Early intervention, free and free - to protect the brain health of MS patients

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by inflammation and ^{neurodegeneration1}
.
Brain atrophy, i.
e.
a gradual decrease in brain volume, reflects irreversible tissue damage leading to persistent clinical dysfunction, which is quite widespread in MS, approaching 0.
5% to 1.
35% per year, far beyond the limits of normal ^aging2,3
.
Brain atrophy is present in the early stages of MS or even before clinical symptoms appear, and it is especially important to note that the rate of brain atrophy in the early stages of the disease is ^4-6
faster.
Neurodegenerative mechanisms cause permanent damage, brain atrophy is a visible association of neurodegenerative degeneration, directly related to cognitive impairment, disability progression and fatigue, is an effective and sensitive indicator of disease burden and progression in MS patients, and can be effectively used in routine clinical practice and treatment ^{trials1,2,4,7}
.
Therefore, it is crucial
to select appropriate drugs to treat MS in the early stages of MS to reduce brain volume loss.

Brain atrophy can occur early in MS ,

The rate of brain atrophy is faster in the early stages of the disease

Brain atrophy occurs at all stages of MS, and studies have shown that brain atrophy occurs in patients with radiological isolation syndrome (RIS) and clinically isolated syndrome (CIS) (Figure 1)^{1, 4, 8}
.
From the early stages, brain atrophy progresses throughout the disease at a faster rate than is associated with the normal aging process in healthy ^individuals1
.

Figure 1.
Brain atrophy occurs at all stages of MS

Brain atrophy rates vary at different stages of MS and progress faster early in the disease: a 2018 prospective cohort study from Spain that included 140 MS patients and 54 healthy controls showed higher rates of annualized total brain volume and gray matter volume loss in patients with ≥5 years of disease compared with patients with <5 years of disease (Figure 2)<b10>5).
； A 2019 5-year prospective cohort study of 650 participants (including 520 patients with recurrent MS and 130 healthy controls) from the United States showed that MS-specific whole brain volume and thalamic volume loss rates were higher in young adult patients compared with older patients, with MS-specific total brain volume loss rates falling from 0.
38% per year at age 30 to 0.
12% per year at age 60, varying 0.
09% ±0.
035% per decade (p=0.
01), A similar pattern was observed in MS-specific thalamic atrophy, which decreased from 0.
59% per year at age 30 to 0.
05% per year at age 60, with a change of 0.
18% ± 0.
08% per 10 years (p<0.
05)<b11>6
.

Figure 2.
Dynamic changes in the rate of annualized whole brain volume and gray matter volume loss during MS disease progression

Brain atrophy is predictable

Future physical disability and cognitive dysfunction

Brain atrophy is the result of a variety of destructive pathological processes, including irreversible demyelination, axon and/or neuronal loss, and astrocyte scarring, associated with disability progression and cognitive ^dysfunction7
.

Disability progression is one of the key features of MS, and as the degree of disability increases, the overall health status of people with MS continues to deteriorate, the proportion of employment decreases significantly, and the economic costs of the disease increase ^{dramatically9}
。 The relationship between brain atrophy and disability progression has been validated through multiple studies: a 5-year longitudinal study in 2013 showed that patients with persistent disability progression had significantly higher percentages of total brain volume (p<0.
0001), cortical volume (p=0.
001), gray matter volume (p=0.
003), and thalamic volume (p=0.
01) compared with <b12>baseline10 compared with patients with persistent disability progression; A 2017 study that divided MS patients into high, medium and low groups based on brain volume showed that patients with severe brain atrophy were more likely to progress in ^disability11; A large, multicentered, longitudinal study in 2018 showed that of all baseline region brain volumes, only deep gray matter capacity predicted the time to progress toward the Extended Disability Status Scale (EDSS) (HR=0.
73, 95% CI 0.
65-0.
82, p<0.
001), i.
e.
, for every standard deviation of baseline deep gray matter capacity, the risk of shortening the time to deterioration of EDSS during follow-up increased by 27%<b14>12
.

Cognitive dysfunction is one of the core symptoms of MS and can occur in up to 70% of MS13, affecting the lives of patients widely, leading to a decline in quality of life, social dysfunction, and employment ^problems14
.
Brain atrophy is significantly associated with cognitive dysfunction, and functional magnetic resonance imaging results show that the most closely related to cognitive dysfunction is regional gray matter atrophy, neural network disruption and poor reserve compensation mechanism, of which gray matter atrophy is a key determinant of cognitive ^{dysfunction15}
.
The results of a 2018 study from the Netherlands that included 328 MS patients showed that cognitive impairment occurred in MS patients with gray matter atrophy (75%) than in MS patients without gray matter atrophy (32%)¹⁶; The results of a 2007 study from 79 MS patients and 16 normal subjects in the United States showed that cognitive performance in all areas of MS had a moderately strong correlation with thalamic volume (r=0.
506-0.
724, p<0.
005), and the more severe the thalamus atrophy, the lower the cognitive function ^score17
.

Brain atrophy has been used to evaluate the efficacy of DMT treatment

Important metrics

Previously commonly used efficacy evaluation indicators – relapsed and new focal MRI lesions – provide useful information on the inflammatory activity of MS but do not adequately explain the progression of neurodegenerative diseases, and disability assessment by EDSS only partially reflects neurodegenerative impairment, cerebral atrophy is a valid, sensitive and reproducible measure of neurodegenerative degeneration in ^MS2,7
.

The MAGNIMS Consensus Recommendation: Application of Brain and Spinal Cord Atrophy Measurements in MS Clinical Practice, published in 2020, states that it is recommended to use whole brain atrophy (at least 12 months for a cycle) as a secondary endpoint or even a primary endpoint for MS clinical trials to assess the effect of drugs on disease-related neurodegenerative changes, and that ongoing and upcoming clinical trials should include gray matter volume loss as a prognostic evaluation ^indicator18 ； Deep Gray Matter Injury in MS: NAIMS Consensus Statement, released in 2021, states that brain atrophy represents irreversible tissue loss, which is what disease revision therapy (DMT) is intended to prevent, and that future research may use atrophy as an outcome rather than a predictor to study the biological mechanisms of volume loss, the effects of DMT on the whole brain volume of MS patients have been widely described, but the study of the effects of DMT on deep gray matter structures has only just begun.
MRI endpoints for deep gray matter atrophy are likely to be included in future clinical ^trials19
.

How to delay brain atrophy in patients with MS

In the treatment of MS, drugs that can control the inflammatory process are not only needed, but also drugs that can stop the progression and neurodegeneration of brain atrophy, and the effects of currently approved DMT drugs on brain atrophy ^vary2
.
For patients with recurrent MS, initiating DMT therapy in the early stages of the disease improves long-term prognosis better than delayed ^therapy20, and in order to minimize brain atrophy, it is critical
to select the appropriate DMT drug for the patient as early as possible.

Regular monitoring is at the heart of MS management, and improving the efficacy of treatment by monitoring MS disease activity is key to maximizing brain health, even in the absence of clinical recurrence or manifestations of disability progression, all disease activity can damage the tissues
of the central nervous system.
With regular MRI check-ups, disease activity can be monitored, early warning of treatment of poorly responded MS, and the detection of brain atrophy suggestive of disability progression and cognitive ^{dysfunction20}
.

MS patients require comprehensive treatment and management, regardless of the type of MS patient, smoking cessation, participation in cardiovascular physical training, maintaining a healthy weight, insisting on nootropic activities, avoiding excessive alcohol consumption, maximizing complications and other lifestyles can help maximize brain health in MS ^patients20
.

Although due to some technical problems, limiting the routine use of brain volume measurement in clinical ^practice21, a number of large clinical studies have confirmed the correlation between brain atrophy and disability progression and cognitive dysfunction, and large sample size phase III studies have confirmed that some DMT drugs can significantly delay brain atrophy and improve cognitive function, therefore, in clinical practice, we should pay attention to brain atrophy as a efficacy evaluation index and select DMT drugs
that can effectively delay brain atrophy for patients as soon as possible 。 With the advent of new regional brain volume measurement technologies and advanced neuroimaging techniques, it is believed that the measurement of brain volume changes will gradually be incorporated into clinical practice to assist in the formulation of treatment decisions and the management of individual patients, thereby contributing to personalized patient ^care22
.

Expert profile

Professor Yang Huan

Chief Physician, Department of Neurology, Xiangya Hospital, Central South University, Director of Subspecialty of Neuroimmunology and Neuromyopathy, Doctoral Supervisor

• He is a member of the Neuroimmunology Group of the Neurology Branch of the Chinese Medical Association

• Member of the Peripheral Neuropathy Collaborative Group

• He is a member of the Neurology Professional Committee of Hunan Medical Association and the leader of the neuroimmunology group

• Standing Director of Hunan Immunology Society, Chairman of Neuroimmunity Branch

• Standing Director of Hunan Rehabilitation Medical Association, Chairman of the Professional Committee of Myopathy and Peripheral Neurology

• Member of the Standing Committee of Hunan Rare Disease Society

• Member of the Standing Committee of the New Technology Professional Committee of Hunan Medical Education Science and Technology Society

• He is a member of the editorial boards of Chinese Journal of Neurology and Chinese Journal of General Practitioners

• Associate Editor, Journal of Neuroimmunology, SCI journal

• He has won 6 National Natural Science Foundation of China, 1 "New Century Excellent Talents Fund of the Ministry of Education" and other projects

• In 2021, he won the second Hunan Provincial Top Ten Medical Clinical Innovation Technology Award

---

Expert reviews

MS is a progressive disease, and inflammation and neurodegenerative degeneration are important features of
MS.
Brain atrophy represents irreversible tissue loss and is more closely
associated with neurodegenerative degeneration than clinical recurrence, MRI evidence of disease activity, and worsening disability.
Brain atrophy occurs early in MS at a significantly faster rate than in healthy people, and younger patients have a higher
rate of brain volume loss.
Brain atrophy is associated with and predictable progression of long-term disability and cognitive decline, and has become an important indicator
for evaluating the effectiveness of DMT treatment.

In view of the important position of brain atrophy in MS, attention should be paid to brain atrophy in clinical practice, pay attention to the evidence of the efficacy of DMT drugs to delay brain atrophy, and select appropriate DMT drugs for patients in the early stage of the disease to maximize the brain health of MS patients and improve cognitive function
.
Key phase III studies of some existing DMT drugs in China have not achieved consistent results in delaying brain atrophy, and new drugs are still needed to further meet patient needs
.

Two of the largest positive controlled phase III clinical studies published in Lancet Neurology showed that Ozamod significantly delayed total brain atrophy, cortical gray matter atrophy and thalamic atrophy compared with interferon β-1a, with a high 84% reduction in the risk of cortical gray matter atrophy, and for the first time reported on thalamic atrophy in the main analysis of the MS phase III study; Ozamode significantly improved cognitive function, and after 3 years of continuous treatment, 77% of patients received cognitive function protection or improvement
.
It is expected that Ozamad will be approved for marketing as soon as possible, bringing new brain protection options
to Chinese MS patients.

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