# The Ageing Brain and Multiple Sclerosis: What Imaging Reveals

Ageing and multiple sclerosis (MS) are not separate challenges—they interact in ways that can amplify damage to the brain and spinal cord, leading to greater disability. A major international consensus review from the MAGNIMS network explains how the ageing immune system becomes less protective and more inflammatory, and how MRI (magnetic resonance imaging) can reveal the combined effects of ageing and MS on brain structure. The review shows that older MS patients may have fewer flare-ups but more progressive disability, and that doctors need to adjust treatment plans based on age. This patient-friendly summary translates the key scientific findings into practical knowledge for people living with MS.

# The Ageing Brain and Multiple Sclerosis: What Imaging Reveals

## Table of Contents

- Key Points
- Why Ageing Matters in Multiple Sclerosis
- How This Review Was Assembled
- The Ageing Immune System in MS
- Cellular Senescence and 'Inflammageing'
- Pathological Mechanisms in the Ageing MS Brain
- Perivascular Spaces and Brain Waste Clearance
- Clinical Implications for Patients
- Limitations of the Review
- Recommendations for Patients
- Frequently Asked Questions
- Source Information

## Key Points

- Ageing and MS interact, so their combined damage to the brain and spinal cord can be greater than either alone.
- Older MS patients may have fewer relapses but still accumulate disability through progressive brain tissue loss.
- Chronic MS inflammation can accelerate brain ageing, so cognitive decline may appear earlier than expected.
- Managing vascular risks such as high blood pressure, diabetes, smoking, and high cholesterol directly affects MS outcomes.
- MRI can show MS lesions plus age-related changes like atrophy, iron deposits, and enlarged perivascular spaces.

## Why Ageing Matters in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (the brain and spinal cord). It causes damage to myelin—the protective coating around nerve fibres—and gradually destroys nerve cells themselves. This process is called demyelination and neurodegeneration. MS leads to a progressive accumulation of disability over time.

Ageing, on its own, also changes the brain. Normal ageing brings reduced plasticity (the brain's ability to rewire itself), loss of grey matter volume (grey matter is the brain's outer layer, packed with nerve cell bodies), increased white matter abnormalities (white matter contains the nerve fibres that connect different brain regions), and the build-up of ischaemic lesions—small areas where blood flow has been reduced, often without noticeable symptoms.

When MS and ageing occur together, the effects are not simply additive. They can multiply each other's damage. The physiological decline of ageing—including a reduced capacity to repair and regenerate—can make the brain less able to recover from MS-related attacks. Conversely, chronic inflammation from MS can accelerate ageing-related brain changes, leading to premature brain ageing. This may appear as earlier cognitive decline and faster brain shrinkage (atrophy) than would be expected for a person's age.

The authors of the review emphasise that **older MS patients may experience more severe disease progression and disability** than younger people who have had the disease for the same amount of time. They also note that the proportion of people who receive their first MS diagnosis at an advanced age has increased in recent years. At the same time, because of better treatments and healthcare, more MS patients are living to an older age. This means doctors and patients increasingly face the complicated interaction of two powerful forces: a chronic neurological disease and the ageing process.

Ageing also affects how patients respond to MS therapies. Older patients tend to have fewer clinical relapses (flare-ups) and fewer new lesions on MRI scans, but they are at higher risk for side effects from certain medications. This is why the authors call for age-adjusted treatment considerations. MRI is a very sensitive tool for tracking both MS-related damage and age-related changes in the brain, so it can help doctors decide which treatment is safest and most effective for an individual patient.

## How This Review Was Assembled

This article is a consensus review, not a single new experimental study. On 10 November 2023, an international group of experts from the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) network met to discuss the latest evidence about ageing and the central nervous system in MS. The group included neurologists, immunologists, pathologists, physicists, and neuroradiologists with expertise in MS and MRI.

The experts reviewed recent scientific literature using a structured search strategy (details are provided in the original paper's supplementary material). Each expert summarised a specific topic, and the group reached a consensus. A first draft was then circulated among the speakers and other leading experts for critical discussion and revision. This process ensures that the findings reflect a broad range of expert knowledge, not just one research group's opinion.

## The Ageing Immune System in MS

The immune system changes dramatically as we age, and these changes are deeply connected to MS. The review begins with a phenomenon called **immunosenescence**—the gradual decline in immune function that happens with age. This decline makes the body less effective at fighting infections and repairing damaged tissue, but it also leads to an increase in chronic, low-grade inflammation.

Some of the key changes occur in both the first-line (innate) and adaptive immune cells:

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**Microglia**—the brain's resident immune cells—become dystrophic (they develop a shrivelled, less complex shape). Their ability to detect problems and to "clean up" cellular debris through phagocytosis declines.
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**CNS-associated macrophages (CAMs)** increase in number with age. These include cells in the meninges (the brain's protective layers), the choroid plexus (which produces cerebrospinal fluid), and around blood vessels. Like microglia, they become more pro-inflammatory and less efficient at maintaining the blood-brain barrier.
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**T lymphocytes** (a type of white blood cell) start to show markers of T helper (Th)1 and Th17 activity—both linked to inflammation—and lose some of their regulatory abilities.
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**B lymphocytes** produce more inflammatory molecules such as tumour necrosis factor (TNF) and interleukin 6 (IL-6). They can also produce autoantibodies (antibodies that mistakenly attack the body's own tissues) and multiply excessively after chronic viral infections like Epstein-Barr virus (EBV) or cytomegalovirus (CMV).

These ageing immune changes create what researchers call the **senescence-associated secretory phenotype (SASP)**. Senescent cells—cells that have stopped dividing but do not die—release high levels of pro-inflammatory chemicals, including growth factors, proteases, and tiny sacs called exosomes that carry enzymes, microRNA, and DNA fragments. This constant low-level inflammation can damage surrounding tissue and has been called "inflammageing."

Inflammageing is not just a passive by-product of ageing. It is influenced by genetics, infections, diet, smoking, and other environmental factors. In MS, inherited susceptibility accounts for about one-third of the overall disease risk. The other two-thirds come from external triggers that can activate the disease in vulnerable people—such as infections, nutritional factors, smoking, and low vitamin D levels.

For patients, this means that the ageing immune system may switch from a protective role to a damaging one. The aged CNS environment in MS can keep microglia persistently activated—not only in chronic active lesions but also in the normal-appearing white matter (areas that look normal on an MRI scan but may already be under stress).

## Cellular Senescence and 'Inflammageing'

The link between cell ageing and MS goes deeper. During ageing, the thymus (the organ where T cells mature) shrinks and stem cells become exhausted. This leads to a condition called the **"immune risk phenotype."** The signs include:

- A ratio of CD4 to CD8 T cells below 1 (in healthy younger adults, CD4 cells usually outnumber CD8 cells)
- Poor T-cell proliferative responses (the cells do not multiply well when they encounter a threat)
- Increased numbers of late-differentiated CD8+ T cells
- Low B cell numbers
- Positive tests for cytomegalovirus (a common, usually harmless virus that stays in the body for life)

The authors explain that regulatory T cells (Tregs) are especially important. Their job is to keep the immune system from attacking the body's own tissues. In healthy ageing, the role of Tregs is still debated, but during inflammageing they work less effectively. In patients with MS, the number of Tregs may be unchanged, but their suppressive power is reduced. In fact, they tend to produce Th1-type inflammatory molecules—the very kind that fuel MS attacks. As a result, autoimmune clones (self-reactive immune cells) are no longer kept in check, which supports ongoing neurodegeneration.

An intriguing new finding involves **endogenous retroviruses (ERVs)**—remnants of ancient viral DNA that make up part of the human genome. In ageing cells, the most recently integrated ERVs, called HERVK (HML-2), can be "unlocked." They start to transcribe viral genes and produce retrovirus-like particles (RVLPs). These particles can trigger senescence in young cells, spreading the ageing process. The authors note that the activation of ERVs has been observed in tissues and serum from older donors, and that repressing ERV activity can improve cellular ageing. This opens up a possible future avenue for treatments that aim to improve immune performance during ageing.

## Pathological Mechanisms in the Ageing MS Brain

Because life expectancy for MS patients has increased, more people now live long enough to experience age-related brain changes on top of MS. The review presents striking survival statistics:

- In a **Norwegian study** of 1,388 MS patients whose disease began between 1953 and 2012, the standardized mortality ratio (SMR)—a measure of how much more likely MS patients are to die compared with the general population—dropped over time:

- 3.1 for onset during 1953–1974
- 2.6 for onset during 1975–1996
- 0.7 for onset during 1997–2012

- In a **Danish study** of 18,847 patients with definite or probable MS with onset between 1950 and 1999, the SMR fell from 4.48 (onset 1950–1959) to 1.80 (onset 1990–1999). The mean age of death for MS patients rose from 50.6 years (death during 1950–1959) to 65.4 years (death during 2000–2009).
- A **Global Burden of Disease Study** estimated an 11.5% global decrease in age-standardised death rates for MS in 2016 compared with 1990.

This longer survival means that MS patients are now reaching the ages at which vascular problems and age-related brain changes become common. Those conditions may interact with MS pathology and worsen the clinical picture.

What happens in the MS brain as it ages? The authors explain that the basic disease process is the same across all forms of MS, but there are important quantitative differences over time. In the early stages, **active lesions** containing massive numbers of inflammatory macrophages are common. As the disease progresses, these active lesions become rare. Instead, **chronic active lesions** (also called slowly expanding lesions) become more common. They peak at the transition from relapsing-remitting MS to progressive MS and gradually expand over years. The extent of **remyelination** (the brain's attempt to repair damaged myelin) remains similar across all stages, but the overall capacity for remyelination declines with age and chronic inflammation.

Cortical lesions (in the grey matter) and diffuse injury in the normal-appearing white matter become more frequent as the disease advances. New lesions, when they do appear, tend to occur near the ventricles (fluid-filled spaces in the middle of the brain) and in the subpial layers of the brain's outer cortex, as well as in the lateral and posterior columns of the spinal cord.

Several molecular and genetic factors contribute to progressive damage:

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**Oxidative injury** and **mitochondrial dysfunction** damage cells and are amplified by ageing and by iron accumulation in the brain.
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**Microglial activation** is prominent in age-related neurodegeneration. Genetic variations in microglial genes are associated with susceptibility to Alzheimer's disease.
- Chronic brain inflammation can cause **misfolded proteins** to build up inside neurons, which may contribute to nerve cell death.
- Four potential genes have been linked to MS severity:

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**Zinc finger protein 386** – helps repress unintegrated viral DNA (possibly from Epstein-Barr virus and HERV-W)
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**Dysferlin** – involved in repairing cell membrane damage
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**Dynamin 3** – also involved in membrane repair
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**Phosphatidylinositol glycan anchor (GPI) biosynthesis class C protein** – important for expressing GPI-anchored membrane proteins

The last three genes are all involved in repairing damaged cells or cell processes. If these repair mechanisms fail, age-related and MS-related damage can accumulate more quickly.

Vascular (blood vessel) problems are especially relevant. The authors point out that vasculo-ischaemic diseases—conditions that reduce blood flow to the brain, such as high blood pressure, diabetes, and high cholesterol—share molecular mechanisms with MS progression. However, the review also notes an important counterpoint. In experimental studies, demyelination appears to promote amyloid deposition (a hallmark of Alzheimer's disease), and amyloid-β oligomers (toxic protein clumps) damage myelin. Yet, in human patients with long-lasting progressive MS, there was **no significant difference in the development of Alzheimer's-related neuropathology** compared with age-matched people without MS. Still, Alzheimer's disease can occur in ageing MS patients, and when it does, it may amplify cognitive disabilities.

## Perivascular Spaces and Brain Waste Clearance

One of the most rapidly advancing areas in ageing and MS research involves **Virchow-Robin spaces**, also called perivascular spaces. These are fluid-filled passages that surround the blood vessels in the brain. They sit between the basement membrane of the brain's "end-feet" (from star-shaped cells called astrocytes) and the endothelium (inner lining) of arteries, capillaries, and veins.

These spaces are not just anatomical gaps—they are part of the brain's **waste clearance system**. Cerebrospinal fluid enters from the subarachnoid space (the fluid-filled area around the brain) into the peri-arterial compartment. This flow is helped by a protein called **aquaporin 4 (AQP4)**, which moves water across cell membranes to drive fluid into the brain's interstitial space (the spaces between cells). Once there, the fluid picks up waste products and travels along an **intramural peri-arterial drainage pathway**—moving against the direction of blood flow—and eventually exits via the smooth muscle of the arteries in the subarachnoid space.

Under normal conditions, perivascular spaces in the deep white matter are too small to be seen on standard MRI scans at 1.5 or 3 Tesla (the magnetic field strengths commonly used in clinical practice). But as people age, these spaces often become **enlarged perivascular spaces (ePVS)**. Enlarged perivascular spaces are visible on MRI and are associated with a broad range of neurological conditions. The authors note that different mechanisms—likely involving impaired fluid drainage, inflammation, and blood-brain barrier dysfunction—may drive these changes, and they are now being investigated in MS.

This is an important area for patients to understand: MRI images that show enlarged perivascular spaces may indicate that the brain's cleanup system is not working as well as it should. This, in turn, may affect how the brain copes with MS-related damage.

## Clinical Implications for Patients

The review carries several messages that patients may find important:

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**Ageing can make MS worse.** The combination of age-related brain shrinkage and MS-related damage can lead to faster disability progression. Older patients may have fewer relapses, but they may still accumulate disability through progressive brain tissue loss.
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**MS can make ageing worse.** Chronic inflammation from MS can accelerate brain ageing, so age-related cognitive decline may happen earlier than in people without MS.
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**Comorbidities matter.** Vascular risk factors like high blood pressure, diabetes, smoking, and high cholesterol can add to the burden. Managing these conditions is not just part of general health—it directly affects MS outcomes.
-
**Treatment decisions may need to change with age.** Because older patients are more vulnerable to side effects of certain MS medications, doctors should balance potential benefits against age-specific risks. The authors recommend that treatment strategies be adjusted for each patient's age and comorbidity profile.
-
**MRI is a powerful tool.** MRI can detect not only MS lesions but also age-related changes such as brain atrophy, iron deposits, myelin changes, and enlarged perivascular spaces. Regular MRI monitoring can help doctors track the combined effects of age and MS over time.

The authors also highlight that the proportion of patients with late-onset MS (first symptoms after age 50, for example) is growing. They argue that age at onset should be taken into account when applying diagnostic criteria, because some MRI changes that look like MS could be age-related. Conversely, an older patient with MS might be misdiagnosed if their symptoms are attributed purely to ageing.

## Limitations of the Review

This article is a consensus review, not a single experimental study with new patient data. As such, the conclusions draw on many individual studies with different designs, populations, and MRI techniques. Some of the findings are associative rather than confirmed causal links—for example, the relationship between enlarged perivascular spaces and MS progression is still being investigated.

Another limitation is that the original article discusses many topics, including the influence of age on diagnostic criteria, late-onset MS, iron dynamics, myelin changes, and treatment effects in ageing patients. The full scope of those topics is covered in the original paper, but the underlying evidence base for some areas is still evolving. MRI measures such as "normal-appearing white matter" damage are not yet standard in everyday clinical practice everywhere.

The statistical results described here are from large population studies with strong designs, but they were not performed within a single unified research protocol. The authors state that they used a structured search strategy and reached a consensus among experts, but a formal systematic review or meta-analysis was not performed.

## Recommendations for Patients

Based on the evidence presented in this review, patients with MS—especially those over 50—can take several practical steps:

1.
**Keep up with regular MRI scans.** MRI is the best tool to see both new MS activity and age-related brain changes. Talk to your neurologist about how often you need scans.
1.
**Manage your vascular health.** Treat high blood pressure, high cholesterol, and diabetes seriously. Do not smoke. These actions may help protect your brain from the combination of MS and age-related blood vessel damage.
1.
**Discuss your treatment plan with your neurologist.** Ask whether your current disease-modifying therapy is still the best choice for your age and whether its side effects outweigh its benefits. The authors emphasise that "age-adjusted treatment considerations" are necessary.
1.
**Monitor your cognitive health.** Because MS can accelerate brain ageing, pay attention to memory, concentration, and processing speed. If you notice changes, mention them to your doctor—cognitive testing and rehabilitation may be available.
1.
**Stay physically and mentally active.** Brain plasticity declines with age, but exercise and cognitive engagement can support the brain's ability to compensate for MS-related and age-related damage.
1.
**Ask about enlarged perivascular spaces.** If your MRI report mentions enlarged Virchow-Robin spaces, ask your neurologist what it might mean for your disease course. Researchers are still learning about this, but it is a clue that the brain's waste clearance system is being assessed.

The authors conclude that understanding the interaction between ageing and MS is crucial for improving patient care. MRI is at the centre of this effort because it can non-invasively show the brain's structure, damage, and repair. By combining the latest imaging techniques with a deeper understanding of immunosenescence and pathological ageing, doctors can better tailor treatment decisions—ultimately helping people with MS live longer, healthier, and more independent lives.

## Frequently Asked Questions

### Does ageing make multiple sclerosis worse?

Yes. Ageing and MS interact and can multiply each other's damage. Normal ageing reduces the brain's ability to repair itself, so it recovers less well from MS attacks. Meanwhile, chronic MS inflammation can accelerate ageing-related brain changes, leading to earlier cognitive decline and faster brain shrinkage than expected for a person's age.

### Why might older people with MS have fewer relapses but still get worse?

Older patients tend to have fewer clinical relapses and fewer new lesions on MRI scans. However, they may still accumulate disability through progressive brain tissue loss, because age-related brain shrinkage combines with MS-related damage. This is why the authors call for treatment plans to be adjusted according to each patient's age.

### What does an enlarged perivascular space on my MRI mean?

Perivascular spaces are fluid-filled passages around brain blood vessels and part of the brain's waste clearance system. They are usually too small to see on standard MRI, but they often enlarge with age. Enlarged perivascular spaces may indicate that the brain's cleanup system is not working as well as it should, though researchers are still investigating this in MS.

### Can MS cause memory and thinking problems earlier than normal ageing?

Chronic inflammation from MS can accelerate brain ageing, so age-related cognitive decline may happen earlier than in people without MS. Because of this, patients are advised to pay attention to memory, concentration, and processing speed, and to mention any changes to their doctor, since cognitive testing and rehabilitation may be available.

### Should my MS treatment change as I get older?

Possibly. Older patients are more vulnerable to side effects from certain MS medications, so doctors should balance potential benefits against age-specific risks. The authors recommend that treatment strategies be adjusted for each patient's age and other health conditions. Discuss with your neurologist whether your current disease-modifying therapy is still the most appropriate choice for you.

### What can I do to protect my brain from MS and ageing combined?

Keep up with regular MRI scans and ask your neurologist how often you need them. Manage vascular health by treating high blood pressure, high cholesterol, and diabetes seriously, and do not smoke. Stay physically and mentally active, since exercise and cognitive engagement can support the brain's ability to compensate for MS-related and age-related damage.

### What is inflammageing and how does it relate to MS?

Inflammageing is chronic, low-grade inflammation linked to ageing. Senescent cells, which have stopped dividing but do not die, release high levels of pro-inflammatory chemicals. In MS, the ageing immune system may switch from a protective role to a damaging one, and the aged central nervous system environment can keep microglia persistently activated, including in normal-appearing white matter.

### When should someone with multiple sclerosis seek a second opinion about their treatment plan as they get older?

Age changes how multiple sclerosis behaves and how it should be treated. Older patients tend to have fewer relapses and fewer new lesions on MRI, but they face higher risk of side effects from certain medications, and disability can still accumulate through progressive brain tissue loss. Because treatment strategies should be adjusted for each patient's age and comorbidity profile, a second opinion can help when you are unsure whether your current disease-modifying therapy remains the right choice for your age, or whether its risks outweigh its benefits. Diagnostic Detectives Network provides independent expert second opinions.

## Source Information

**Original article title:** The ageing central nervous system in multiple sclerosis: the imaging perspective.

**Authors:** Filippi M, Preziosa P, Barkhof F, Ciccarelli O, Cossarizza A, De Stefano N, Gasperini C, Geraldes R, Granziera C, Haider L, Lassmann H, Margoni M, Pontillo G, Ropele S, Rovira À, Sastre-Garriga J, Yousry TA, Rocca MA.

**Publication details:** BRAIN, 2024, Volume 147, pages 3665–3680. Published by Oxford University Press on behalf of the Guarantors of Brain. DOI: [10.1093/brain/awae251](https://doi.org/10.1093/brain/awae251)

**Access:** This is an Open Access article distributed under the terms of the Creative Commons Attribution License.

*Note: This patient-friendly article is based on peer-reviewed research published in the journal BRAIN. It is intended to help patients and caregivers understand the scientific findings in a more accessible way. It is not a substitute for professional medical advice. Always consult your neurologist or healthcare team about your specific situation.*


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