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

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

References

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2. University of California, San Francisco MS-EPIC Team, Cree BAC, Hollenbach JA, et al. Silent progression in disease activity-free relapsing multiple sclerosis. Ann Neurol. 2019;85(5):653-666.

3. Duffy SS, Lees JG, Moalem-Taylor G. The contribution of immune and glial cell types in experimental autoimmune encephalomyelitis and multiple sclerosis. Mult Scler Int. 2014;2014:285245.

4. Machado-Santos J, Saji E, Tröscher AR, et al. The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells. Brain. 2018;141(7):2066-2082.

5. Ortiz GG, Pacheco-Moisés FP, Macías-Islas MÁ, et al. Role of the blood-brain barrier in multiple sclerosis. Arch Med Res. 2014;45(8):687-697.

6. Mahajan KR, Ontaneda D. The Role of Advanced Magnetic Resonance Imaging Techniques in Multiple Sclerosis Clinical Trials. Neurotherapeutics. 2017;14(4):905-923.

7. Magliozzi R, Howell OW, Reeves C, et al. A Gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann Neurol. 2010;68(4):477-493.

8. Monaco S, Nicholas R, Reynolds R, Magliozzi R. Intrathecal Inflammation in Progressive Multiple Sclerosis. Int J Mol Sci. 2020;21(21):8217. Published 2020 Nov 3.

9. Bruschi, N., Boffa, G. & Inglese, M. Ultra-high-field 7-T MRI in multiple sclerosis and other demyelinating diseases: from pathology to clinical practice. Eur Radiol Exp 4, 59 (2020).

10. Elliott C, Wolinsky JS, Hauser SL, et al. Slowly expanding/evolving lesions as a magnetic resonance imaging marker of chronic active multiple sclerosis lesions. Mult Scler. 2019;25(14):1915-1925.

11. Elliott C, Belachew S, Wolinsky JS, et al. Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis. Brain. 2019;142(9):2787-2799.

12. Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain. 2005;128(Pt 11):2705-2712.

13. Mistry N, Abdel-Fahim R, Mougin O, Tench C, Gowland P, Evangelou N. Cortical lesion load correlates with diffuse injury of multiple sclerosis normal appearing white matter. Mult Scler. 2014;20(2):227-233.

14. Solana E, Martinez-Heras E, Martinez-Lapiscina EH, et al. Magnetic resonance markers of tissue damage related to connectivity disruption in multiple sclerosis. Neuroimage Clin. 2018;20:161-168. Published 2018 Jul 12.

15. Maranzano J, Dadar M, Zhernovaia M, Arnold DL, Collins DL, Narayanan S. Automated separation of diffusely abnormal white matter from focal white matter lesions on MRI in multiple sclerosis. Neuroimage. 2020;213:116690.

16. Carotenuto A, Giordano B, Dervenoulas G, et al. [18F]Florbetapir PET/MR imaging to assess demyelination in multiple sclerosis. Eur J Nucl Med Mol Imaging. 2020;47(2):366-378.

17. Haider L, Zrzavy T, Hametner S, et al. The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain. Brain. 2016;139(Pt 3):807-815.

18. Giovannoni G, Butzkueven H, Dhib-Jalbut S, et al. Brain health: time matters in multiple sclerosis. Mult Scler Relat Disord. 2016;9 Suppl 1:S5-S48.