Searching for Signs of Disease Progression in the Brain
Neurologists and researchers are similar to explorers, who use various techniques to understand what underlies multiple sclerosis (MS) and its progression.
MS is an immune-mediated disease of the central nervous system and the leading cause of non-traumatic disability in young adults, affecting people in the prime of their lives.1 Disease progression used to only be associated with secondary progressive and primary progressive forms of MS. It is now recognised in relapsing-remitting MS – and even if a person is not experiencing relapses.2
Recent research has shown that a complex and dynamic interaction between different immune cells – namely B cells, T cells and myeloid lineage cells – play a role in disease progression in all forms of MS.3 Follow along on the search for five of the diverse biological processes that underlie MS disease progression.
Focal inflammation in active MS lesions
The hallmark of MS is the formation of active lesions in the brain.4 These are areas of damage or scarring, which is where the name sclerosis comes from.
In people with MS, the breakdown of the blood-brain barrier allows immune cells to enter the brain and cause inflammation.5 This leads to loss of myelin, which function is to insulates and supports nerve cells along their long extensions called axons.5 This type of inflammation ultimately leads to loss of axons.5
Active lesions can be detected by standard MRI techniques.6
B-cell rich inflammatory infiltrates in the meninges
Lesions can often be found near the outer lining of the brain, called the meninges.7 The immune cells causing this inflammation may also accumulate in the meninges to form ectopic lymphoid follicles.7
These follicles allow immune cells to maintain permanent residence in the brain and lead to loss of myelin and nerve cells.7 This type of inflammation can happen without the traditional signs of blood-brain-barrier breakdown.8
Follicles may be detected with advanced MRI techniques, but better methods are needed.7,9
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Cortical lesions are often located near inflammatory infiltrates in the connective tissue sheets surrounding the brain, called the meninges.
Immune cells may accumulate in the meninges, forming aggregates now also known as ectopic or tertiary lymphoid follicles.
The inflammation within the meninges is dominated by CD20-positive B cells and is associated with extensive demyelination along the cortical ribbon, as well as death of cortical neurons — especially in the superficial layers.
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The infiltrates are most evident in deep recesses of the brain, called sulci, where the flow of cerebrospinal fluid slows or pools.
This type of chronic inflammation can occur without any obvious signs of blood–brain barrier disruption.
Meningeal inflammation may be detectable to a modest degree with advanced MRI, but better non-invasive methods are still needed.
Chronic active lesions
Chronic active, or slowly expanding, lesions correlate with MS progression and can also occur without active breakdown of the blood-brain barrier.10,11
These lesions are characterised by inflammation on their outer edge, with little to no inflammation in the centre.10 Immune cells on the outer edge of these lesions contribute to the chronic, slowly expanding damage to myelin and axons.10
Chronic active lesions can be detected with standard MRI that is taken over time with special imaging analysis.11
Widespread (diffuse) inflammation and gliosis
Widespread – or diffuse – inflammation throughout the brain is more prominent in advanced cases of progressive MS and can happen without active breakdown of the blood-brain barrier.12
Immune cells already in the brain may cause loss of myelin and damage to axons that causes them to swell and eventually die.12 This type of inflammation is usually seen in people with many inflammatory lesions in the brain.13
Diffuse inflammation can be detected with special MRI or other imaging techniques, but better and more sensitive methods are needed.14,15,16
Age-related neurodegeneration
Although inflammation decreases over time in most people with MS, the loss of nerve cells is worsened by factors related to aging.17 As a person ages, iron can accumulate in immune cells and other cells that support myelin.17 Over time, an increase in iron and other signaling molecules can damage nerve cells.17
In people with MS, the central nervous system loses some of its resilience over years of MS disease activity and, when combined with the loss of nerve cells due to normal aging, can result in slow, progressive worsening of the disease.18
It be detected with standard MRI techniques that measure widespread brain volume loss.18
We’ve learned so much from clinical trials over the last decade. Treatments that address multiple biological processes of MS can lead to positive effects on disability progression, especially with early intervention.18
Ongoing research continues to advance our understanding of MS disease progression and what lies within the jungle of the brain.
Understanding progression in MS
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The central nervous system, or CNS, is a network that sends information between nerve cells. This takes the form of electrical signals traveling along nerve fibres. Imagine it like a rail network, but with billions of trains traveling at a hundred meters per second to reach their destinations. On a rail network, when the tracks are damaged, they can be repaired — but only so many times. Eventually, damage can no longer be repaired, and trains are unable to travel on those tracks. This could negatively affect the network,
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but when a track is closed, the signaller can reroute the trains, and services may be able to carry on as normal. Similarly, in MS, inflammation damages the CNS, which can sometimes be repaired by the body — but when it can't, nerve cells and fibres are lost. This permanent loss of nerve cells and fibres is known as disease progression. Disease progression starts at the very beginning of MS, often before diagnosis, and it happens in all forms of MS, regardless of the form a person has or is diagnosed with.
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Like the trains that can be rerouted onto other tracks, those living with MS may not have disability that is visible to others. This may be because MS affects functions that others cannot see, or because their CNS has ways to hide it. At the start of MS, disease progression can be difficult to detect because the CNS can initially compensate for the loss of nerve cells and fibres with what's called neurological reserve. The CNS does this by sending signals through undamaged areas or adapting undamaged areas to take on new functions,
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in addition to repairing damaged areas. On the rail network, it’s only when all remaining tracks are at full capacity and signallers run out of options that the network starts to experience problems and passengers notice. In the case of MS, when the CNS can no longer compensate for damage, this is the point where symptoms become more noticeable or disability worsens. Because disease progression is a steady but permanent process that can go unnoticed for many years, it is important that those living with MS
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speak with a healthcare provider about disease progression and how to identify and delay it. An MRI can measure the loss of brain tissue, especially when images are compared over time. It can be challenging to accurately measure disease progression early in the disease course. Roche is collaborating with research institutes and other companies to develop novel tools and biological markers to identify and potentially predict the progression individuals might experience in the future. Treatment as early as possible
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with a therapy that impacts progression — not just relapses — is important to minimize the permanent loss of nerve cells and the impact that this disease can have on daily life and the years to come.
References
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