Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases.
Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases.
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预防肌萎缩侧索硬化症：症状前神经退行性疾病的见解。
DOI：
10.1093/brain/awab404
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发表时间：
2022-03-29
期刊：
影响因子：
--
通讯作者：
First International Pre-Symptomatic ALS Workshop
中科院分区：
文献类型：
--
作者：
Benatar M;Wuu J;McHutchison C;Postuma RB;Boeve BF;Petersen R;Ross CA;Rosen H;Arias JJ;Fradette S;McDermott MP;Shefner J;Stanislaw C;Abrahams S;Cosentino S;Andersen PM;Finkel RS;Granit V;Grignon AL;Rohrer JD;McMillan CT;Grossman M;Al-Chalabi A;Turner MR;First International Pre-Symptomatic ALS Workshop
在了解肌萎缩侧索硬化症的症状前阶段方面已经取得了重大进展。虽然仍有许多未知之处，但其他神经退行性疾病的进展提供了宝贵的见解。事实上，越来越清楚的是，公认的阿尔茨海默病、帕金森氏病、亨廷顿病、脊髓性肌萎缩症和额颞叶痴呆症等临床症状之前，都有一个不同持续时间的症状前期或先兆时期，在此期间，潜在的疾病过程会展开，伴随着相关的代偿性变化和固有系统冗余的丧失。来自这些疾病的关键见解突出了肌萎缩侧索硬化症的发现机会。反映淀粉样蛋白和tau蛋白的生物标记物的发展已经导致了根据推断的潜在组织病理学来定义阿尔茨海默病的转变。帕金森病在神经退行性疾病中是独一无二的，因为有症状前疾病的非遗传生物标记物的数量和多样性，最明显的是REM睡眠行为障碍。亨廷顿氏病得益于根据年龄和CAG重复长度预测临床明显疾病的可能时间的能力，以及可靠的萎缩神经成像标记物。脊髓性肌萎缩症的临床试验强调了早期治疗干预的转化价值，对额颞叶痴呆的研究表明了基于基因的生物标记物的不同作用。肌萎缩侧索硬化症的类似进展将改变我们对发病机制中关键事件的理解，从而显著加快疾病预防的进展。破译症状前肌萎缩侧索硬化症的生物学依赖于一个明确的概念框架来定义疾病的早期阶段。临床上明显的肌萎缩侧索硬化症可能会突然出现，特别是那些携带与快速进展性肌萎缩侧索硬化症相关的基因突变的人。然而，疾病也可能演变得更缓慢，在表型转化为临床明显疾病之前，显示出轻度运动障碍的前驱时期。同样，认知和行为障碍，如果存在，可能会逐渐出现，在进展为肌萎缩侧索硬化症之前，经历轻度认知障碍或轻度行为障碍的前驱期。生物标记物对于研究症状前肌萎缩侧索硬化症至关重要，对于在临床显性疾病出现之前进行治疗干预的努力也是必不可少的。然而，非遗传生物标记物的使用在咨询、知情同意、结果通报和现有立法提供的有限保护方面构成了挑战。症状前基因检测和咨询的经验，以及针对基于基因数据的歧视的法律保护，可以作为指导。在我们所学知识的基础上--更广泛地说，从其他无症状的神经退行性疾病，特别是从肌萎缩侧索硬化症基因突变携带者那里--我们提出了对所有形式的肌萎缩侧索硬化症进行早期干预，甚至疾病预防的路线图。贝纳塔尔等人。提供关于一系列神经退行性疾病的症状前阶段的已知情况的现场摘要。他们确定了重要的经验教训，可以改变对肌萎缩侧索硬化症早期阶段的理解，从而加快肌萎缩侧索硬化症预防的进展。
Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer’s disease based on inferred underlying histopathology. Parkinson’s disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington’s disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned—more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers—we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis. Benatar et al. provide a state-of-the-field summary of what is known about the pre-symptomatic phase of an array of neurodegenerative diseases. They identify important lessons that could transform understanding of the earliest stages of ALS, and thereby accelerate progress towards ALS prevention.
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影响因子：
--
作者：
BENTON, AL;VARNEY, NR;HAMSHER, KD
通讯作者：
HAMSHER, KD
影响因子：
10.6
作者：
Aylward, Elizabeth H.;Liu, Dawei;Nopoulos, Peggy C.;Ross, Christopher A.;Pierson, Ronald K.;Mills, James A.;Long, Jeffrey D.;Paulsen, Jane S.
通讯作者：
Paulsen, Jane S.
影响因子：
8.6
作者：
Berg, Daniela;Postuma, Ronald B.;Bloem, Bastiaan;Chan, Piu;Dubois, Bruno;Gasser, Thomas;Goetz, Christopher G.;Halliday, Glenda M.;Hardy, John;Lang, Anthony E.;Litvan, Irene;Marek, Kenneth;Obeso, Jose;Oertel, Wolfgang;Olanow, C. Warren;Poewe, Werner;Stern, Matthew;Deuschl, Guenther
通讯作者：
Deuschl, Guenther
影响因子：
11.2
作者：
Benatar, Michael;Wuu, Joanne;Malaspina, Andrea
通讯作者：
Malaspina, Andrea
DOI：
10.1016/s0140-6736(15)00461-4
发表时间：
2015-10-24
期刊：
Lancet (London, England)
影响因子：
--
作者：
Bang J;Spina S;Miller BL
通讯作者：
Miller BL