Reviews

Epidemiology and treatment of

multiple sclerosis in elderly populations
Caila B. Vaughn    1, Dejan Jakimovski   2, Katelyn S. Kavak1, Murali Ramanathan3,
Ralph H. B. Benedict1, Robert Zivadinov2,4 and Bianca Weinstock-​Guttman    1*
Abstract | The prevalence of multiple sclerosis (MS) and the age of affected patients are
increasing owing to increased longevity of the general population and the availability of effective
disease-​modifying therapies. However, ageing presents unique challenges in patients with MS
largely as a result of their increased frequency of age-​related and MS-​related comorbidities as
well as transition of the disease course from an inflammatory to a neurodegenerative phenotype.
Immunosenescence (the weakening of the immune system associated with natural ageing) might
be at least partly responsible for this transition, which further complicates disease management.
Currently approved therapies for MS are effective in preventing relapse but are not as effective
in preventing the accumulation of disability associated with ageing and disease progression.
Thus, ageing patients with MS represent a uniquely challenging population that is currently
underserved by existing therapeutic regimens. This Review focuses on the epidemiology of MS in
ageing patients. Unique considerations relevant to this population are discussed, including the
immunology and pathobiology of the complex relationship between ageing and MS, the safety
and efficacy of disease-​modifying therapies, when discontinuation of treatment might be
appropriate and the important role of approaches to support wellness and cognition.

1
Jacobs Multiple Sclerosis
Center for Treatment and
Research, Department of
Neurology, Jacobs School of
Medicine and Biomedical
Sciences, State University of
New York (SUNY), Buffalo,
NY, USA.
2
Buffalo Neuroimaging
Analysis Center, Department
of Neurology, Jacobs School
of Medicine and Biomedical
Sciences, State University of
New York (SUNY), Buffalo,
NY, USA.
3
Department of
Pharmaceutical Sciences,
Jacobs School of Medicine
and Biomedical Sciences,
State University of New York
(SUNY), Buffalo, NY, USA.
4
Center for Biomedical
Imaging at the Clinical
Translational Science Institute,
State University of New York
(SUNY), Buffalo, NY, USA.
*e-​mail: bw8@buffalo.edu
https://doi.org/10.1038/
s41582-019-0183-3
Worldwide, the average age of individuals with multi-
ple sclerosis (MS) is increasing1. Advances in treating
vascular comorbidities, as well as the large armamentar-
ium of effective disease-​modifying therapies, have con-
tributed to an increased likelihood of achieving stable
disease and to the increased longevity of patients with
MS. However, all randomized controlled trials (RCTs)
performed to date to evaluate the safety and efficacy of
disease-​modifying therapies have specifically excluded
elderly patients with MS. In addition, few studies have
evaluated the complex interaction of this chronic disease
with the natural ageing process.
Some patients with MS present with a progressive
course from disease onset, termed primary progressive
MS (PPMS), but ~80% of patients with MS present with
a relapsing–remitting course. Relapsing–remitting MS
(RRMS) is characterized by acute episodes of neurolog-
ical impairment followed by a return to baseline func-
tion. Eventually, recovery from these episodes becomes
incomplete and neurological disability accumulates,
which marks the transition to secondary progressive MS
(SPMS). Most individuals are diagnosed with MS at age
20–50 years2, and within this subgroup, >30% remain in
the RRMS phase of the disease into old age3,4. However, a
few individuals are diagnosed with MS after age 50 years
(termed late-​onset MS (LOMS)) or even after age 60 years
(termed very-​late-onset MS (VLOMS)). Therefore,
managing MS in elderly populations presents unique
challenges related to age-​related and disease-​related
comorbidities as well as the disease itself.
This Review summarizes the epidemiology of MS
as it pertains to ageing individuals and discusses the
unique challenges facing elderly patients with MS. These
challenges include the complexity of the relationship
between ageing and MS, the lack of clarity regarding the
safety and efficacy of disease-​modifying therapies in
elderly individuals, controversy over when and whether
discontinuation of treatment is appropriate and the
importance of supporting wellness and cognition.
Epidemiology of MS in elderly patients
Incidence and prevalence. MS is a chronic demyelinat-
ing condition of the CNS associated with good survival;
these patients’ life expectancy is only slightly below that
of the general population5–8. Contemporary estimates
suggest an average reduction in lifespan of 6–10 years
for patients with MS8,9. Therefore, the number of elderly
individuals with MS is increasing in conjunction with
ageing of the general population. In 2004, an analysis
of data from a large MS registry in the United States
revealed that ~14% of patients with MS were ≥65 years
of age10.

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Reviews
Key points
• The prevalence of ageing individuals with multiple sclerosis (MS) is increasing
worldwide.
• Ageing people with MS present with unique challenges, including a high burden of
comorbidities and an altered immune system profile.
• Data on the safety and efficacy of current disease-​modifying therapy regimens in
elderly patients with MS are lacking, indicating the need for further studies in this
specific population.
• A substantial proportion of elderly patients with stable MS will need to consider
whether to discontinue disease-​modifying therapy; data are currently insufficient to
provide evidence-​based recommendations on this topic.
• Complementary lifestyle modifications that promote wellness and cognition can help
ageing patients with MS to manage their comorbidities and improve their quality of life.
An overall increase in the prevalence of MS, regard-
less of age, has been reported worldwide, including in
Canada11, Norway12, New Zealand13 and in commercial
insurance databases in the United States14. Longitudinal
data from large registries have also documented an
increase in the prevalence of MS specifically in the age-
ing population in Canada1,11, Italy15 and Australia16,17.
Substantial published data supporting an increase specif-
ically in ageing individuals with MS come from Canada,
a nation with a high prevalence of MS1. The prevalence
of MS in Manitoba, Canada, was estimated to be 226.7
cases per 100,000 of the population in 2006, a statistically
significant increase from 32.6 per 100,000 in 1984 (ref.1).
This study also documented a gradual upward trend in
the age of peak prevalence of MS, from 35–39 years in
1984 to older age groups in subsequent years. The most
recent assessment (in 2004) found that the age of peak
prevalence of MS had risen to 55–59 years1. A 2015
report from Genoa, Italy, estimated the prevalence of MS
to be ~148.5 per 100,000 individuals and, importantly,
that 18% of all patients with MS were >65 years of age15.
In Australia, the prevalence of MS increased from <20
per 100,000 individuals to ~60 per 100,000 over a time
span of 45 years, and the most notable increase occurred
in individuals >60 years of age16.
Several reasons probably contribute to this increase
in the prevalence of MS. Chief among those reasons is
increased longevity, although changes in diagnostic cri-
teria and improvements in diagnostic tools, including
the availability of advanced imaging modalities, are also
likely to be involved. An increase in the incidence of MS
in central Finland was almost entirely attributable to the
increased diagnostic use of MRI18. Similarly, a study con-
ducted in the United States found that the incidence of
MS remained stable over a period of 15 years after adjust-
ment for age and sex19; comparable results were obtained
in a study conducted in Bavaria20. Conversely, studies
conducted in Italy21 and Australia22, as well as a large
meta-​regression analysis23, suggested that the overall inci-
dence of MS is rising along with the increases in its prev-
alence. Differences in methods of case ascertainment,
emphasis on the use of MRI, increased awareness of the
disease and changes in diagnostic criteria might partially
explain the lack of consensus among these studies.
Regardless of whether the incidence of MS is truly ris-
ing, the diagnosis of incident MS after the age of 50 years
was formerly infrequent; indeed, symptom onset after age
330 | JUNE 2019 | volume 15 www.nature.com/nrneurol
50 years was once an exclusionary diagnostic criterion
for MS24–26. However, LOMS now accounts for 3.4−4.8%
and VLOMS for 0.5% of all MS diagnoses27–30. Finally, a
report from Denmark published in 2018 stated that the
incidence of MS specifically in individuals >50 years of
age has increased substantially in both men and women31.
Additional studies are recommended to determine
whether the incidence of LOMS and VLOMS is increasing.
LOMS and VLOMS provide unique challenges for
the management of MS. Trials of all existing disease-​
modifying therapies for MS specifically excluded age-
ing patients, and because a substantial portion of these
individuals still have RRMS (which responds favourably
to these treatments), information on the safety and effi-
cacy of these agents in this specific population is greatly
needed. In addition, older patients with MS are more likely
than younger patients with MS to have comorbidities that
complicate their medical management32,33. The presence
of comorbidities (particularly vascular, autoimmune or
musculoskeletal disease) at symptom onset has also been
associated with substantial delays in the diagnosis of MS34.
Mortality. Patients with MS show higher mortality than
the general population33,35–38. Although the accumulation
of progressive disability caused by the disease process itself
is not always the immediate cause of death, MS is recorded
as an underlying cause of death for ~50% of patients with
MS36. The results of a large study of individuals included
in the US Department of Defense administrative claims
database showed that patients with MS have an increased
all-​cause mortality ratio (2.9, 95% CI 2.7–3.2) compared
with the non-​MS population33. The largest increase in
mortality ratio (9.4, 95% CI 5.3–16.7) occurred in patients
with MS aged 50–59 years33. These findings were repli-
cated in a similar study completed in Norway8. However,
as patients age, direct causes of death other than MS (such
as cardiovascular disease, respiratory disease, infections
and cancer) become increasingly prevalent39.
Despite the documented increase in the prevalence
of MS, mortality in patients with MS seems to be either
stable or perhaps decreasing. A study of MS-​related
mortality in Canada suggested that whereas overall
MS-​related mortality itself has remained fairly stable
over the past ~35 years, deaths attributed to MS have
steadily shifted to older age groups40. This change reflects
both the ageing of the population and the increased life
expectancy of patients with MS, which probably results
from improved treatments for both MS and prevalent
comorbidities. A study that examined trends in mortal-
ity for patients with MS in the United States found that
MS-​specific mortality peaks at ~74 years of age and then
declines substantially41. Individuals with MS are now
living longer; therefore, consideration of appropriate
disease-​modifying therapies and other ways of main-
taining wellness and treating comorbidities in elderly
individuals with MS are necessary.
Immunopathology
A well-​functioning immune system seamlessly inte-
grates the innate response to an immediate threat with
the adaptive response necessary for future protection.
Dysregulation at many levels of the immune system is

central to the development and progression of MS42.
For example, autoreactive peripheral lymphocytes cross
the degraded blood–brain barrier (BBB) into the CNS,
where they recognize myelin fragments and initiate an
immune response43. The resulting demyelination is the
most recognized hallmark of MS44.
MS was originally thought to be primarily a dis-
ease of the adaptive immune system. Indeed, studies
in the most appropriate animal model of MS, exper-
imental autoimmune encephalomyelitis, identified
that cells of the adaptive immune system — primarily
T cells45 but also B cells46 — are major drivers of MS
pathophysiology. The success of therapies directed
against T cell and B cell targets provides support for
this hypothesis47. However, subsequent investigations
have shown that the innate immune system might also
be involved in MS, particularly at progressive stages of
the disease48.
Lesion characteristics on imaging. Inflammation and
T cell infiltration are present in active MS lesions dur-
ing the acute and relapsing phases of the disease and
can contribute to neurodegeneration, including axon
and cell loss47,49. A study that examined inflamma-
tion and neurodegeneration in the brains of patients
with MS found that T cell infiltration and substantial
inflammation were seen most frequently in active MS
lesions50, which are associated with acute and relaps-
ing disease. However, increasing numbers of T cells
were also found in lesions associated with progressive
disease, such as slowly expanding lesions 50. On the
contrary, few T cells were seen in inactive and remy-
elinated (shadow) lesions. Although brain tissue from
ageing individuals with long disease durations demon-
strated profound neurodegeneration, inflammation in
remyelinated lesions had declined to levels compara-
ble to those in the brains of age-​matched individuals
without MS50.
Lesion characteristics vary dynamically according to
the patient’s age, disease duration and disease pheno-
type51. At any given time, various types of MS lesions
can coexist. Lesions are histopathologically character-
ized as active (highly inflammatory with a dense mac-
rophage population), slowly expanding (with a central
astrocytic scar and activated microglia on the lesion
edge), inactive (containing demyelinated axons with
an astrocytic scar and no ongoing inflammatory activ-
ity) or remyelinated (shadow lesions, which have an
inflammation level comparable to that in age-​matched
controls)52. Advanced patient age and prolonged disease
duration are associated with a reduced chance of detect-
ing active lesions and an increased chance of detecting
smouldering plaques51. Smouldering plaques, which are
often also termed chronically active or slowly expanding
plaques, demonstrate lesion-​specific rim activity asso-
ciated with iron-​laden macrophages and amplification
of the oxidative injury owing to ferritin accumulation53.
As the presence of smouldering lesions is particularly
associated with the onset of progressive disease and
with the accelerated accumulation of physical disability,
they have the potential to become an important imaging
biomarker of progressive MS52.
NATure ReviewS | NeURology
Reviews
Inflammageing and immunosenescence. Ageing is
generally accompanied by immunosenescence54, a pro-
found weakening of both the innate and adaptive com-
ponents of the immune system, which leads to ageing
individuals having a reduced capacity for mounting an
adequate immune response54. Along with natural age-
ing, patients with MS also experience an accumulation
of iron within the CNS, resulting in oxidative stress55,56.
As oligodendrocytes are damaged by the disease pro-
cess, iron is released and its extracellular accumula-
tion potentiates oxidative stress and results in further
neurodegeneration55.
Autophagy, the intrinsic mechanism that compen-
sates for the accumulation of non-​functional organelles
and toxic products, supports cellular health when it
is functioning appropriately57. If this mechanism is
overwhelmed, waste products accumulate, leading to
cellular senescence and ultimately apoptosis, which
destroys damaged cells58. Evidence suggests that auto-
phagy becomes less proficient in ageing cells57 (Fig. 1). In
general, neurodegeneration is associated with decreased
autophagy. However, patients with active, relapsing MS
show increased autophagy in peripheral immune cells
compared with cells from healthy controls59. The para-
dox observed in progressive MS is the presence of neu-
rodegeneration despite evidence of increased autophagy
in the brain tissue59 (Fig. 2).
In young patients, the robust repair capacity of the
brain compensates for changes in the early (inflamma-
tory) stage of MS, but in ageing individuals a decreased
repair capacity and the neurodegenerative processes
associated with ageing both lead to a decrease in com-
pensatory reserve60. Therefore, over time, axonal degen-
eration, iron deposition and oxidative stress accumulate,
eventually overwhelming the brain’s natural reserves and
leading to disease progression61.
Ageing is often accompanied by chronic low-​grade
inflammation, a phenomenon known as inflammage-
ing62, probably as a result of chronic exposure to infectious
agents such as cytomegalovirus and Epstein–Barr virus.
Senescent immune cells accumulate in ageing individuals
and create a pro-​inflammatory environment attributable
to ongoing secretion of growth factors, pro-​inflammatory
cytokines and autoreactive antibodies, among other fac-
tors62–64. These senescent cells are no longer able to con-
tribute to tissue repair; instead, they recruit inflammatory
cells that further contribute to tissue damage65 (Fig. 1).
This chronic inflammation is believed to be associated
with the development of many age-​related diseases62.
Thymic involution (the shrinking in size of the thy-
mus that occurs in ageing individuals) could also help
to explain this diminished immune response. Thymic
involution results in a decline in the production of
naive T cells, which leads to reduced T cell activity in
elderly individuals and an associated increase in the risk
of infection66,67. Another potential explanation for the
reduced immune function observed in elderly patients
with MS is the reduction in neurotrophic factors68,69.
This decreased neurotrophic support corresponds to a
decreased capacity for remyelination and to an overall
reduction in brain plasticity, which further compound
the effects of ageing and MS69.
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SASP

Phagosome
Mitochondrion Lysosome

ROS +
Or
Apoptosis

ER

Nucleus

If the accumulation of damaged organelles

overburdens the autophagy process

Fig. 1 | Cellular processes involved in inflammageing and immunosenescence. Increased energy demands in ageing
immune cells lead to mitochondrial swelling and failure. The damaged mitochondria release large amounts of cytotoxic
reactive oxygen species (ROS), which damage other organelles as well as the cell’s own DNA , leading to functional
alterations. The damaged organelles are initially engulfed by autophagosomes, which merge with lysosomes to form
autophagolysosomes that digest and recycle their contents, a process termed autophagy. However, if autophagy becomes
overwhelmed, the cell either undergoes apoptosis or becomes senescent. Senescent cells exit the cell cycle and no longer
respond to pro-​apoptotic signals. Accordingly , these cells increase in size, do not proliferate and show increased
production of cytokines and other products, which can damage neighbouring cells. These features are termed the
senescence-​associated secretory phenotype (SASP). ER , endoplasmic reticulum.

The limited lesion-​repair capacity of elderly patients
with MS is partly related to a lack of remyelination,
which is a factor requiring consideration in the devel-
opment of new therapies56,70. In an autopsy series, the
brains of patients with progressive MS had a higher
lesion load and were also much less likely to have remy-
elinated lesions than were those of patients with RRMS71.
The authors suggest that the remyelination deficit is due
to widespread axonal degradation, which leaves only few
axons available for remyelination71. This study also con-
firmed a previous report that documented the presence
of substantial inflammation in the brains of patients with
MS50, even those with progressive MS71. Together with the
knowledge that BBB permeability is decreased in
patients with progressive MS72, these findings suggest
that disease activity remains compartmentalized behind
the BBB in progressive MS, which might present an
additional challenge for treatment.
Finally, the well-​established observation that immu-
nomodulatory and anti-​inflammatory therapies are
most effective in the early stages of RRMS42,55 sug-
gests that mechanisms involved in early disease stages
might not be as relevant in progressive MS42. Although
disease-​modifying therapies have proved effective for
preventing relapse, many have not demonstrated a con-
vincing reduction in the accrual of disability in indi-
viduals with progressive disease42,73. As a result, many
investigators have concluded that different mechanisms
underlie RRMS and progressive MS42.
MRI findings in MS and ageing
MRI-​derived evidence of MS pathology is an important
tool not only in establishing the diagnosis but also in
predicting and detecting disease progression and in eval-
uating responses to therapy74. The increasing utilization
of MRI has greatly contributed to understanding the
changes in MS pathology associated with increasing age
and with progressive MS. Here, we introduce some MRI
features of MS that are particularly affected by ageing:
lesion accumulation and detection; global, regional and
nuclei-​specific brain atrophy; spinal cord pathology;
and the identification of comorbidities.
The aforementioned increase in iron concentration
at the rim of slowly expanding lesions provides the basis
for lesion visualization on gradient-​based susceptibility-​
weighted imaging (SWI) and quantitative susceptibility

332 | JUNE 2019 | volume 15 www.nature.com/nrneurol

 Reviews

Autoreactive T cell Fig. 2 | The influence of ageing on MS pathophysiology.

Young patients with relapsing–remitting multiple sclerosis
Natural killer cell (RRMS) have a highly active peripheral immune system,
which includes autoreactive T cells and B cells. These
B cell activated lymphoid cells are able to migrate through the
damaged and disrupted blood–brain barrier (BBB) and
Neutrophil 1
The MS brain enter the brain, where they cause inflammation. In ageing
patients with multiple sclerosis (MS), the overall level of
activation of the immune peripheral immune system is
considerably reduced compared with that in young
patients with RRMS, but ageing greatly increases BBB
permeability , resulting in increased cellular trafficking (1).
MS, along with other neurodegenerative diseases, shares
Proliferating the hallmark of an altered balance between M1-like
astrocytes (pro-inflammatory) and M2-like (anti-​inflammatory)
Cytokines
3 microglia, leading to an increased proportion of
M1-like microglia, which promote inflammatory
Neuron
neurodegeneration (2). The chronic inflammatory state
associated with ageing leads to proliferation of astrocytes
2 Myelin and astrocytosis (scar formation) and prevents effective
lesion repair, remyelination and debris clearance by
macrophages (which engulf myelin debris and present it to
B cells and T cells) (3). This persistent inflammatory activity
also leads to increased loss of neuronal synaptic processes.
Ageing neurons also exhibit decreased synaptic plasticity ,
which further exacerbates their synaptic dysfunction (4).
Damaged neuron
Increased accumulation of activated memory B cells
M2-like and plasma cells within the meninges and meningeal
M1-like microglia tertiary follicle-​like structures is found in ageing patients
microglia with progressive MS. These cells serve as a constant
Oligodendrocyte source of pro-​inflammatory signals (5). Activated and
Myelin debris compartmentalized T cells also maintain and self-​sustain
4
the chronic inflammatory state within the brain in ageing
patients with progressive MS (6).
Macrophage

T cell
receptor
6
Activated B cell Activated
T cell
Plasma cell
Dendritic spine
5
mapping75,76. Although visualization of the paramagnetic
lesion rims can be readily performed by 7 T scanners,
only in the past few years have these findings been repli-
cated using clinically available 3 T scanners77. MS-​related
processes occurring behind the restored BBB can also
be imaged using ultra-​small superparamagnetic iron
oxide particles taken up by circulating macrophages that
migrate to sites of inflammation78.
Another potential imaging biomarker is atrophied
lesion volume, which refers to the volume of periven-
tricular lesions (which are gradually replaced by cerebro-
spinal fluid (CSF) or other local atrophic changes)79. In
one study, the atrophied lesion volume on T2-weighted
MRI was higher in patients with progressive MS than in
those with RRMS or clinically isolated syndrome (CIS)79.
This measure explained a substantial proportion of the
variance in predictions of disability, even after con-
trolling for brain atrophy and new or enlarging lesion
activity79. Therefore, atrophied lesion volume has poten-
tial as a tool for assessing the severity of progressive MS
in the ageing population79.
Lastly, the presence of a high burden of cortical
lesions (which occurs more frequently in progressive
MS than in RRMS or CIS) has been associated with a
high degree of physical and (especially) cognitive dis-
ability80,81. The visualization and quantification of cor-
tical lesions using either double-​inversion recovery or
gradient-​based sequences are useful to determine the
MS lesion burden82. Use of high-​field-strength MRI
scanners and novel sequences is likely to further con-
tribute to understanding the overall process of lesion
development83. Meningeal lymphoid follicle-​like struc-
tures can be detected in 25–50% of patients with MS
(reviewed elsewhere) 84, although their prevalence
is strongly influenced by the proportion of ageing
patients and individuals with progressive MS in the
study population81. These structures are thought to har-
bour autoreactive B cells, which could exacerbate local
inflammation and cause cortical demyelination. These
structures can be imaged as leptomeningeal contrast
enhancement foci. Multiple reports have corroborated
the finding of an increased prevalence of leptomenin-
geal contrast-​enhancing structures in older patients with
progressive MS85,86.

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Ageing patients with MS also have a substantial
increase in diffuse brain atrophy87. Over the past two
decades, the rate of brain atrophy in patients with
MS has been repeatedly shown to predict short-​term,
medium-​term and long-​term disability progression88.
Several longitudinal studies have attempted to identify
a cut-​off value to define the threshold between ‘physio-
logical’ and ‘pathological’ brain atrophy rates, which is
proposed to be 0.4% per year89. However, brain volume
in humans undergoes substantial variation throughout
life90. The loss of brain volume is thought to be ~0.2%
per year from early adulthood to mid-​life, after which
it gradually rises to ~0.5% per year at 60 years of age90.
Given that the loss of brain volume in healthy elderly
individuals exceeds the supposedly pathological rate of
0.5% per year, attempts to further refine these cut-​off
values are futile90.
In addition to the effect of overall brain atrophy
on the outcomes of patients with MS, accumulat-
ing evidence has pinpointed cortical atrophy as the
main driver of physical and cognitive disability 91,92.
Compared with individuals who have CIS or RRMS,
patients with SPMS demonstrate more atrophy in
grey matter but not in white matter92. Furthermore,
in longitudinal studies, patients with SPMS have up to
10-fold more grey matter atrophy than patients with
RRMS and up to 14-fold more grey matter atrophy
than healthy age-​matched and sex-​matched controls91.
Two independent studies employing component-​based
and event-​based analysis have found anatomically dis-
tinct patterns of cortical atrophy in patients with MS.
These patterns occur in a nonrandom manner that is
at least partially driven by disease duration93,94. As in
Alzheimer disease (AD), understanding the tempo-
ral and spatial progression of grey matter atrophy in
patients with MS could lead to improvements in clini-
cal trial design and the development of individualized
treatment, tailored to age and disease duration, for
patients with MS95.
Measures related to specific brain areas might be
more appropriate than total brain measures. Central
grey matter structures such as the thalamus are espe-
cially vulnerable to MS pathology owing to their expo-
sure to CSF-​borne neurotoxic factors96,97 and their role as
major sites of connection between afferent and efferent
axons97,98. The results of a large, multicentre MRI study
have corroborated the clinical importance of this vul-
nerability to neurodegeneration in deep grey matter
structures99. Regardless of the clinical phenotype of MS,
deep grey matter had the fastest longitudinal atrophy
rate, and the loss of deep grey matter volume was the
only measure of grey matter atrophy significantly asso-
ciated with disability accrual (P < 0.001)99. Lower deep
grey matter volumes at baseline were strongly associated
with shorter times to progression of Expanded Disability
Status Scale (EDSS) scores99. Furthermore, another study
showed that the thalamic atrophy rate remains consist-
ent throughout the entire MS disease course, making it
a convenient MRI-​based primary end point100. The total
cerebellar volume and cerebellar cortex volume are other
potential MRI-​based neurodegenerative outcome meas-
ures that can be used in both ageing patients with MS
334 | JUNE 2019 | volume 15 www.nature.com/nrneurol
and those with PPMS. In addition, atrophy within the
cerebellar VI, crus I and VIIIa lobules contributes to spe-
cific features of motor and cognitive impairment101,102.
Although standardization and technical advances in
MRI hardware and software have made analyses of brain
atrophy clinically feasible at the group level, these neu-
rodegenerative outcomes are still not informative at an
individual patient level88.
A large subgroup of patients with suspected MS
present with spinal demyelinating lesions and substan-
tial spinal cord atrophy, a pathology associated not only
with increased risk of conversion to clinically definite
MS but also with long-​term disability progression103. In
contrast to their lack of cranial findings, patients with
PPMS might present with diffuse spinal cord changes,
which are associated with demyelination and axonal
loss104,105. Spinal cord atrophy can be demonstrated by
either measuring the cross-​sectional area at the level of
specific anatomical markers (such as specific cervical
vertebrae) or by measuring the cord volume between
two spinal levels. Patients with progressive MS have both
a higher cervical cord lesion load and a lower cervical
cross-​sectional cord area than those of patients with
RRMS, and both of these measures are independent
contributors to increased levels of disability103. Patients
with progressive MS also demonstrate marked atrophy
of the spinal grey matter, which is strongly associated
with worse ambulation106. A longitudinal MRI study
demonstrated that spinal cord volume loss is largely
independent of the cranial T2 lesion load and brain
atrophy measures107. In this study, spinal cord atrophy
was the only MRI-​derived metric associated with both
physical disability level and disease progression107. In a
separate study, spinal cord atrophy was the only inde-
pendent MRI measure that could identify patients with
onset of progressive MS108.
In ageing patients with MS, the gradual development
of age-​associated immunosenescence precludes the use of
inflammation-​based MRI outcome measures, which
do not provide adequate or sufficient responsiveness to
intervention. New MRI measures that perform consist-
ently across multiple MS phenotypes are greatly needed
and currently lacking. Use of global and regional meas-
ures (such as grey matter atrophy, thalamic volume loss
and expansion of the lateral ventricles) or composite
measures derived from several differentially affected
brain regions could ultimately serve as neurodegenerative
MRI end points in MS clinical trials.
Comorbidities
Ageing in patients with MS, as in the general population,
is accompanied by the development and accumulation of
comorbidities, which increase these individuals’ risk
of both disability and death109. Moreover, some of the
comorbidities associated with ageing, such as cognitive
decline, are also potential sequelae of MS. Identifying
whether these features are due to MS or to normal ageing
can be a challenge.
Several studies have examined the incidence and
prevalence of comorbidities associated with MS10,32,33,110.
All patients with MS are at an increased risk of devel-
oping mobility limitations, but this risk is particularly

T1-MRI DWI
a b
FLAIR FLAIR
d c
SWI SWI
e f
Fig. 3 | Cerebrovascular disease can mimic MS-​specific pathology on MRI. T1-weighted
MRI (T1-MRI) (part a) and diffusion-​weighted imaging (DWI) (part b) scans from the same
patient with multiple sclerosis (MS). A hypointense lesion on T1-MRI shows enhancement
on DWI suggestive of a lacunar stroke within the left capsula interna (a, large black arrow;
b, white arrow). Lacunar stroke can resemble the appearance of an MS-​derived lesion. The
small arrow indicates an MS-​related T1-weighted hypointense lesion, also known as an MS
black hole. Fluid-​attenuated inversion recovery (FL AIR) images from two different patients
with MS (parts c,d), showing (right) T2-hyperintense bands in the periventricular white
matter and multiple small T2-hyperintense lesions outside the borders of the lateral
ventricles (white arrows), consistent with cerebral small-​vessel disease, and (left) symmetrical
T2-hyperintense areas posterior to the lateral ventricles, suggestive of a microvascular
ischaemic process. Small hypointensities (white arrow) suggest cystic microinfarcts. Cerebral
microbleeds (white arrows) are present in susceptibility-​weighted imaging (SWI) scans from
an ageing healthy individual (part e) and an ageing patient with MS (part f).
NATure ReviewS | NeURology
Reviews
apparent for ageing individuals10. Difficulty with walk-
ing is reported by >85% of patients with MS ≥65 years
of age, compared with 65% of those aged <65 years10.
Patients with MS aged ≥65 years were also much more
likely to report bowel and bladder difficulties than were
younger individuals with MS10. An analysis of the US
Department of Defense administrative claims database
found evidence of an increased risk of several catego-
ries of comorbidities in patients with MS33. Compared
with age-​matched non-​MS controls, patients with MS
had higher rates of malignancies, cardiovascular dis-
ease, psychiatric disorders, infections and other systemic
diseases, including diabetes mellitus33. Some of these
associations are discussed in more detail below.
Cardiovascular disease and diabetes mellitus. The
strongest associations relate to an increased risk of car-
diovascular disease (event rate ratio 3.6, 95% CI 3.5–3.8)
and ischaemic stroke (event rate ratio 3.8, 95% CI 3.5–4.2)
in patients with MS versus the non-​MS population33.
Patients with MS who have cardiovascular disease also
seem to have a higher risk of death from this cause than
the general population6. Similar increases in the preva-
lence of cardiovascular comorbidities110, diabetes mel-
litus111 and other vascular comorbidities33,112 have also
been documented in other studies of patients with MS,
and several population-​based case–control and cohort
studies have documented an increased risk of hyperten-
sion112,113 and stroke109,114,115. However, an analysis of a
large administrative claims database in Canada found
that rates of hypertension, hyperlipidaemia and diabetes
mellitus were similar in patients with MS and the gen-
eral population116, suggesting that additional studies are
needed to clarify these associations.
Regardless, ageing patients with MS can present with
a plethora of comorbidities associated with cerebrovas-
cular pathology, including small-​vessel disease, cerebral
hypoxia, iron accumulation and mitochondrial dysfunc-
tion. These cerebrovascular diseases are heterogeneous,
can coexist and look similar to MS pathology on imaging
studies117. These cerebrovascular features include but are
not limited to punctate or confluent white matter hyper-
intensities, cerebral microbleeds118, enlarged perivascu-
lar (Virchow–Robin) spaces, lacunae, small subcortical
or cortical microinfarcts and brain atrophy119 (Fig. 3). Of
note, the presence of white matter hyperintensities in the
juxta-​cortical region, spinal cord or optic nerve and
the involvement of U-​fibres are specific signs of MS pathol-
ogy117. Furthermore, the presence of a central vein is an
additional well-​known characteristic of MS lesions that
can be seen on T2*-weighted MRI as a thin hypointense
line that runs partially or entirely through the lesion120.
In the healthy ageing population, age-​associated cerebro-
vascular pathology has been associated with decreased
total and regional cerebral volumes121,122. Multiple studies
have shown that patients with MS and comorbid cardio­
vascular disease have lower cross-​sectional (and accel-
erated longitudinal loss of) global and regional brain
volumes123,124. Successful differentiation of both the ori-
gin of white matter hyperintensities and age-​associated
neuronal loss will help to guide clinical decision-​making
in ageing patients with MS.
volume 15 | JUNE 2019 | 335
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Neurological and psychiatric disorders. Some data risk of comorbidities, particularly as these patients age,
suggest that the prevalence of other neurological disor- and to ensure that their comorbidities are managed
ders, such as epilepsy, is also increased in patients with appropriately.
MS32. The concurrence of psychiatric disorders, includ-
ing depression, and MS is well established. In a meta-​ Safety and efficacy in elderly patients. Because clin-
analysis, the risk of depression in patients with MS was ical trials of existing disease-​modifying therapies for
estimated to be up to 23-fold higher than in the general MS have systematically excluded ageing patients, our
population32. However, long disease durations might knowledge of the safety and efficacy of these treatments
mitigate the strength of this association; older age125 in elderly populations is insufficient. In subgroup ana­
and longer time from disease onset126 have been asso- lyses, however, fingolimod was not more effective than
ciated with less-​severe depression in patients with MS, placebo in reducing the annualized relapse rate in
although other studies have reported little to no change patients >40 years of age149. Furthermore, when natali-
in patients’ depressive symptoms over time127,128. zumab was assessed for efficacy in patients with SPMS,
Little is understood about the association between the trial failed to meet its primary end point of reducing
MS and AD. Cognitive impairment affects individuals a multicomponent disability measure comprising the
with both diseases, although the clinical presentation of EDSS, Timed 25-Foot  Walk Test150 and the Nine-​Hole
cognitive impairment differs129. In MS, cognitive process- Peg Test151, although natalizumab did demonstrate effi-
ing speed is very commonly impaired, whereas in AD, cacy in reducing disease progression as assessed by the
episodic memory is typically most strongly affected129. Nine-​Hole Peg Test alone152.
One study conducted in individuals with LOMS
Disease-​modifying therapy examined the association between IFNβ treatment and
In late March 2019, two additional disease-​modifying disability progression in patients with RRMS153. The
therapies (cladribine and siponimod) were approved in results showed no evidence of a reduction in disability
the United States for the treatment of RRMS and active in this cohort of older (aged ≥50 years) patients with MS
SPMS130,131. It will be critical to see how the utilization of exposed to IFNβ compared with historical controls153.
these therapies affects ageing individuals with MS. Of The researchers acknowledged several potential reasons
the 15 previously FDA-​approved therapies for RRMS, for this negative finding. As previously described, ageing
14 remain on the market. By contrast, FDA approval patients with MS seem to have an inflammatory milieu
had previously been obtained for only one disease-​ different from that in their younger counterparts that
modifying therapy for PPMS (ocrelizumab) and only might not respond to immunomodulatory agents in the
one for SPMS (mitoxantrone)132. Therefore, few options same manner. Elderly patients with MS also often have
for disease-​modifying therapies were available in indi- comorbidities that can affect the efficacy of disease-​
viduals with progressive MS, who represent the majority modifying treatments. Finally, most studies are either
of patients with MS >65 years of age. The majority of too short or are not appropriately timed154 to capture
approved therapies for RRMS have failed to demonstrate either disease progression or disability accrual in elderly
efficacy in clinical trials as a treatment for progressive individuals, for whom MS is often not very active153.
MS. An apparent decrease in the effectiveness of disease-​ Taken together, these studies provide substantial evi-
modifying therapy in patients with progressive MS sug- dence suggesting that the role of the adaptive immune
gests that different pathobiological mechanisms might system in MS changes as individuals age.
come into play in the progressive stages of the disease. Studies of both approved155 and emerging147 disease-​
Notably, the clinical trials of disease-​modifying ther- modifying therapies have demonstrated slowing of
apies for RRMS were not designed to assess efficacy in disability progression in patients with progressive MS.
ageing patients. In fact, the pivotal clinical trials of the However, the participants in these trials were still fairly
most widely used disease-​modifying therapies specifi- young. In the ocrelizumab study in PPMS, the upper
cally excluded individuals aged >45 years (glatiramer age limit for eligibility was 55 years155, and for the
acetate133), aged >50 years (IFNβ1b134, natalizumab135 siponimod study in SPMS it was 60 years147. Cladribine
and alemtuzumab136,137) and aged >55 years (IFNβ1a138,139, is an oral medication that has now been approved by
dimethyl fumarate140,141, fingolimod142,143 and terifluno- the FDA131 for the treatment of RRMS, and has already
mide144,145). A currently recruiting phase III study of ocre- been approved in the European Union and several other
lizumab in patients with progressive MS (including some countries. In post hoc analyses of cladribine trial data
with SPMS) will have the highest upper age limit used presented at the 2018 annual meetings of the European
thus far in MS clinical trials — 65 years of age146 (Table 1). Committee for Treatment and Research in Multiple
Notably, clinical trials of siponimod, an oral selective Sclerosis (ECTRIMS) and the European Academy of
modulator of sphingosine 1-phosphate receptors 1 and 5 Neurology (EAN), the medication was similarly effective
(S1P1 and S1P5, respectively), demonstrated a significant in younger and older patients with RRMS — defined as
reduction in disability progression among patients with age above and below 45 years of age, respectively, in the
SPMS147. This therapy has now been approved by the CLARITY study152 and above and below 50 years of age,
FDA for the treatment of CIS, RRMS and active SPMS131. respectively, in the other study153.
In patients with MS, the presence of comorbidities is Real-​world data are needed from longitudinal MS
associated with a decreased likelihood of using disease-​ registries or prospective cohort studies to identify the
modifying therapy148. Therefore, it is important for clini- effects of disease-modifying therapies in elderly pati­ents
cians to counsel patients with MS about their increased with MS. RCTs also typically exclude elderly patients with

336 | JUNE 2019 | volume 15 www.nature.com/nrneurol


MS who have comorbidities, for whom careful consid-
eration of treatment options is very important. The fact
that elderly patients with progressive MS have a very
low probability of relapse156 and decreased immune
activity51 should also be kept in mind. Therefore, studies
designed to examine the efficacy of disease-modifying
therapies in elderly patients with progressive MS should
evaluate non-​traditional markers of disease progression
and activity157–159.
Treatment discontinuation. Controversy has flared over
whether ageing patients with MS can safely discontinue
disease-​modifying therapies after a certain age or disease
duration160,161. Data from real-​world observational stud-
ies in support of either continuation or discontinuation
are lacking, and experts consequently disagree on treat-
ment recommendations for ageing patients with stable
MS. Relapse frequency decreases substantially with age,
with the result that relapses are very infrequent among
patients with MS aged ≥60 years156,162,163. Some experts
argue that an age ≥60 years represents an appropriate
point to consider discontinuation of disease-​modifying
therapies, especially those with unfavourable safety pro-
files160. In an observational study of patients with MS aged
≥60 years, ~30% chose to discontinue disease-​modify-
ing therapies, most often at the recommendation of their
provider163. In this population, only one relapse was doc-
umented, although ~10% of patients who discontinued
disease-​modifying therapy chose to reinitiate it during
follow-​up163. However, in another observational study,
which had the advantage of a propensity-​matched com-
parison group who chose to continue disease-​modifying
therapies, the time to confirmed disability progression
was significantly shorter in the patients who discon-
tinued disease-​modifying therapies than in those who
continued to take them164.
In the absence of information from clinical trials
about the efficacy of disease-​modifying therapy in elderly
patients with MS, investigators have attempted to use
existing data to characterize the relationship between
drug efficacy and age. One meta-​analysis determined that
the efficacy of disease-​modifying therapy showed a strong
inverse association with increasing age165. This meta-​
analysis of 38 clinical trials, involving all FDA-​approved
disease-​modifying therapies, showed that age accounted
for almost 60% of the variation in slowing disability pro-
gression for IFNβ clinical trials and >40% of the variation
in slowing disability progression for all disease-​modifying
therapies. In a linear regression model weighted for trial
duration and sample size, adjustment for baseline EDSS
scores did not significantly improve the fit of the model,
which predicted that no disease-​modifying therapies were
effective beyond the age of ~53 years. Moreover, high-
efficacy drugs were superior to low-efficacy drugs in terms
of slowing MS disability progression only in patients  with MS170. RCTs of dietary interventions in patients with
<40 years of age.
Also requiring consideration is the fact that a large
proportion of elderly patients with MS still have RRMS,
which is highly amenable to treatment. However, even
interventions that are highly effective against RRMS as
well as progressive MS interventions, such as autologous
haematopoietic stem cell transplantation (HSCT), seem
NATure ReviewS | NeURology
Reviews
to be most efficacious in young individuals with MS166,167.
The results of a large cohort study in patients with all
phenotypes of MS (although ~78% had progressive MS)
showed that each additional year of age was associated
with a 3% increase in the risk of neurological progression
after autologous HSCT168. However, most studies of this
intervention in patients with MS have been conducted in
individuals with median ages of ~25–40 years, and very
few patients aged >50 years have been included167,168.
Given the increasing prevalence of elderly individuals
with MS and the lack of data on the safety and efficacy
of current disease-​modifying therapies in the elderly MS
population, further studies specific to this subgroup are
both necessary and warranted. We are hopeful that the
results of a large ongoing RCT that will assess therapy
discontinuation in adults ≥55 years of age will provide
guidance on this very important issue169.
Additional considerations in elderly patients
Wellness. A growing emphasis is being placed on life-
style strategies as a complement to traditional therapy
in patients with MS. One of the most frequently targeted
lifestyle factors is smoking. In addition to potentially
increasing the risk of developing MS, the literature con-
sistently shows that smoking is associated with increased
disability and worse prognosis in patients with MS170.
Conversion to SPMS is significantly accelerated in
patients who continue to smoke after diagnosis of MS
versus those who quit (by 4.7% for each year of continued
smoking; P < 0.001)171. Other studies have documented
an increased risk of attaining disability milestones (EDSS
scores 4.0 and 6.0) among smokers compared with either
non-​smokers or former smokers172,173.
Another highly studied lifestyle behaviour that
has been evaluated in patients with MS is exercise.
Routine exercise does seem to improve fatigue in these
patients170, but evidence is inconsistent with respect to
whether exercise slows either disease progression or
cognitive impairment174,175. Despite this inconsistency,
exercise is clearly important and recommended for
patients with MS by the US National Center on Health,
Physical Activity and Disability, even if only for the
beneficial effects of reducing obesity and preventing
obesity-​related comorbidities as these patients age170.
Similarly inconsistent results have been documented
for dietary interventions in patients with MS. Many dif-
ferent types of diets have been evaluated in this popula-
tion, including the Mediterranean diet, so-​called Paleo
diets, low-​sodium and low-​fat diets and the Swank diet.
To date, no substantial, consistent evidence favours one
specific diet over another. However, following a plant-​
based, anti-​inflammatory diet is helpful for promoting
overall health and might help to minimize comorbid
conditions and potentially other symptoms associated
MS are ongoing, and their results are expected to pro-
vide additional evidence regarding this modifiable
lifestyle behaviour176–178.
Social support for ageing patients with MS is also
extremely important. Qualitative studies have identified
social support and social engagement to be critical to
healthy ageing in patients with MS179,180. On the whole,
volume 15 | JUNE 2019 | 337
Reviews
Table 1 | Pivotal clinical trials of disease-​modifying therapies for MS
Name and design
Phase III double-​blind RCT
PRISMS: phase III
double-​blind RCT
Phase III double-​blind RCT
Double-​blind RCT
MIMS: phase III
double-​blind RCT
Phase III double-​blind RCT
FREEDOMS: phase III
double-​blind RCT
TRANSFORMS: phase III
double-blind, active-
comparator RCT
TEMSO: phase III
double-​blind RCT
TOPIC: phase III
double-​blind RCT
TOWER: phase III
double-​blind RCT
CONFIRM: phase III double-​
blind, active-​comparator RCT
DEFINE: phase III
double-​blind RCT
CAMMS223: phase II double-​
blind, active-​comparator RCT
CARE-​MS I: phase III double-​
blind, active-​comparator RCT
338 | JUNE 2019 | volume 15 www.nature.com/nrneurol
Primary outcome
Difference in relapse rate
Number of relapses during the study
Time to sustained disability progression
(≥1.0 point on EDSS)
• Difference in relapse rate
• Proportion of relapse-​free patients
Composite of five clinical measures: change
in EDSS score at 24 months; change in
ambulation index at 24 months; number of
relapses treated with corticosteroids; time
to first treated relapse; and change from
baseline in neurological status at 24 months
• Rate of clinical relapse at 1 year
• Rate of sustained EDSS progression
at 2 years
Difference in annualized relapse rate
Annualized relapse rate
Annualized relapse rate
Time to relapse (conversion to clinically
definite MS)
Annualized relapse rate
Annualized relapse rate over 2 years
Proportion of patients who had relapsed
by 2 years
• Efficacy (time to sustained accumulation
of disability)
• Relapse rate
• Relapse rate
• Time to 6-month sustained disability
accumulation
Participants Upper Refs
age limit
• 251 patients with RRMS 45 years 133
• 125 assigned to glatiramer acetate
• 126 assigned to placebo
• 502 patients with RRMSa 50 years 139
• 167 received 22 µg IFNβ1a
• 165 received 44 µg IFNβ1a
• 170 received placebo
• 301 patients with RRMS 55 years 138
• 158 assigned to IFNβ1a
• 143 assigned to placebo
• 372 ambulatory patients with RRMS 50 years 134
• 125 assigned to 1.6 MIU IFNβ1b
• 124 assigned to 8.0 MIU IFNβ1b
• 123 assigned to placebo
• 188 patients with worsening RRMS or SPMSa 55 years 192
• 64 received 5 mg/m2 mitoxantrone
• 60 received 12 mg/m2 mitoxantrone
• 64 received placebo
• 942 patients with RRMS 50 years 135
• 627 assigned to natalizumab
• 315 assigned to placebo
• 1,272 patients with RRMS 55 years 142
• 429 assigned to 1.25 mg fingolimod
• 425 assigned to 0.50 mg fingolimod
• 418 assigned to placebo
• 1,153 patients with RRMSa 55 years 143
• 369 received 1.25 mg fingolimod
• 398 received 0.50 mg fingolimod
• 386 received IFNβ1a
• 1,088 patients with RRMS 55 years 144
• 365 assigned to 7 mg teriflunomide
• 358 assigned to 14 mg teriflunomide
• 363 assigned to placebo
• 614 patients with CIS 55 years 145
• 203 assigned to oral 7 mg teriflunomide
• 214 assigned to oral 14 mg teriflunomide
• 197 assigned to placebo
• 1,165 patients with RRMSa 55 years 193
• 407 received 7 mg teriflunomide
• 370 received 14 mg teriflunomide
• 388 received placebo
• 1,417 patients with RRMS 55 years 141
• 359 assigned to twice daily dimethyl fumarate
• 345 assigned to thrice daily dimethyl fumarate
• 350 assigned to glatiramer acetate
• 363 assigned to placebo
• 1,234 patients with RRMS 55 years 140
• 410 assigned to twice daily dimethyl fumarate
• 416 assigned to thrice daily dimethyl fumarate
• 408 assigned to placebo
• 334 patients with RRMS 50 years 136
• 110 assigned to 24 mg alemtuzumab daily
• 113 assigned to 12 mg alemtuzumab daily
• 111 assigned to subcutaneous IFNβ1a three
times weekly
• 563 patients with RRMS 50 years 137
• 376 assigned to alemtuzumab
• 187 assigned to IFNβ1a
 Reviews

Table 1 (cont.) | Pivotal clinical trials of disease-modifying therapies for MS

Name and design Primary outcome Participants Upper Refs
age limit
OPERA I and OPERA II: two Annualized relapse rate • OPERA I: 821 patients with RRMS 55 years 194

identical phase III double-​ • OPERA II: 835 patients with RRMS
blind, active-​comparator RCTs • 600 mg ocrelizumab every 24 weeks versus
44 μg IFNβ1a three times weekly
ORATORIO: phase III, Percentage of patients with disability • 732 patients with PPMS 55 years 155

double-​blind RCT progression at 12 weeks • 488 assigned to ocrelizumab

• 244 assigned to placebo
CONSONANCEb: open-​label • Proportion of participants without • 600 patients with progressive MSc 65 years 146

efficacy and safety study evidence of progression • All patients assigned to 600 mg ocrelizumab
• Proportion of participants without every 24 weeks
evidence of progression for ≥24 weeks
and no active disease
Numbers of patients refer to the intention to treat (randomized) population, except where noted. CIS, clinically isolated syndrome; EDSS, Expanded Disability
Status Scale; MIU, million international units; MS, multiple sclerosis; PPMS, primary progressive MS; RCT, randomized controlled trial; RRMS, relapsing–remitting
MS; SPMS, secondary progressive MS. aPer-​protocol population. bCurrently enrolling patients. cIncludes both SPMS and PPMS.

lifestyle behaviours are an important complement to
therapy in this population and can have a strong effect
on quality of life as patients with MS age.
Cognition. Cognitive decline is a particular concern
in ageing patients with MS as it can be a consequence
of both the disease and the normal ageing process.
Cognitive impairment eventually develops in as many
as 65% of patients with MS181. Furthermore, cognitive
decline can become apparent early in the disease pro-
cess, potentially even before conversion from CIS to
RRMS181. Interestingly, the rate of cognitive decline in
patients with MS does not accelerate with ageing182,183;
in fact, studies of cognitive decline in patients with MS
show that, after controlling for age, the frequency of
MS-​associated cognitive impairment stays roughly the
same throughout life183. The trial investigators suggested
that rapid cognitive decline in ageing patients with MS
should prompt an evaluation for comorbid neurologi-
cal disease183. Good evidence suggests that cognitive
reserve moderates the rate of cognitive decline in MS,
as it does in AD184,185. Cognitive training has shown
success in improving cognitive functioning, including
motor tasks186, working memory187 and quality of life188,
in patients with MS and should be encouraged for ageing
individuals with cognitive impairment.
Conclusions
The data consistently show that patients with MS are
living longer. However, ageing in this population comes
with a multitude of concerns relating to the complex
interactions of the disease process with normal age-
ing, comorbidities and therapy (disease-​modifying
regimens and symptomatic treatments or therapies for
comorbidities). In addition, ageing patients with MS
differ from their younger counterparts in that they have
more neurodegeneration and less-​effective neuronal
repair processes. The specific pathobiology underlying
the weakening of repair processes in ageing patients
with MS is not well understood, but the reduced effi-
cacy of disease-​modifying treatment in this population
clearly indicates that prevention of neurodegeneration
and the accumulation of disability are of critical impor-
tance. To that end, well-​designed studies are needed to
understand the functioning of these repair processes
specifically in ageing individuals and to evaluate the
efficacy and safety of treatments with neuroprotective
and repair-​based mechanisms (including remyelination)
in elderly patients with MS. For those with stable dis-
ease on existing disease-​modifying therapy regimens,
the timing and appropriateness of discontinuing this
therapy must also be specifically evaluated.
Future studies are also needed to address the comor-
bidities that affect elderly patients with MS. Studies that
evaluated symptomatic therapies for improving cogni-
tion in elderly patients with MS have largely reported
negative results. For example, donepezil (a centrally
acting reversible acetylcholinesterase inhibitor used
to treat cognitive dysfunction in patients with AD)
was not effective in patients with MS189. Similarly, the
N-​methyl-d-​aspartate receptor inhibitor memantine
(which modestly improves cognition in patients with
AD) did not improve cognitive function in patients
with MS and had a particularly concerning safety pro-
file in this population190,191. Separately from medications,
an emphasis should also be placed on promoting well-
ness and improving quality of life for patients with MS,
including social support and cognitive training.
Published online 18 April 2019

1. Marrie, R. A., Yu, N., Blanchard, J., Leung, S. &
Elliott, L. The rising prevalence and changing age
distribution of multiple sclerosis in Manitoba.
Neurology 74, 465–471 (2010).
2. Finlayson, M. Concerns about the future among older
adults with multiple sclerosis. Am. J. Occup. Ther. 58,
54–63 (2004).
3. Tutuncu, M. et al. Onset of progressive phase is an
age-​dependent clinical milestone in multiple sclerosis.
Mult. Scler. 19, 188–198 (2013).
4. Scalfari, A., Neuhaus, A., Daumer, M., Muraro, P. A. &
Ebers, G. C. Onset of secondary progressive phase and
long-​term evolution of multiple sclerosis. J. Neurol.
Neurosurg. Psychiatry 85, 67–75 (2014).
5. Koch-​Henriksen, N., Laursen, B., Stenager, E. &
Magyari, M. Excess mortality among patients with
multiple sclerosis in Denmark has dropped
significantly over the past six decades: a population
based study. J. Neurol. Neurosurg. Psychiatry 88,
626–631 (2017).
6. Hirst, C., Swingler, R., Compston, D. A., Ben-​Shlomo, Y.
& Robertson, N. P. Survival and cause of death in
multiple sclerosis: a prospective population-​based
study. J. Neurol. Neurosurg. Psychiatry 79,
1016–1021 (2008).
7. Hurwitz, B. J. Analysis of current multiple sclerosis
registries. Neurology 76 (Suppl. 1), S7–S13 (2011).
8. Lunde, H. M. B., Assmus, J., Myhr, K. M., Bo, L. &
Grytten, N. Survival and cause of death in multiple
sclerosis: a 60-year longitudinal population study.

NATure ReviewS | NeURology volume 15 | JUNE 2019 | 339

Reviews
J. Neurol. Neurosurg. Psychiatry 88, 621–625
(2017).
9. Kingwell, E. et al. Relative mortality and survival in
multiple sclerosis: findings from British Columbia.
J. Neurol. Neurosurg. Psychiatry 83, 61–66 (2012).
10. Minden, S. L., Frankel, D., Hadden, L. S., Srinath, K. P.
& Perloff, J. N. Disability in elderly people with
multiple sclerosis: an analysis of baseline data from
the Sonya Slifka Longitudinal Multiple Sclerosis Study.
Neurorehabilitation 19, 55–67 (2004).
11. Rotstein, D. L. et al. Temporal trends in multiple
sclerosis prevalence and incidence in a large
population. Neurology 90, e1435–e1441 (2018).
12. Grytten, N., Torkildsen, O. & Myhr, K. M. Time trends
in the incidence and prevalence of multiple sclerosis in
Norway during eight decades. Acta Neurol. Scand.
132, 29–36 (2015).
13. Alla, S., Pearson, J., Debernard, L., Miller, D. &
Mason, D. The increasing prevalence of multiple
sclerosis in New Zealand. Neuroepidemiology 42,
154–160 (2014).
14. Dilokthornsakul, P. et al. Multiple sclerosis prevalence
in the United States commercially insured population.
Neurology 86, 1014–1021 (2016).
15. Solaro, C. et al. The changing face of multiple
sclerosis: prevalence and incidence in an aging
population. Mult. Scler. 21, 1244–1250 (2015).
16. Barnett, M. H., Williams, D. B., Day, S., Macaskill, P.
& McLeod, J. G. Progressive increase in incidence
and prevalence of multiple sclerosis in Newcastle,
Australia: a 35-year study. J. Neurol. Sci. 213,
(1–6 (2003).
17. Simpson, S. Jr. et al. Trends in the epidemiology of
multiple sclerosis in Greater Hobart, Tasmania:
1951 to 2009. J. Neurol. Neurosurg. Psychiatry 82,
180–187 (2011).
18. Sarasoja, T., Wikstrom, J., Paltamaa, J., Hakama, M.
& Sumelahti, M. L. Occurrence of multiple sclerosis in
central Finland: a regional and temporal comparison
during 30 years. Acta Neurol. Scand. 110, 331–336
(2004).
19. Mayr, W. T. et al. Incidence and prevalence of multiple
sclerosis in Olmsted County, Minnesota, 1985–2000.
Neurology 61, 1373–1377 (2003).
20. 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. 9, 871 (2018).
21. Grassivaro, F. et al. Multiple sclerosis incidence and
prevalence trends in the province of Padua, northeast
Italy, 1965–2018. Neuroepidemiology 52, 41–46
(2018).
22. Ribbons, K., Lea, R., Tiedeman, C., Mackenzie, L. &
Lechner-​Scott, J. Ongoing increase in incidence and
prevalence of multiple sclerosis in Newcastle,
Australia: a 50-year study. Mult. Scler. 23,
(1063–1071 (2017).
23. Koch-​Henriksen, N. & Sorensen, P. S.
The changing demographic pattern of multiple
sclerosis epidemiology. Lancet Neurol. 9, 520–532
(2010).
24. Bermel, R. A., Rae-​Grant, A. D. & Fox, R. J. Diagnosing
multiple sclerosis at a later age: more than just
progressive myelopathy. Mult. Scler. 16, 1335–1340
(2010).
25. Poser, C. M. & Brinar, V. V. Diagnostic criteria for
multiple sclerosis: an historical review. Clin. Neurol.
Neurosurg. 106, 147–158 (2004).
26. Gafson, A., Giovannoni, G. & Hawkes, C. H.
The diagnostic criteria for multiple sclerosis: from
Charcot to McDonald. Mult. Scler. Relat. Disord. 1,
9–14 (2012).
27. Polliack, M. L., Barak, Y. & Achiron, A. Late-​onset
multiple sclerosis. J. Am. Geriatr. Soc. 49, 168–171
(2001).
28. Delalande, S., De Seze, J., Ferriby, D., Stojkovic, T. &
Vermersch, P. Late onset multiple sclerosis [French].
Rev. Neurol. (Paris) 158, 1082–1087 (2002).
29. Tremlett, H. & Devonshire, V. Is late-​onset multiple
sclerosis associated with a worse outcome? Neurology
67, 954–959 (2006).
30. Hooge, J. P. & Redekop, W. K. Multiple sclerosis with
very late onset. Neurology 42, 1907–1910 (1992).
31. Koch-​Henriksen, N., Thygesen, L. C., Stenager, E.,
Laursen, B. & Magyari, M. Incidence of MS has
increased markedly over six decades in Denmark
particularly with late onset and in women. Neurology
90, e1954–e1963 (2018).
32. Marrie, R. A. et al. A systematic review of the
incidence and prevalence of comorbidity in multiple
sclerosis: overview. Mult. Scler. 21, 263–281 (2015).
340 | JUNE 2019 | volume 15 www.nature.com/nrneurol
33. Capkun, G. et al. Mortality and comorbidities in
patients with multiple sclerosis compared with a
population without multiple sclerosis: an observational
study using the US Department of Defense
administrative claims database. Mult. Scler. Relat.
Disord. 4, 546–554 (2015).
34. Marrie, R. A. et al. Comorbidity delays diagnosis and
increases disability at diagnosis in MS. Neurology 72,
117–124 (2009).
35. Manouchehrinia, A., Tanasescu, R., Tench, C. R. &
Constantinescu, C. S. Mortality in multiple sclerosis:
meta-​analysis of standardised mortality ratios.
J. Neurol. Neurosurg. Psychiatry 87, 324–331
(2016).
36. Scalfari, A. et al. Mortality in patients with multiple
sclerosis. Neurology 81, 184–192 (2013).
37. Kaufman, D. W. et al. Survival in commercially insured
multiple sclerosis patients and comparator subjects in
the U.S. Mult. Scler. Relat. Disord. 3, 364–371
(2014).
38. Bronnum-​Hansen, H., Koch-​Henriksen, N. &
Stenager, E. Trends in survival and cause of death in
Danish patients with multiple sclerosis. Brain 127,
844–850 (2004).
39. Ragonese, P., Aridon, P., Salemi, G., D’Amelio, M. &
Savettieri, G. Mortality in multiple sclerosis: a review.
Eur. J. Neurol. 15, 123–127 (2008).
40. Warren, S. A., Janzen, W., Warren, K. G., Svenson, L. W.
& Schopflocher, D. P. Multiple sclerosis mortality rates
in Canada, 1975–2009. Can. J. Neurol. Sci. 43,
134–141 (2016).
41. Amezcua, L., Rivas, E., Joseph, S., Zhang, J. & Liu, L.
Multiple sclerosis mortality by race/ethnicity, age, sex,
and time period in the United States, 1999–2015.
Neuroepidemiology 50, 35–40 (2018).
42. Hemmer, B., Kerschensteiner, M. & Korn, T. Role of the
innate and adaptive immune responses in the course
of multiple sclerosis. Lancet Neurol. 14, 406–419
(2015).
43. Weissert, R. The immune pathogenesis of multiple
sclerosis. J. Neuroimmune Pharmacol. 8, 857–866
(2013).
44. Garg, N. & Smith, T. W. An update on
immunopathogenesis, diagnosis, and treatment of
multiple sclerosis. Brain Behav. 5, e00362 (2015).
45. Fletcher, J. M., Lalor, S. J., Sweeney, C. M., Tubridy, N.
& Mills, K. H. G. T cells in multiple sclerosis and
experimental autoimmune encephalomyelitis.
Clin. Exp. Immunol. 162, 1–11 (2010).
46. ‘t Hart, B. A. et al. A B cell-​driven autoimmune
pathway leading to pathological hallmarks of
progressive multiple sclerosis in the marmoset
experimental autoimmune encephalomyelitis model.
Front. Immunol. 8, 804 (2017).
47. Reich, D. S., Lucchinetti, C. F. & Calabresi, P. A.
Multiple sclerosis. N. Engl. J. Med. 378, 169–180
(2018).
48. Gandhi, R., Laroni, A. & Weiner, H. L. Role of the
innate immune system in the pathogenesis of multiple
sclerosis. J. Neuroimmunol. 221, 7–14 (2010).
49. Kasper, L. H. & Shoemaker, J. Multiple sclerosis
immunology: the healthy immune system versus the
MS immune system. Neurology 74 (Suppl. 1), S2–S8
(2010).
50. Frischer, J. M. et al. The relation between
inflammation and neurodegeneration in multiple
sclerosis brains. Brain 132, 1175–1189 (2009).
51. Frischer, J. M. et al. Clinical and pathological insights
into the dynamic nature of the white matter multiple
sclerosis plaque. Ann. Neurol. 78, 710–721 (2015).
52. Lassmann, H., van Horssen, J. & Mahad, D.
Progressive multiple sclerosis: pathology and
pathogenesis. Nat. Rev. Neurol. 8, 647–656 (2012).
53. Stephenson, E., Nathoo, N., Mahjoub, Y., Dunn, J. F.
& Yong, V. W. Iron in multiple sclerosis: roles in
neurodegeneration and repair. Nat. Rev. Neurol. 10,
459–468 (2014).
54. Grebenciucova, E. & Berger, J. R. Immunosenescence:
the role of aging in the predisposition to neuro-​
infectious complications arising from the treatment of
multiple sclerosis. Curr. Neurol. Neurosci. Rep. 17, 61
(2017).
55. Lassmann, H. Pathology and disease mechanisms in
different stages of multiple sclerosis. J. Neurol. Sci.
333, 1–4 (2013).
56. Sanai, S. A. et al. Aging and multiple sclerosis.
Mult. Scler. 22, 717–725 (2016).
57. Plaza-​Zabala, A., Sierra-​Torre, V. & Sierra, A. Autophagy
and microglia: novel partners in neurodegeneration and
aging. Int. J. Mol. Sci. 18, E598 (2017).
58. Aguilera, M. O., Delgui, L. R., Romano, P. S. &
Colombo, M. I. Chronic infections: a possible scenario
for autophagy and senescence cross-​talk. Cells 7,
E162 (2018).
59. Alirezaei, M. et al. Elevated ATG5 expression in
autoimmune demyelination and multiple sclerosis.
Autophagy 5, 152–158 (2009).
60. Peterson, J. W. & Trapp, B. D. Neuropathobiology
of multiple sclerosis. Neurol. Clin. 23, 107–129
(2005).
61. Dutta, R. & Trapp, B. D. Relapsing and progressive
forms of multiple sclerosis: insights from pathology.
Curr. Opin. Neurol. 27, 271–278 (2014).
62. Cevenini, E., Monti, D. & Franceschi, C. Inflamm-​
ageing. Curr. Opin. Clin. Nutr. Metab. Care 16, 14–20
(2013).
63. Franceschi, C. et al. Inflamm-​aging. An evolutionary
perspective on immunosenescence. Ann. NY Acad. Sci.
908, 244–254 (2000).
64. Thewissen, M. et al. Analyses of immunosenescent
markers in patients with autoimmune disease.
Clin. Immunol. 123, 209–218 (2007).
65. Childs, B. G. et al. Senescent cells: an emerging target
for diseases of ageing. Nat. Rev. Drug Discov. 16,
718–735 (2017).
66. Aw, D. & Palmer, D. B. The origin and implication of
thymic involution. Aging Dis. 2, 437–443 (2011).
67. Haegert, D. G. Multiple sclerosis: a disorder of altered
T cell homeostasis. Mult. Scler. Int. 2011, 461304
(2011).
68. Musella, A. et al. Interplay between age and
neuroinflammation in multiple sclerosis: effects on
motor and cognitive functions. Front. Aging Neurosci.
10, 238 (2018).
69. Budni, J., Bellettini-​Santos, T., Mina, F., Garcez, M. L.
& Zugno, A. I. The involvement of BDNF, NGF and
GDNF in aging and Alzheimer’s disease. Aging Dis. 6,
331–341 (2015).
70. Rist, J. M. & Franklin, R. J. Taking ageing into account
in remyelination-​based therapies for multiple sclerosis.
J. Neurol. Sci. 274, 64–67 (2008).
71. Luchetti, S. et al. Progressive multiple sclerosis
patients show substantial lesion activity that
correlates with clinical disease severity and sex:
a retrospective autopsy cohort analysis. Acta
Neuropathol. 135, 511–528 (2018).
72. Correale, J., Gaitan, M. I., Ysrraelit, M. C. & Fiol, M. P.
Progressive multiple sclerosis: from pathogenic
mechanisms to treatment. Brain 140, 527–546
(2017).
73. Buck, D. & Hemmer, B. Treatment of multiple
sclerosis: current concepts and future perspectives.
J. Neurol. 258, 1747–1762 (2011).
74. Thompson, A. J. et al. Diagnosis of multiple sclerosis:
2017 revisions of the McDonald criteria. Lancet
Neurol. 17, 162–173 (2018).
75. Hammond, K. E. et al. Quantitative in vivo magnetic
resonance imaging of multiple sclerosis at 7 Tesla
with sensitivity to iron. Ann. Neurol 64, 707–713
(2008).
76. Bagnato, F. et al. Tracking iron in multiple sclerosis:
a combined imaging and histopathological study at 7
Tesla. Brain 134, 3602–3615 (2011).
77. Absinta, M. et al. Identification of chronic active
multiple sclerosis lesions on 3 T MRI. AJNR Am.
J. Neuroradiol. 39, 1233–1238 (2018).
78. Vellinga, M. M. et al. Pluriformity of inflammation
in multiple sclerosis shown by ultra-​small iron
oxide particle enhancement. Brain 131, 800–807
(2008).
79. Dwyer, M. G. et al. Atrophied brain lesion volume:
a new imaging biomarker in multiple sclerosis.
J. Neuroimaging 28, 490–495 (2018).
80. Calabrese, M. et al. Cortical lesion load associates
with progression of disability in multiple sclerosis.
Brain 135, 2952–2961 (2012).
81. Calabrese, M. et al. Exploring the origins of grey
matter damage in multiple sclerosis. Nat. Rev.
Neurosci. 16, 147–158 (2015).
82. Filippi, M. et al. Imaging cortical damage and
dysfunction in multiple sclerosis. JAMA Neurol. 70,
556–564 (2013).
83. Absinta, M., Sati, P. & Reich, D. S. Advanced MRI and
staging of multiple sclerosis lesions. Nat. Rev. Neurol.
12, 358–368 (2016).
84. Zurawski, J., Lassmann, H. & Bakshi, R. Use of
magnetic resonance imaging to visualize
leptomeningeal inflammation in patients with multiple
sclerosis: a review. JAMA Neurol. 74, 100–109 (2016).
85. Zivadinov, R. et al. Leptomeningeal contrast
enhancement is associated with progression of cortical
atrophy in MS: a retrospective, pilot, observational
longitudinal study. Mult. Scler. 23, 1336–1345
(2016).

86. Harrison, D. M. et al. Leptomeningeal enhancement at
7 T in multiple sclerosis: frequency, morphology, and
relationship to cortical volume. J. Neuroimaging 27,
461–468 (2017).
87. Miller, D. H., Barkhof, F., Frank, J. A., Parker, G. J. &
Thompson, A. J. Measurement of atrophy in multiple
sclerosis: pathological basis, methodological aspects
and clinical relevance. Brain 125, 1676–1695
(2002).
88. Zivadinov, R. et al. Clinical relevance of brain atrophy
assessment in multiple sclerosis. Implications for its
use in a clinical routine. Expert Rev. Neurother. 16,
777–793 (2016).
89. De Stefano, N. et al. Establishing pathological cut-​offs
of brain atrophy rates in multiple sclerosis. J. Neurol.
Neurosurg. Psychiatry 87, 93–99 (2016).
90. Hedman, A. M., van Haren, N. E., Schnack, H. G.,
Kahn, R. S. & Hulshoff Pol, H. E. Human brain changes
across the life span: a review of 56 longitudinal
magnetic resonance imaging studies. Hum. Brain
Mapp. 33, 1987–2002 (2012).
91. Fisher, E., Lee, J. C., Nakamura, K. & Rudick, R. A.
Gray matter atrophy in multiple sclerosis: a
longitudinal study. Ann. Neurol. 64, 255–265
(2008).
92. Fisniku, L. K. et al. Gray matter atrophy is related to
long-​term disability in multiple sclerosis. Ann. Neurol.
64, 247–254 (2008).
93. Steenwijk, M. D. et al. Cortical atrophy patterns in
multiple sclerosis are non-​random and clinically
relevant. Brain 139, 115–126 (2016).
94. Eshaghi, A. et al. Progression of regional grey matter
atrophy in multiple sclerosis. Brain 141, 1665–1677
(2018).
95. Stankoff, B. & Louapre, C. Can we use regional grey
matter atrophy sequence to stage neurodegeneration
in multiple sclerosis? Brain 141, 1580–1583 (2018).
96. Cristofanilli, M. et al. Progressive multiple sclerosis
cerebrospinal fluid induces inflammatory
demyelination, axonal loss, and astrogliosis in mice.
Exp. Neurol. 261, 620–632 (2014).
97. Vidaurre, O. G. et al. Cerebrospinal fluid ceramides
from patients with multiple sclerosis impair neuronal
bioenergetics. Brain 137, 2271–2286 (2014).
98. Haider, L. et al. The topograpy of demyelination and
neurodegeneration in the multiple sclerosis brain.
Brain 139, 807–815 (2016).
99. Eshaghi, A. et al. Deep grey matter volume loss drives
disability worsening in multiple sclerosis. Ann. Neurol.
83, 210–222 (2018).
100. Azevedo, C. J. et al. Thalamic atrophy in MS: an MRI
marker of neurodegeneration throughout disease.
Ann. Neurol. 83, 223–234 (2018).
101. Cocozza, S. et al. Cerebellar lobule atrophy and
disability in progressive MS. J. Neurol. Neurosurg.
Psychiatry 88, 1065–1072 (2017).
102. Moroso, A. et al. Posterior lobules of the cerebellum
and information processing speed at various stages of
multiple sclerosis. J. Neurol. Neurosurg. Psychiatry
88, 146–151 (2016).
103. Kearney, H., Miller, D. H. & Ciccarelli, O. Spinal cord
MRI in multiple sclerosis — diagnostic, prognostic and
clinical value. Nat. Rev. Neurol. 11, 327–338 (2015).
104. Abdel-​Aziz, K. et al. Evidence for early
neurodegeneration in the cervical cord of patients with
primary progressive multiple sclerosis. Brain 138,
1568–1582 (2015).
105. Tsagkas, C. et al. Preferential spinal cord volume loss
in primary progressive multiple sclerosis. Mult. Scler.
https://doi.org/10.1177/1352458518775006
(2018).
106. Schlaeger, R. et al. Association between thoracic spinal
cord gray matter atrophy and disability in multiple
sclerosis. JAMA Neurol. 72, 897–904 (2015).
107. Tsagkas, C. et al. Spinal cord volume loss: a marker of
disease progression in multiple sclerosis. Neurology
91, e349–e358 (2018).
108. Zeydan, B. et al. Cervical spinal cord atrophy: an early
marker of progressive MS onset. Neurol. Neuroimmunol.
Neuroinflamm. 5, e435 (2018).
109. Murtonen, A., Kurki, S., Hanninen, K.,
Soilu-​Hanninen, M. & Sumelahti, M. L. Common
comorbidities and survival in MS: risk for stroke, type 1
diabetes and infections. Mult. Scler. Relat. Disord. 19,
109–114 (2018).
110. Tettey, P., Simpson, S. Jr., Taylor, B. V. &
van der Mei, I. A. Vascular comorbidities in the onset
and progression of multiple sclerosis. J. Neurol. Sci.
347, 23–33 (2014).
111. Hussein, W. I. & Reddy, S. S. Prevalence of diabetes in
patients with multiple sclerosis. Diabetes Care 29,
1984–1985 (2006).
NATure ReviewS | NeURology
112. Kang, J. H., Chen, Y. H. & Lin, H. C. Comorbidities
amongst patients with multiple sclerosis: a population-​
based controlled study. Eur. J. Neurol. 17,
1215–1219 (2010).
113. Marrie, R. A. et al. Vascular comorbidity is associated
with more rapid disability progression in multiple
sclerosis. Neurology 74, 1041–1047 (2010).
114. Christiansen, C. F. et al. Risk of arterial cardiovascular
diseases in patients with multiple sclerosis:
a population-based cohort study. Neuroepidemiology
35, 267–274 (2010).
115. Jadidi, E., Mohammadi, M. & Moradi, T. High risk of
cardiovascular diseases after diagnosis of multiple
sclerosis. Mult. Scler. 19, 1336–1340 (2013).
116. Marrie, R. A. et al. Rising prevalence of vascular
comorbidities in multiple sclerosis: validation of
administrative definitions for diabetes, hypertension,
and hyperlipidemia. Mult. Scler. 18, 1310–1319
(2012).
117. Geraldes, R. et al. The current role of MRI in
differentiating multiple sclerosis from its imaging
mimics. Nat. Rev. Neurol. 14, 199–213 (2018).
118. Zivadinov, R. et al. Cerebral microbleeds in multiple
sclerosis evaluated on susceptibility-​weighted images
and quantitative susceptibility maps: a case-​control
study. Radiology 281, 884–895 (2016).
119. Ter Telgte, A. et al. Cerebral small vessel disease:
from a focal to a global perspective. Nat. Rev. Neurol.
14, 387–398 (2018).
120. Sati, P. et al. The central vein sign and its clinical
evaluation for the diagnosis of multiple sclerosis:
a consensus statement from the North American
Imaging in Multiple Sclerosis Cooperative. Nat. Rev.
Neurol. 12, 714–722 (2016).
121. Moon, S. Y. et al. Prospective associations between
white matter hyperintensities and lower extremity
function. Neurology 90, e1291–e1297 (2018).
122. Srinivasa, R. N. et al. Cardiovascular risk factors
associated with smaller brain volumes in regions
identified as early predictors of cognitive decline.
Radiology 278, 198–204 (2016).
123. Kappus, N. et al. Cardiovascular risk factors are
associated with increased lesion burden and brain
atrophy in multiple sclerosis. J. Neurol. Neurosurg.
Psychiatry 87, 181–187 (2016).
124. Jakimovski, D. et al. Hypertension and heart disease
are associated with development of brain atrophy in
multiple sclerosis: a 5-year longitudinal study. Eur. J.
Neurol. 26, 87 (2019).
125. Kneebone, I. I., Dunmore, E. C. & Evans, E. Symptoms
of depression in older adults with multiple sclerosis
(MS): comparison with a matched sample of younger
adults. Aging Ment. Health 7, 182–185 (2003).
126. Chwastiak, L. et al. Depressive symptoms and severity
of illness in multiple sclerosis: epidemiologic study
of a large community sample. Am. J. Psychiatry 159,
1862–1868 (2002).
127. Patten, S. B., Metz, L. M. & Reimer, M. A.
Biopsychosocial correlates of lifetime major depression
in a multiple sclerosis population. Mult. Scler. 6,
115–120 (2000).
128. Beal, C. C., Stuifbergen, A. K. & Brown, A.
Depression in multiple sclerosis: a longitudinal
analysis. Arch. Psychiatr. Nurs. 21, 181–191 (2007).
129. Roy, S. et al. Preliminary investigation of cognitive
function in aged multiple sclerosis patients: challenges
in detecting comorbid Alzheimer’s disease. Mult. Scler.
Relat. Disord. 22, 52–56 (2018).
130. U.S. Food and Drug Administration. FDA News Release:
FDA approves new oral treatment for multiple sclerosis.
FDA https://www.fda.gov/NewsEvents/Newsroom/
PressAnnouncements/ucm634837.htm (2019).
131. U.S. Food and Drug Administration. FDA News Release:
FDA approves new oral drug to treat multiple sclerosis.
FDA https://www.fda.gov/NewsEvents/Newsroom/
PressAnnouncements/ucm634469.htm (2019).
132. National Multiple Sclerosis Society. Disease-​modifying
therapies for MS. NationalMSSociety https://www.
nationalmssociety.org/NationalMSSociety/media/
MSNationalFiles/Brochures/Brochure-​MS-Disease-​
Modifying-Medications.pdf (2018).
133. Johnson, K. P. et al. Copolymer 1 reduces relapse rate
and improves disability in relapsing-​remitting multiple
sclerosis: results of a phase III multicenter, double-​
blind placebo-​controlled trial. The Copolymer 1
Multiple Sclerosis Study Group. Neurology 45,
1268–1276 (1995).
134. IFNβ Multiple Sclerosis Study Group. Interferon beta-​
lb is effective in relapsing-​remitting multiple sclerosis.
I. Clinical results of a multicenter, randomized, double-​
blind, placebo-​controlled trial. 1993 [classical article].
Neurology 57 (Suppl. 5), S3–S9 (2001).
Reviews
135. Polman, C. H. et al. A randomized, placebo-​controlled
trial of natalizumab for relapsing multiple sclerosis.
N. Engl. J. Med. 354, 899–910 (2006).
136. CAMMS223 Trial Investigators et al. Alemtuzumab
versus interferon beta-1a in early multiple sclerosis.
N. Engl. J. Med. 359, 1786–1801 (2008).
137. Cohen, J. A. et al. Alemtuzumab versus interferon
beta 1a as first-​line treatment for patients with
relapsing-​remitting multiple sclerosis: a randomised
controlled phase 3 trial. Lancet 380, 1819–1828
(2012).
138. Jacobs, L. D. et al. Intramuscular interferon beta-1a
for disease progression in relapsing multiple sclerosis.
The Multiple Sclerosis Collaborative Research Group
(MSCRG). Ann. Neurol. 39, 285–294 (1996).
139. PRISMS (Prevention of Relapses and Disability by
Interferon β-1a Subcutaneously in Multiple Sclerosis)
Study Group. Randomised double-​blind placebo-​
controlled study of interferon β-1a in relapsing/
remitting multiple sclerosis. Lancet 352, 1498–1504
(1998).
140. Gold, R. et al. Placebo-​controlled phase 3 study of oral
BG-12 for relapsing multiple sclerosis. N. Engl. J. Med.
367, 1098–1107 (2012).
141. Fox, R. J. et al. Placebo-​controlled phase 3 study of
oral BG-12 or glatiramer in multiple sclerosis. N. Engl.
J. Med. 367, 1087–1097 (2012).
142. Kappos, L. et al. A placebo-​controlled trial of oral
fingolimod in relapsing multiple sclerosis. N. Engl. J.
Med. 362, 387–401 (2010).
143. Cohen, J. A. et al. Oral fingolimod or intramuscular
interferon for relapsing multiple sclerosis. N. Engl. J.
Med. 362, 402–415 (2010).
144. O’Connor, P. et al. Randomized trial of oral
teriflunomide for relapsing multiple sclerosis. N. Engl.
J. Med. 365, 1293–1303 (2011).
145. Miller, A. E. et al. Oral teriflunomide for patients with
a first clinical episode suggestive of multiple sclerosis
(TOPIC): a randomised, double-​blind, placebo-​
controlled, phase 3 trial. Lancet Neurol. 13, 977–986
(2014).
146. US National Library of Medicine. ClinicalTrials.gov
https://clinicaltrials.gov/ct2/show/NCT03523858
(2019).
147. Kappos, L. et al. Siponimod versus placebo in
secondary progressive multiple sclerosis (EXPAND):
a double-​blind, randomised, phase 3 study. Lancet
391, 1263–1273 (2018).
148. Zhang, T. et al. Examining the effects of comorbidities
on disease-​modifying therapy use in multiple sclerosis.
Neurology 86, 1287–1295 (2016).
149. Devonshire, V. et al. Relapse and disability outcomes
in patients with multiple sclerosis treated with
fingolimod: subgroup analyses of the double-​blind,
randomised, placebo-​controlled FREEDOMS study.
Lancet Neurol. 11, 420–428 (2012).
150. Motl, R. W. et al. Validity of the timed 25-foot walk as
an ambulatory performance outcome measure for
multiple sclerosis. Mult. Scler. 23, 704–710 (2017).
151. Hervault, M., Balto, J. M., Hubbard, E. A. & Motl, R. W.
Reliability, precision, and clinically important change
of the Nine-​Hole Peg Test in individuals with multiple
sclerosis. Int. J. Rehabil. Res. 40, 91–93 (2017).
152. Kapoor, R. et al. Effect of natalizumab on disease
progression in secondary progressive multiple
sclerosis (ASCEND): a phase 3, randomised,
double-​blind, placebo-​controlled trial with an
open-​label extension. Lancet Neurol. 17, 405–415
(2018).
153. Shirani, A. et al. Multiple sclerosis in older adults:
the clinical profile and impact of interferon beta
treatment. Biomed. Res. Int. 2015, 451912 (2015).
154. Giovannoni, G. et al. Is multiple sclerosis a length-​
dependent central axonopathy? The case for
therapeutic lag and the asynchronous progressive MS
hypotheses. Mult. Scler. Relat. Disord. 12, 70–78
(2017).
155. Montalban, X. et al. Ocrelizumab versus placebo in
primary progressive multiple sclerosis. N. Engl. J.
Med. 376, 209–220 (2017).
156. Paz Soldan, M. M. et al. Relapses and disability
accumulation in progressive multiple sclerosis.
Neurology 84, 81–88 (2015).
157. Wolinsky, J. S. et al. Evaluation of no evidence of
progression or active disease (NEPAD) in patients
with primary progressive multiple sclerosis in the
ORATORIO trial. Ann. Neurol. 84, 527–536 (2018).
158. Fox, E. J. 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. 24,
1862–1870 (2018).
volume 15 | JUNE 2019 | 341
Reviews
159. Manouchehrinia, A. et al. Age related multiple
sclerosis severity score: disability ranked by age.
Mult. Scler. 23, 1938–1946 (2017).
160. Kister, I. Disease-​modifying therapies can be safely
discontinued in an individual with stable relapsing-​
remitting MS — YES. Mult. Scler. 23, 1188–1190
(2017).
161. Tobin, W. O. & Weinshenker, B. G. Disease-​modifying
therapies can be safely discontinued in an individual
with stable relapsing-​remitting MS — NO. Mult. Scler.
23, 1190–1192 (2017).
162. Tremlett, H., Zhao, Y., Joseph, J. & Devonshire, V.
Relapses in multiple sclerosis are age- and time-​
dependent. J. Neurol. Neurosurg. Psychiatry 79,
1368–1374 (2008).
163. Hua, L. H., Fan, T. H., Conway, D., Thompson, N. &
Kinzy, T. G. Discontinuation of disease-modifying
therapy in patients with multiple sclerosis over
age 60. Mult. Scler. https://doi.org/10.1177/
1352458518765656 (2018).
164. Kister, I. et al. Discontinuing disease-​modifying
therapy in MS after a prolonged relapse-​free period:
a propensity score-​matched study. J. Neurol.
Neurosurg. Psychiatry 87, 1133–1137 (2016).
165. Weideman, A. M., Tapia-​Maltos, M. A., Johnson, K.,
Greenwood, M. & Bielekova, B. Meta-​analysis of the
age-​dependent efficacy of multiple sclerosis
treatments. Front. Neurol. 8, 577 (2017).
166. Sormani, M. P. et al. Autologous hematopoietic stem
cell transplantation in multiple sclerosis: a meta-​
analysis. Neurology 88, 2115–2122 (2017).
167. Muraro, P. A. et al. Autologous haematopoietic stem
cell transplantation for treatment of multiple sclerosis.
Nat. Rev. Neurol. 13, 391–405 (2017).
168. Muraro, P. A. et al. Long-​term outcomes after
autologous hematopoietic stem cell transplantation
for multiple sclerosis. JAMA Neurol. 74, 459–469
(2017).
169. US National Library of Medicine. ClinicalTrials.gov
https://clinicaltrials.gov/ct2/show/NCT03073603
(2019).
170. Moss, B. P., Rensel, M. R. & Hersh, C. M. Wellness and
the role of comorbidities in multiple sclerosis.
Neurotherapeutics 14, 999–1017 (2017).
171. Ramanujam, R. et al. Effect of smoking cessation on
multiple sclerosis prognosis. JAMA Neurol. 72,
1117–1123 (2015).
172. D’Hooghe, M. B., Haentjens, P., Nagels, G. &
De Keyser, J. Alcohol, coffee, fish, smoking and disease
progression in multiple sclerosis. Eur. J. Neurol. 19,
616–624 (2012).
173. Manouchehrinia, A. et al. Tobacco smoking and
disability progression in multiple sclerosis: United
Kingdom cohort study. Brain 136, 2298–2304 (2013).
174. Sandroff, B. M., Motl, R. W., Scudder, M. R. &
DeLuca, J. Systematic, evidence-​based review of
exercise, physical activity, and physical fitness effects
on cognition in persons with multiple sclerosis.
Neuropsychol. Rev. 26, 271–294 (2016).
175. Sandroff, B. M., Johnson, C. L. & Motl, R. W.
Exercise training effects on memory and hippocampal
342 | JUNE 2019 | volume 15 www.nature.com/nrneurol
viscoelasticity in multiple sclerosis: a novel application
of magnetic resonance elastography. Neuroradiology
59, 61–67 (2017).
176. US National Library of Medicine. ClinicalTrials.gov
https://clinicaltrials.gov/ct2/show/NCT02282878
(2017).
177. US National Library of Medicine. ClinicalTrials.gov
https://clinicaltrials.gov/ct2/show/NCT03718247
(2018).
178. US National Library of Medicine. ClinicalTrials.gov
https://clinicaltrials.gov/ct2/show/NCT03808545
(2019).
179. Ploughman, M. et al. Factors influencing healthy aging
with multiple sclerosis: a qualitative study. Disabil.
Rehabil. 34, 26–33 (2012).
180. Harrison, T., Blozis, S. & Stuifbergen, A. Longitudinal
predictors of attitudes toward aging among women
with multiple sclerosis. Psychol. Aging 23, 823–832
(2008).
181. Julian, L. J. Cognitive functioning in multiple sclerosis.
Neurol. Clin. 29, 507–525 (2011).
182. Bodling, A. M., Denney, D. R. & Lynch, S. G. Cognitive
aging in patients with multiple sclerosis: a cross-​
sectional analysis of speeded processing. Arch. Clin.
Neuropsychol. 24, 761–767 (2009).
183. Roy, S. et al. Differential effects of aging on motor and
cognitive functioning in multiple sclerosis. Mult. Scler.
23, 1385–1393 (2017).
184. Sumowski, J. F., Chiaravalloti, N. & DeLuca, J.
Cognitive reserve protects against cognitive
dysfunction in multiple sclerosis. J. Clin. Exp.
Neuropsychol. 31, 913–926 (2009).
185. Benedict, R. H., Morrow, S. A., Weinstock Guttman, B.,
Cookfair, D. & Schretlen, D. J. Cognitive reserve
moderates decline in information processing speed in
multiple sclerosis patients. J. Int. Neuropsychol. Soc.
16, 829–835 (2010).
186. Charvet, L. E., Shaw, M. T., Haider, L., Melville, P. &
Krupp, L. B. Remotely-​delivered cognitive remediation
in multiple sclerosis (MS): protocol and results from a
pilot study. Mult. Scler. J. Exp. Transl Clin. 1,
2055217315609629 (2015).
187. Perez-​Martin, M. Y., Gonzalez-​Platas, M., Eguia-​Del
Rio, P., Croissier-​Elias, C. & Jimenez Sosa, A. Efficacy
of a short cognitive training program in patients with
multiple sclerosis. Neuropsychiatr. Dis. Treat. 13,
245–252 (2017).
188. Grasso, M. G. et al. Evaluation of the impact of
cognitive training on quality of life in patients
with multiple sclerosis. Eur. Neurol. 78, 111–117
(2017).
189. O’Carroll, C. B. et al. Is donepezil effective for
multiple sclerosis-​related cognitive dysfunction?
A critically appraised topic. Neurologist 18, 51–54
(2012).
190. Villoslada, P., Arrondo, G., Sepulcre, J., Alegre, M. &
Artieda, J. Memantine induces reversible neurologic
impairment in patients with MS. Neurology 72,
1630–1633 (2009).
191. Peyro Saint Paul, L. et al. Efficacy and safety profile of
memantine in patients with cognitive impairment in
multiple sclerosis: a randomized, placebo-​controlled
study. J. Neurol. Sci. 363, 69–76 (2016).
192. Hartung, H. P. et al. Mitoxantrone in progressive
multiple sclerosis: a placebo-​controlled, double-​blind,
randomised, multicentre trial. Lancet 360,
2018–2025 (2002).
193. Confavreux, C. et al. Oral teriflunomide for
patients with relapsing multiple sclerosis (TOWER):
a randomised, double-​blind, placebo-​controlled,
phase 3 trial. Lancet Neurol. 13, 247–256 (2014).
194. Hauser, S. L. et al. Ocrelizumab versus interferon
beta-1a in relapsing multiple sclerosis. N. Engl.
J. Med. 376, 221–234 (2017).
Acknowledgements
The authors’ research is supported in part by grants from the
National Multiple Sclerosis Society (HC 1411–02004) and
Biogen Idec (US-​M SG-15-10855) to B.W.-G. and from
Advancing Research in Multiple Sclerosis (ARMS) to the
Jacobs Multiple Sclerosis Center for Treatment and Research.
Author contributions
C.B.V., D.J., K.S.K., R.Z. and B.W.-G. were involved in all
aspects of article preparation. M.R. and R.H.B.B. contributed
to discussions of the article content, writing and review or
editing of the manuscript before submission.
Competing interests
C.B.V. declares that she has received consultancy fees from
Merck/EMD Serono. M.R. declares that he has received
research funding from the US National Institute of
Neurological Disorders and Stroke and the US National
Science Foundation. R.H.B.B. declares that he has received
research support from Accorda, Biogen, Genzyme,
Mallinckrodt and Novartis; consultancy fees from Biogen,
Genentech, Genzyme, Novartis, Roche, Sanofi and Teva; and
compensation for activities relating to continuing medical
education from EMD Serono. R.Z. declares that he has
received speakers’ and consultancy fees from Celgene, Claret
Medical, EMD Serono, Genzyme-​Sanofi, IMS Health, Novartis
and Roche-​Genentech and financial research support from
Claret Medical, IMS Health, Intekrin, Genzyme-​Sanofi and
Novartis. B.W.-G. declares that she has received fees for con-
sultancy, acting as a speaker and serving on the scientific
advisory boards of Biogen Idec, EMD Serono, Genzyme-​
Sanofi, Novartis, Questcor and Teva Neuroscience, and finan-
cial research support from Aspreva, Biogen Idec, EMD
Serono, Genzyme, the Immune Tolerance Network Clinical
Trials Group, the National Multiple Sclerosis Society, the NIH
(not related to the present work), Novartis and Teva
Neuroscience. D.J. and K.S.K. declare no competing
interests.
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Reviewer information
Nature Reviews Neurology thanks M. Magyari and other
anonymous reviewer(s) for their contribution to the peer
review of this work.