Multiple sclerosis (MS) is a chronic autoimmune disease, characterized by inflammation and neurodegenerative change
1
. brain atrophy , that is, the gradual decrease in brain capacity, reflects irreversible tissue damage that leads to persistent clinical dysfunction , which is quite extensive in MS, approaching 0.5% to 1.35% per year, far exceeding the limit of normal aging
2,3.
Brain atrophy exists in the early stages of MS and even before clinical symptoms appear. It is particularly important to note that the rate of brain atrophy in the early stages of the disease is faster
4-6.
neurodegenerative mechanism can cause permanent damage. brain atrophy is a visible association of neurodegenerative change. It is directly related to cognitive impairment, disability progression and fatigue. It is an effective and sensitive indicator for measuring the disease burden and progress of MS patients. can be effectively used in routine clinical practice and treatment trials
1, 2, 4, 7
. Therefore, it is crucial to select appropriate medications to treat MS in the early stages of MS to reduce brain volume loss.
Brain atrophy can occur in the early stage of MS, and
Early brain atrophy rate is faster in the early stages of disease
Brain atrophy occurs at all stages of MS. study shows that cerebral atrophy has occurred in patients with radiological isolation syndrome (RIS) and clinical isolation syndrome (CIS) (Figure 1) 1, 4, 8. From the early stages, brain atrophy has been progressing throughout the disease process at a rate faster than the atrophy associated with the normal aging process of healthy individuals 1.
Figure 1. Brain atrophy occurs at all stages of MS
Brain atrophy rate varies at different stages of MS and progresses faster in the early stages of the disease: 2018 A prospective cohort study of from 140 MS patients and 54 healthy controls in Spain showed that compared with patients with ≥5 years of illness, patients with ≥5 years of illness, the annualized whole brain capacity and gray matter volume of patients with ≥5 years of illness A 5-year prospective cohort study of 650 subjects (including 520 relapsed MS patients and 130 healthy controls) in 2019 showed that compared with older patients, MS-specific whole-brain volume and thalamic volume loss rates were higher in younger adult patients, with MS-specific whole-brain volume loss rates ranging from 0.38% per year at age 30. It decreased to 0.12% per year at age 60, with a change of 0.09% ± 0.035% per decade (p=0.01), and a similar pattern was observed in MS-specific thalamic atrophy, 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 decade (p<0.05)>6.
Figure 2. Dynamic changes in annualized whole brain capacity and gray matter capacity loss rate during MS disease progression
Brain atrophy can predict
Future physical disability and cognitive dysfunction
Brain atrophy is the result of various destructive pathological processes, including irreversible demyelination , axonal and/or neuronal loss, and astrocyte scarring, which is related to disability progression and cognitive dysfunction 7.
Disability progress is one of the key characteristics of MS. With the increase of disability, the overall health status of MS patients continues to deteriorate, the employment proportion has dropped significantly, and the economic costs of diseases have increased sharply. The relationship between brain atrophy and disability progression has been verified by several studies : A 5-year longitudinal study in 2013 showed that the percentage of decreases in patients with continuous disability progression (p <>10; A 2017 study divided MS patients into three groups according to brain capacity. The results showed that patients with severe brain atrophy were more likely to have disability progression 11; a large, multicenter, longitudinal study in 2018 showed that among all baseline areas, only deep gray matter capacity could predict the time of progression to the Extended Disability Status Scale (EDSS) (HR=0.73, 95%CI 0.65-0.82, p <>12.
Cognitive dysfunction is one of the core symptoms of MS and can occur in up to 70% of MS patients, which widely affects patients' lives, leading to decreased quality of life, social dysfunction and employment problems. Brain atrophy is significantly related to cognitive dysfunction . Functional magnetic resonance imaging results show that the most closely related to cognitive dysfunction are regional gray matter atrophy, neural network disruption and poor reserve compensation mechanisms, among which gray matter atrophy is a key determinant of cognitive dysfunction 15. A 2018 study from Dutch included in 328 MS patients, showed that MS patients with gray matter atrophy (75%) had gray matter atrophy (75%). The incidence of cognitive impairment was higher than that of MS patients without gray matter atrophy (32%). The results of a 2007 study from 79 MS patients and 16 normal subjects in the United States showed that cognitive performance in all fields in MS was moderately to strong correlation with thalamus volume (r=0.506-0.724, p0.005). The more severe thalamus atrophy, the lower the cognitive function score 17 .
Brain atrophy has become an important indicator for evaluating the therapeutic effect of DMT
Previously commonly used efficacy evaluation indicators—relapse and new focal MRI lesions—provides useful information about MS inflammatory activity, but cannot fully explain the progress of neurodegenerative diseases. Disability assessment through EDSS can only partially reflect neurodegenerative damage. Brain atrophy is an effective, sensitive and reproducible measurement indicator for neurodegenerative changes in MS 2,7.
"MAGNIMS Consensus Recommendations: Application of Brain and Spinal Cord Atrophy Measurement in MS Clinical Practice" released in 2020 pointed out that it is recommended to use whole brain atrophy (at least 12 months is a cycle) as the secondary endpoint or even the primary endpoint of MS clinical trials to evaluate the role of drugs on disease-related neurodegenerative changes. Ongoing and coming clinical trials should use gray matter capacity loss as a prognostic evaluation indicator 18; "Deep Gray Matt Injury in MS: NAIMS Consensus Statement" released in 2021 It is pointed out that brain atrophy represents irreversible tissue loss, which is exactly what disease-corrected treatment (DMT) needs to prevent. Future studies may use atrophy as an outcome rather than a predictor to study the biological mechanism of volume loss. The impact of DMT on the whole brain capacity of MS patients has been widely described, but the study on the impact of DMT on the structure of deep gray matter has just begun. The MRI endpoint of deep gray matter atrophy is likely to be included in future clinical trials 19.
How to delay brain atrophy in MS patients
In the treatment of MS, not only drugs that can control the inflammatory process, but also drugs that can prevent the progression and neurodegeneration of brain atrophy. The currently approved DMT drugs have different effects on brain atrophy 2. For patients with relapsed MS, enabling DMT treatment in the early stages of the disease can better improve long-term prognosis than delayed treatment. 20. In order to maximize brain atrophy, it is crucial to choose suitable DMT drugs for patients as soon as possible. .
Regular monitoring is the core of MS management . Improving the efficacy of treatment by monitoring MS disease activity is the key to maximizing brain health. Even without clinical recurrence or progression of disability, all disease activity can damage the tissue of central nervous system . Regular MRI examinations can monitor disease activity and early warning of poor response to treatment of MS, and brain atrophy that prompts disability progression and cognitive dysfunction 20.
MS patients need comprehensive treatment and management . No matter what type of MS patients, lifestyles such as quitting smoking, participating in cardiovascular physical training, maintaining a healthy weight, insisting on intellectual activities, avoiding excessive drinking, and maximizing the control of complications will help maximize the brain health of MS patients 20.
Although due to some technical problems, the routine use of 21 in clinical practice is limited, many large-scale clinical studies have confirmed the correlation between brain atrophy and disability progression and cognitive dysfunction, and large-sample-sized 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 the efficacy evaluation index of brain atrophy and select patients as soon as possible , which can effectively delay brain atrophy. With the emergence of new regional brain capacity measurement technologies and advanced neuroimaging technologies, it is believed that measurement of brain capacity changes will gradually be incorporated into clinical practice to assist in the formulation of treatment decisions and the management of individual patients, thereby helping to personalize patient care 22.
Expert profile
Professor Yang Huan
Central South University Xiangya Hospital Chief physician of Department of Neurology, Director of the sub-specialty of neuroimmunology and neuromyology, Doctoral supervisor
Member of Neurology Branch of the Chinese Medical Association Neurology Branch
Peripheral Neurology Collaboration Group Member
Member of Neurology Professional Committee of Hunan Medical Association and Leader of Neurology Group
Hunan Standing Director of the Provincial Immunology Society and Chairman of the Neuromus Branch
Standing Director of the Hunan Provincial Rehabilitation Medical Association, Chairman of the Professional Committee of Myopathy and Peripheral Neurology
Standing Committee Member of the Hunan Provincial Rare Disease Society
Standing Committee Member of the New Technology Professional Committee of Hunan Medical Education and Science and Technology Society
" Chinese Journal of Neurology ", "Chinese Journal of General Practitioners" and other magazines
- SCI Journal "Journal The deputy editor-in-chief of Neuroimmunology,
, won the projects including 6 National Natural Science Foundation of China, 1 "Ministry of Education's New Century Outstanding Talent Fund", and
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, 2021, won the second Hunan Provincial Top Ten Medical Clinical Innovation Technology Award
Expert commented
MS is a progressive disease, inflammation and neurodegeneration are important characteristics of MS
Expert comments
MS is a progressive disease, inflammation and neurodegenerative changes are important characteristics of MS
MS is a progressive disease, inflammation and neurodegenerative changes are important characteristics of MS .
Brain atrophy represents irreversible tissue loss, which is more closely related to clinical recurrence, MRI evidence of disease activity and disability worsening and neurodegeneration.
Brain atrophy has occurred in the early stages of MS, which is significantly faster than that of healthy people, and the brain capacity loss rate of young patients is higher in
.
Brain atrophy is related to long-term disability progression and cognitive decline and predicts its development, and has become an important indicator for evaluating the efficacy of DMT treatment.
Given the important position of brain atrophy in MS, we should pay more attention to brain atrophy in clinical practice, pay attention to evidence of the efficacy of DMT drugs to delay brain atrophy, and select appropriate DMT drugs for patients in the early stages of the disease to maximize the brain health of MS patients and improve cognitive function.
The key phase III study of some existing DMT drugs in my country has not achieved consistent results in delaying cerebral atrophy, and new drugs are still needed to further meet the needs of patients. Two clinical studies of
, published in Lancet Neurology, the largest -positive control phase 3 clinical studies, showed that compared with interferon β-1a, ozamod significantly delayed whole-brain atrophy, cortical gray matter atrophy and thalamic atrophy, among which the risk of cortical gray matter atrophy was reduced by up to 84%. The effect on thalamic atrophy was reported for the first time in the main analysis of the MS Phase III study; ozamod significantly improved cognitive function, and continued to be treated for 3 years, and 77% of patients were protected or improved. We look forward to Ozamod being approved for marketing as soon as possible, bringing new brain protection options for Chinese MS patients.
References:
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