephalomyelitis: a comparison. Asian Pac J Allergy Immunol. 2016;34:300–5.

    CAS  PubMed  Google Scholar 

  36. Claes N, Fraussen J, Vanheusden M, Hellings N, Stinissen P, van Wijmeersch B, et al. Age-associated B cells with proinflammatory characteristics are expanded in a proportion of multiple sclerosis patients. J Immunol. 2016;197:4576–83.

    Article  CAS  PubMed  Google Scholar 

  37. Guan JZ, Guan WP, Maeda T, Guoqing X, GuangZhi W, Makino N. Patients with multiple sclerosis show increased oxidative stress markers and somatic telomere length shortening. Mol Cell Biochem. 2015;400:183–7.

    Article  CAS  PubMed  Google Scholar 

  38. Stepensky P, Rensing-Ehl A, Gather R, Revel-Vilk S, Fischer U, Nabhani S, et al. Early-onset Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency. Blood. 2015;125:753–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hickman S, Izzy S, Sen P, Morsett L, el Khoury J. Microglia in neurodegeneration. Nat Neurosci. 2018;21:1359–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Klein B, Mrowetz H, Barker CM, Lange S, Rivera FJ, Aigner L. Age influences microglial activation after cuprizone-induced demyelination. Front Aging Neurosci. 2018;10:278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cadavid D, Balcer L, Galetta S, Aktas O, Ziemssen T, Vanopdenbosch LJ, et al. Predictors of response to opicinumab in acute optic neuritis. Ann Clin Transl Neurol. 2018;5:1154–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kantarci OH, Zeydan B, Atkinson EJ, Conway BL, Castrillo-Viguera C, Rodriguez M. Relapse recovery: the forgotten variable in multiple sclerosis clinical trials. Neurol Neuroimmunol Neuroinflamm. 2020;7:e653.

    Article  PubMed  Google Scholar 

  43. Novotna M, Paz Soldan MM, Abou Zeid N, et al. Poor early relapse recovery affects onset of progressive disease course in multiple sclerosis. Neurology. 2015;85:722–9.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Keegan BM, Kaufmann TJ, Weinshenker BG, Kantarci OH, Schmalstieg WF, Paz Soldan MM, et al. Progressive solitary sclerosis: gradual motor impairment from a single CNS demyelinating lesion. Neurology. 2016;87:1713–9.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Sechi E, Keegan BM, Kaufmann TJ, Kantarci OH, Weinshenker BG, Flanagan EP. Unilateral motor progression in MS: association with a critical corticospinal tract lesion. Neurology. 2019;93:e628–34.

    Article  PubMed  Google Scholar 

  46. Gold EB, Bromberger J, Crawford S, Samuels S, Greendale GA, Harlow SD, et al. Factors associated with age at natural menopause in a multiethnic sample of midlife women. Am J Epidemiol. 2001;153:865–74.

    Article  CAS  PubMed  Google Scholar 

  47. Harlow SD, Gass M, Hall JE, Lobo R, Maki P, Rebar RW, et al. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. J Clin Endocrinol Metab. 2012;97:1159–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bove R, Healy BC, Secor E, Vaughan T, Katic B, Chitnis T, et al. Patients report worse MS symptoms after menopause: findings from an online cohort. Mult Scler Relat Disord. 2015;4:18–24.

    Article  CAS  PubMed  Google Scholar 

  49. Smith R, Studd JW. A pilot study of the effect upon multiple sclerosis of the menopause, hormone replacement therapy and the menstrual cycle. J R Soc Med. 1992;85:612–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Holmqvist P, Wallberg M, Hammar M, Landtblom AM, Brynhildsen J. Symptoms of multiple sclerosis in women in relation to sex steroid exposure. Maturitas. 2006;54:149–53.

    Article  CAS  PubMed  Google Scholar 

  51. Bove R, Musallam A, Healy BC, Houtchens M, Glanz BI, Khoury S, et al. No sex-specific difference in disease trajectory in multiple sclerosis patients before and after age 50. BMC Neurol. 2013;13:73.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Bove R, Healy BC, Musallam A, Glanz BI, de Jager PL, Chitnis T. Exploration of changes in disability after menopause in a longitudinal multiple sclerosis cohort. Mult Scler. 2016;22:935–43.

    Article  CAS  PubMed  Google Scholar 

  53. Ladeira F, Salavisa M, Caetano A, Barbosa R, Sá F, Correia AS. The influence of menopause in multiple sclerosis course: a longitudinal cohort study. Eur Neurol. 2018;80:223–7.

    Article  PubMed  Google Scholar 

  54. Baroncini D, Annovazzi PO, De Rossi N, et al. Impact of natural menopause on multiple sclerosis: a multicentre study. J Neurol Neurosurg Psychiatry. 2019;90:1201–6.

    Article  PubMed  Google Scholar 

  55. Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132:1175–89.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Lassmann H. Mechanisms of neurodegeneration shared between multiple sclerosis and Alzheimer’s disease. J Neural Transm (Vienna). 2011;118:747–52.

    Article  CAS  Google Scholar 

  57. Hinks GL, Franklin RJ. Delayed changes in growth factor gene expression during slow remyelination in the CNS of aged rats. Mol Cell Neurosci. 2000;16:542–56.

    Article  CAS  PubMed  Google Scholar 

  58. Zhao C, Li WW, Franklin RJ. Differences in the early inflammatory responses to toxin-induced demyelination are associated with the age-related decline in CNS remyelination. Neurobiol Aging. 2006;27:1298–307.

    Article  CAS  PubMed  Google Scholar 

  59. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338:278–85.

    Article  CAS  PubMed  Google Scholar 

  60. Bjartmar C, Wujek JR, Trapp BD. Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. J Neurol Sci. 2003;206:165–71.

    Article  CAS  PubMed  Google Scholar 

  61. Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain. 2003;126:770–82.

    Article  PubMed  Google Scholar 

  62. Rist JM, Franklin RJ. Taking ageing into account in remyelination-based therapies for multiple sclerosis. J Neurol Sci. 2008;274:64–7.

    Article  CAS  PubMed  Google Scholar 

  63. Frischer JM, Weigand SD, Guo Y, Kale N, Parisi JE, Pirko I, et al. Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. Ann Neurol. 2015;78:710–21.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Zhang H, Podojil JR, Luo X, Miller SD. Intrinsic and induced regulation of the age-associated onset of spontaneous experimental autoimmune encephalomyelitis. J Immunol. 2008;181:4638–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Marrie RA, Yu N, Blanchard J, Leung S, Elliott L. The rising prevalence and changing age distribution of multiple sclerosis in Manitoba. Neurology. 2010;74:465–71.

    Article  CAS  PubMed  Google Scholar 

  66. Daltrozzo T, Hapfelmeier A, Donnachie E, Schneider A, Hemmer B. A systematic assessment of prevalence, incidence and regional distribution of multiple sclerosis in Bavaria from 2006 to 2015. Front Neurol. 2018;9:871.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Schweitzer F, Laurent S, Fink GR, Barnett MH, Reddel S, Hartung HP, et al. Age and the risks of high-efficacy disease modifying drugs in multiple sclerosis. Curr Opin Neurol. 2019;32:305–12.

    Article  CAS  PubMed  Google Scholar 

  68. Weideman AM, Tapia-Maltos MA, Johnson K, Greenwood M, Bielekova B. Meta-analysis of the age-dependent efficacy of multiple sclerosis treatments. Front Neurol. 2017;8:577.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Mayo Clinic, 200 First Street, SW, Rochester, MN, 55905, USA

    Burcu Zeydan & Orhun H. Kantarci

  2. Department of Radiology, Mayo Clinic, 200 First Street, SW, Rochester, MN, 55905, USA

    Burcu Zeydan

  3. Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, 200 First Street, SW, Rochester, MN, 55905, USA

    Burcu Zeydan & Orhun H. Kantarci

Authors
  1. Burcu Zeydan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Orhun H. Kantarci
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Burcu Zeydan.

Ethics declarations

Conflict of Interest

Dr. Zeydan reports grants from National Institutes of Health: (U54 AG44170), outside the submitted work.

Dr. Kantarci has nothing to disclose.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Demyelinating Disorders

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zeydan, B., Kantarci, O.H. Impact of Age on Multiple Sclerosis Disease Activity and Progression. Curr Neurol Neurosci Rep 20, 24 (2020). https://doi.org/10.1007/s11910-020-01046-2

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11910-020-01046-2

Keywords

Search

Navigation