A workshop on ageing and multiple sclerosis (MS) took place in Philadelphia in April, organised by the International Advisory Committee on Clinical Trials in MS, which is supported jointly by the US National MS Society and ECTRIMS.
“Ageing was highlighted by the Committee members as an area of key significance. The overarching goal was to review the current perspectives on ageing and identify the gaps in the field. The symposium covered many topics, including discussions on the underlying science related to ageing in MS, considerations about the impact of age on clinical trials design and conduct, treatment strategies and clinical management of MS in patients as they age and people who are diagnosed with MS at their older age. The key outcomes of the presentations will be disseminated to promote advancement of the research in this field,” explains Dr. Anna Lampe, Director of Research at the National MS Society.
What are the unmet needs of older people with MS? We ask Professor Xavier Montalban, Chair of the International Advisory Committee on Clinical Trials in MS and professor at the Autonomous University of Barcelona and University of Vic – Central University of Catalonia. “The mean age of our patients is higher than 20 years ago. We need to clinically manage the older population with MS,” says Professor Montalban. “The diagnosis of MS in older patients is challenging, because they typically have more vascular risk factors and comorbidities. One can find white spots in the brain that are not necessarily due to MS, but rather to ischemic problems or other conditions. When making a diagnosis of MS, it is crucial to avoid mistakes. We intend to preserve sensitivity – correctly identify people with MS – but also to increase specificity – correctly detect people who do not have MS. Therefore, in the revision of McDonald diagnostic criteria we will require additional criteria: one spinal cord lesion, or the presence of oligoclonal bands in cerebrospinal fluid, or central vein signs.”
Two sections of the workshop were dedicated to the pathophysiology of MS at older age. As individuals age, so does their immune system [1]. In MS patients, immune ageing – known also as immunosenescence – starts prematurely and the immune function is reduced [2]. Immunosenescence is characterised by specific markers – the immune risk phenotype – consisting of high CD8 and low CD4 numbers, seropositivity to cytomegalovirus (CMV), an increased number of CD8+CD28- T cells, poor T cell proliferation, low B cell numbers [1, 3]. Different therapeutic strategies bear the potential to rejuvenate the immune system with a beneficial impact on MS therapies [1]. Professor Montalban, who is also director of the Multiple Sclerosis Center of Catalonia (Cemcat) at the Vall d’Hebron University Hospital, adds: “There is a need to investigate the effects of immunosenescence on the repair mechanisms in older population with MS. Also, the capacity of remyelination in older people is not the same as in younger adults. These aspects must be considered when designing clinical trials of potential pro-remyelinating therapies. So far, people enrolled in clinical trials were between 15 and 55 years old. We need to also involve older patients. Many challenges remain on how to deal with the safety of medications used nowadays in older patients with or without comorbidities. In specific cases, the treatment can be de-escalated or discontinued. With patients with MS older than 55, who have been inactive for 5 years, do not show changes on MRI, and were treated with a moderate-efficacy therapy, neurologists can perfectly well consider de-escalating or stopping treatment.”
Brain reserve and rehabilitation at older age
As individuals with MS age, central nervous system (CNS) reserve can play a very important role. Some individuals can cope better than others with a similar brain damage or pathology, due to individual differences in their CNS [4]. During the lifespan, people build up structural and functional resources – reserve – that help attenuate the impact of neural decline [5]. People with a higher reserve can tolerate a larger damage, before showing clinical manifestations [4]. Structural and functional CNS reserve can be depleted due to ageing and disease burden, but can also be protected through a healthy lifestyle, and effective treatments [6].
Dr. Jaume Sastre-Garriga from Cemcat explains to us: “CNS reserve can be defined as the “capital” that each person accumulates over a lifetime, particularly before the disease. Structural brain reserve is indicated by the maximum size a brain grew throughout a life – maximal lifetime brain growth. It can be estimated with the head size or intracranial volume. Functional or cognitive reserve, instead, is enriched through cognitively stimulating experience – level of education, intellectually demanding jobs, leisure activities, such as reading, writing, or playing a musical instrument. Thanks to brain reserve, one becomes more resistant to cognitive deterioration. Although brain reserve is built up before the disease onset, it can be leveraged during the disease. With the rehabilitation people can work on their reserve”.
J Sumowski and colleagues observed that patients with MS with a larger intracranial volume benefited from a better cognitive status. Indeed, for these patients, the impact of disease burden – as measured by T2 lesion load using magnetic resonance imaging (MRI) – on cognitive status was alleviated [7]. Spinal cord reserve is another factor that can help modulate the effects of damage in MS. Dr. Sastre-Garriga and his colleagues found that a larger area of the spinal canal – an estimation of the maximal lifetime growth of the spinal cord – was associated with lower scores on a patient-reported outcome measure, called PDDS (Patient Determined Disease Steps). Spinal cord reserve can be protective against disability in MS [8].
Dr. Sastre-Garriga tells us: “One can imagine brain and spinal cord reserve as a storage of food at home. If you store food in a cupboard, you can mitigate the impact of unexpected food shortages. During the period of shortage, you can live with the food you stocked. You can endure longer with a larger cupboard, filled with more food, which was better-preserved. You can also work on efficiently handling the available food. Leaving the analogy aside, the rehabilitation can help manage your brain reserve. This is especially true for older patients. Rehabilitation must be adapted to older people, both in terms of the elements that need to be considered and the goals that need to be set”.
Older people with MS face unique needs and challenges. This symposium allowed international key thought leaders to share specific considerations concerning the diagnosis and pathophysiology of MS at older age, the clinical trials and treatment in older population and to recommend future directions. “About 65 experts convened during this workshop, alongside individuals affected by MS and representatives from patient organisations,” says Dr. Katherine Daniels, director of Global Initiatives of the National MS Society. “Our primary focus was on identifying the issues directly impacting older individuals with MS. Surveys conducted within the community further contributed to detect the specific needs of people affected by MS during the workshop.”
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Written by Stefania de Vito
Special thanks to Professor Xavier Montalban (Cemcat), Dr. Jaume Sastre-Garriga (Cemcat), and to Dr. Kate Daniels and Dr. Anne Lampe from the National MS Society for their insights.
References
[1] Dema M et al. Autoimmun. Rev. 2021; 20(9), 102893.
[2] Redondo J et al. Mult. Scler. 2018; 24: 919-931.
[3] Wikby A et al J. Gerontol. A. Biol. Sci. Med. Sci. 2005; 60(5), 556-565.
[4] Stern Y Neuropsychologia 2009; 47(10), 2015-2028.
[5] Fittipaldi S et al Nat. Mental Health 2024; 1-13.
[6] Brandstadter R, Katz Sand I & Sumowski JF (2019). Mult. Scler. J. 2019; 25(10), 1372-1378.
[7] Sumowski JF et al Neurology 2013; 80(24): 2186-2193.
[8] Sastre-Garriga J JNNP 2023; 94(7), 502-510.