Hereditary transthyretin amyloid neuropathies: advances in pathophysiology, biomarkers, and treatment

遗传性转甲状腺素蛋白淀粉样神经病: 病理生理学，生物标志物和治疗进展

Hereditary transthyretin (TTR) amyloid polyneuropathy is an autosomal dominant life-threatening disorder. TTR is produced mainly by the liver but also by the choroid plexus and retinal pigment epithelium. Detailed clinical characterisation, identification of clinical red flags for misdiagnosis, and use of biomarkers enable early diagnosis and treatment. In addition to liver transplantation and TTR stabilisers, three other disease-modifying therapies have regulatory approval: one antisense oligonucleotide (inotersen) and two small interfering RNAs (siRNAs; patisiran and vutrisiran). The siRNAs have been shown to stop progression of neuropathy and improve patients' quality of life. As none of the disease-modifying therapies can cross the blood-brain barrier, TTR deposition in the CNS, which can cause stroke and cognitive impairment, remains an important unaddressed issue. CRISPR-Cas9-based one-time TTR editing therapy is being investigated in a phase 1 clinical study. Identification of the earliest stages of pathogenesis in TTR variant carriers is a major challenge that needs addressing for optimal management.

遗传性甲状腺素运载蛋白 (TTR) 淀粉样多神经病是一种常染色体显性威胁生命的疾病。TTR主要由肝脏产生，但也由脉络丛和视网膜色素上皮产生。详细的临床特征，识别误诊的临床危险信号以及使用生物标志物可以进行早期诊断和治疗。除肝移植和TTR稳定剂外，其他三种疾病缓解疗法已获得监管部门的批准: 一种反义寡核苷酸 (inotersen) 和两种小干扰rna (sirna; patisiran和vutrisiran)。Sirna已被证明可以阻止神经病变的进展并改善患者的生活质量。由于没有一种疾病改善疗法可以穿过血脑屏障，因此CNS中的TTR沉积可能导致中风和认知障碍，仍然是一个重要的未解决的问题。CRISPR-Cas9-based一次性TTR编辑疗法正在1期临床研究中进行研究。鉴定TTR变异携带者发病机理的最早阶段是需要解决以实现最佳管理的主要挑战。

REF: Adams D, Sekijima Y, Conceição I, et al. Hereditary transthyretin amyloid neuropathies: advances in pathophysiology, biomarkers, and treatment. Lancet Neurol. 2023;22(11):1061-1074. doi:10.1016/S1474-4422(23)00334-4 PMID: 37863593

Stimulation of TREM2 with agonistic antibodies—an emerging therapeutic option for Alzheimer's disease

用激动性抗体刺激TREM2-阿尔茨海默氏病的新兴治疗选择

Neurodegenerative disorders, including Alzheimer's disease, are associated with microgliosis. Microglia have long been considered to have detrimental roles in Alzheimer's disease. However, functional analyses of genes encoding risk factors that are linked to late-onset Alzheimer's disease, and that are enriched or exclusively expressed in microglia, have revealed unexpected protective functions. One of the major risk genes for Alzheimer's disease is TREM2. Risk variants of TREM2 are loss-of-function mutations affecting chemotaxis, phagocytosis, lipid and energy metabolism, and survival and proliferation. Agonistic anti-TREM2 antibodies have been developed to boost these protective functions in patients with intact TREM2 alleles. Several anti-TREM2 antibodies are in early clinical trials, and current efforts aim to achieve more efficient transport of these antibodies across the blood-brain barrier. PET imaging could be used to monitor target engagement. Data from animal models, and biomarker studies in patients, further support a rationale for boosting TREM2 functions during the preclinical stage of Alzheimer's disease.

神经退行性疾病，包括阿尔茨海默病，与小胶质细胞增生有关。长期以来，小胶质细胞被认为在阿尔茨海默病中具有有害作用。然而，编码与迟发性阿尔茨海默病相关的风险因子的基因的功能分析，以及在小胶质细胞中富集或专门表达的基因，揭示了意想不到的保护功能。阿尔茨海默病的主要风险基因之一是trem2。TREM2的风险变体是影响趋化性，吞噬作用，脂质和能量代谢以及存活和增殖的功能丧失突变。已经开发了激动性anti-TREM2抗体来增强具有完整TREM2等位基因的患者的这些保护功能。几种anti-TREM2抗体处于早期临床试验中，目前的努力旨在实现这些抗体更有效地运输穿过血脑屏障。PET成像可用于监测目标接合。来自动物模型和患者生物标志物研究的数据进一步支持了在阿尔茨海默病临床前阶段增强TREM2功能的原理。

REF: Schlepckow K, Morenas-Rodríguez E, Hong S, Haass C. Stimulation of TREM2 with agonistic antibodies-an emerging therapeutic option for Alzheimer's disease. Lancet Neurol. 2023;22(11):1048-1060. doi:10.1016/S1474-4422(23)00247-8 PMID: 37863592

Global, regional, and national burden of spinal cord injury, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

1990至2019脊髓损伤的全球、区域和国家负担: 全球疾病负担研究2019的系统分析

Spinal cord injury (SCI) is a major cause of health loss due to premature mortality and long-term disability. We aimed to report on the global, regional, and national incidence, prevalence, and years of life lived with disability (YLDs) for SCI from 1990 to 2019, using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. Although age-standardised rates of incidence, prevalence, and YLDs for SCI changed only slightly, absolute counts increased substantially from 1990 to 2019. Geographical heterogeneity in demographic, spatial, and temporal patterns of SCI, at both the national and regional levels, should be considered by policy makers aiming to reduce the burden of SCI.

脊髓损伤 (SCI) 是导致过早死亡和长期残疾的健康损失的主要原因。我们的目的是使用全球疾病负担，伤害和危险因素研究 (GBD) 2019的数据，报告1990年至2019年SCI的全球，区域和国家发病率，患病率和残疾寿命 (YLDs)。尽管SCI的年龄标准化发病率，患病率和YLDs仅略有变化，但从1990年到2019年，绝对计数大幅增加。政策制定者应在国家和区域两级考虑SCI的人口，空间和时间模式的地理异质性，以减轻SCI的负担。

REF: GBD Spinal Cord Injuries Collaborators. Global, regional, and national burden of spinal cord injury, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2023;22(11):1026-1047. doi:10.1016/S1474-4422(23)00287-9 PMID: 37863591 PMCID: PMC10584692

Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study

在非洲和非洲混合人群中识别与帕金森氏病相关的遗传风险基因座和因果见解: 全基因组关联研究

An understanding of the genetic mechanisms underlying diseases in ancestrally diverse populations is an important step towards development of targeted treatments. Research in African and African admixed populations can enable mapping of complex traits, because of their genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. We aimed to do a comprehensive genome-wide assessment in African and African admixed individuals to better understand the genetic architecture of Parkinson's disease in these underserved populations. Our study identified a novel genetic risk factor in GBA1 in people of African ancestry, which has not been seen in European populations, and it could be a major mechanistic basis of Parkinson's disease in African populations. This population-specific variant exerts substantial risk on Parkinson's disease as compared with common variation identified through GWAS and it was found to be present in 39% of the cases assessed in this study. This finding highlights the importance of understanding ancestry-specific genetic risk in complex diseases, a particularly crucial point as the Parkinson's disease field moves towards targeted treatments in clinical trials. The distinctive genetics of African populations highlights the need for equitable inclusion of ancestrally diverse groups in future trials, which will be a valuable step towards gaining insights into novel genetic determinants underlying the causes of Parkinson's disease. This finding opens new avenues towards RNA-based and other therapeutic strategies aimed at reducing lifetime risk of Parkinson's disease.

了解祖先不同人群中疾病的遗传机制是开发靶向治疗的重要一步。由于非洲和非洲混合种群的遗传多样性，广泛的种群子结构和独特的连锁不平衡模式，对非洲和非洲混合种群的研究可以绘制复杂性状的图谱。我们的目标是在非洲和非洲混合个体中进行全面的全基因组评估，以更好地了解这些服务不足的人群中帕金森病的遗传结构。我们的研究确定了非洲血统人群中GBA1的一种新的遗传风险因素，这在欧洲人群中没有发现，这可能是非洲人群帕金森病的主要机制基础。与通过gas鉴定的常见变异相比，这种人群特异性变异对帕金森氏病具有很大的风险，并且发现该变异存在于本研究评估的39% 病例中。这一发现强调了理解复杂疾病中祖先特异性遗传风险的重要性，这是帕金森病领域在临床试验中转向靶向治疗的一个特别关键的点。非洲人口的独特遗传学强调了在未来的试验中公平纳入祖先多样化群体的必要性，这将是深入了解帕金森病病因的新遗传决定因素的宝贵一步。这一发现为基于RNA的治疗策略和其他旨在降低帕金森病终生风险的治疗策略开辟了新的途径。

REF: Rizig M, Bandres-Ciga S, Makarious MB, et al. Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study. Lancet Neurol. 2023;22(11):1015-1025. doi:10.1016/S1474-4422(23)00283-1 PMID: 37633302 PMCID: PMC10593199

Intracranial pressure monitoring with and without brain tissue oxygen pressure monitoring for severe traumatic brain injury in France (OXY-TC): an open-label, randomised controlled superiority trial

有或没有脑组织氧分压监测的颅内压监测在法国严重创伤性脑损伤 (oxy-tc): 一项开放标签，随机对照优势试验

Optimisation of brain oxygenation might improve neurological outcome after traumatic brain injury. The OXY-TC trial explored the superiority of a strategy combining intracranial pressure and brain tissue oxygen pressure (PbtO2) monitoring over a strategy of intracranial pressure monitoring only to reduce the proportion of patients with poor neurological outcome at 6 months. After severe non-penetrating traumatic brain injury, intracranial pressure and PbtO2 monitoring did not reduce the proportion of patients with poor neurological outcome at 6 months. Technical failures related to intracerebral catheter and intracerebral haematoma were more frequent in the intracranial pressure and PbtO2 group. Further research is needed to assess whether a targeted approach to multimodal brain monitoring could be useful in subgroups of patients with severe traumatic brain injury-eg, those with high intracranial pressure on admission.

优化脑氧合可能会改善创伤性脑损伤后的神经系统结果。Oxy-tc试验探讨了将颅内压和脑组织氧压 (PbtO2) 监测相结合的策略优于仅颅内压监测策略的优越性，以减少6个月时神经系统预后不良的患者比例。严重非穿透性颅脑损伤后，颅内压和PbtO2监测未降低6个月时神经功能不良患者的比例。在颅内压和PbtO2组中，与脑内导管和脑内血肿有关的技术故障更为常见。需要进一步的研究来评估有针对性的多模式脑监测方法是否对严重创伤性脑损伤患者亚组有用-例如入院时颅内压高的患者。

REF: Payen JF, Launey Y, Chabanne R, et al. Intracranial pressure monitoring with and without brain tissue oxygen pressure monitoring for severe traumatic brain injury in France (OXY-TC): an open-label, randomised controlled superiority trial. Lancet Neurol. 2023;22(11):1005-1014. doi:10.1016/S1474-4422(23)00290-9 PMID: 37863590

Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial

降血压药物对小血管疾病患者微血管功能的影响 (trete-svds): 一项多中心、开放标签、随机、交叉试验

Hypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect microvascular function in people with small vessel disease. 4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in people with sporadic small vessel disease but did result in differential treatment effects in patients with CADASIL. Whether antihypertensive drug classes differentially affect clinical outcomes in people with small vessel diseases requires further research.

高血压是脑小血管病的主要危险因素。我们的目的是确定抗高血压药物种类是否对小血管疾病患者的微血管功能有不同的影响。在散发性小血管疾病患者中，氨氯地平，氯沙坦或阿替洛尔治疗4周对脑血管反应性的影响没有差异，但在CADASIL患者中确实产生了不同的治疗效果。抗高血压药物种类是否会对小血管疾病患者的临床结局产生不同影响，需要进一步研究。

REF: Kopczak A, Stringer MS, van den Brink H, et al. Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial. Lancet Neurol. 2023;22(11):991-1004. doi:10.1016/S1474-4422(23)00293-4 PMID: 37863608

Sleep, melatonin, and cardiovascular disease

睡眠，褪黑激素和心血管疾病

Melatonin is a key circadian mediator that governs the synchronisation of peripheral biological rhythms with the central clock (ie, the suprachiasmatic nucleus) and regulates the sleep–wake cycle. The synthesis of this hormone by the pineal gland follows a nyctohemeral pattern that aligns with the day–light cycle: production is low during the day and high at night. The rhythmic secretion of melatonin from the pineal gland is controlled by a multisynaptic pathway, through the retinal–hypothalamic–suprachiasmatic nucleus tract to the superior cervical ganglia. These ganglia convey circadian information to the pineal gland, dictating nocturnal melatonin secretion through sympathetic adrenergic stimulation. Melatonin also has cardiovascular effects, including vasodilation and scavenging of reactive oxygen species. 1 Sleep disturbance and cardiovascular disease are common comorbidities. 2 Disrupted sleep might increase the risk of cardiovascular disease through multiple mechanisms, including sympathetic activation. However, emerging data suggest that the relationship between poor sleep and cardiovascular disease could be bidirectional—ie, cardiovascular disease might elicit sleep disorders.

褪黑激素是一种关键的昼夜节律介体，它控制着周围生物节律与中央时钟 (即视交叉上核) 的同步，并调节睡眠-觉醒周期。松果体对这种激素的合成遵循与昼夜周期一致的夜色模式: 白天产量低，晚上产量高。松果体褪黑素的节律性分泌由多突触途径控制，通过视网膜-下丘脑-视交叉上核束到上颈神经节。这些神经节将昼夜节律信息传递到松果体，通过交感肾上腺素能刺激指示夜间褪黑激素分泌。褪黑激素还具有心血管作用，包括血管舒张和清除活性氧。1睡眠障碍和心血管疾病是常见的合并症。睡眠中断可能通过多种机制增加心血管疾病的风险，包括交感神经激活。然而，新出现的数据表明，睡眠不足与心血管疾病之间的关系可能是双向的，即心血管疾病可能引发睡眠障碍。

REF: Covassin N, Somers VK. Sleep, melatonin, and cardiovascular disease. Lancet Neurol. 2023;22(11):979-981. doi:10.1016/S1474-4422(23)00363-0 PMID: 37863599

Radiologically isolated syndrome: knowns and unknowns

放射学孤立综合征: 已知和未知

Radiologically isolated syndrome (RIS) was defined by Darin Okuda and colleagues in 2009 to describe people who have incidental MRI findings suggestive of multiple sclerosis but no symptoms of multiple sclerosis. 1 Non-specific white matter hyperintensities on MRI are very common in the general population and, given the increased availability of MRI scanners in many countries and technical improvements in scanning methods, there will undoubtedly also be a greater number of people identified as having RIS in the coming few years. In longitudinal studies, around half of people with RIS developed clinical symptoms leading to a diagnosis of multiple sclerosis within 10 years. 2 Risk of subsequent diagnosis of multiple sclerosis has been associated with several demographic factors (eg, being younger than 37 years and male sex), laboratory biomarkers (eg, CSF-restricted oligoclonal bands), and neuroradiological features (eg, spinal cord, infratentorial, or gadolinium-enhancing lesions).

放射学孤立综合征 (RIS) 由Darin Okuda及其同事在2009年定义，用于描述具有提示多发性硬化症但没有多发性硬化症症状的偶然MRI发现的人。1 MRI上的非特异性白质高信号在普通人群中非常常见，并且鉴于许多国家MRI扫描仪的可用性增加以及扫描方法的技术改进，毫无疑问，在未来几年中，也将有更多的人被确定为患有ri。在纵向研究中，大约一半的RIS患者在10年内出现临床症状，导致多发性硬化症的诊断。随后诊断为多发性硬化的风险与多种人口统计学因素 (如小于37岁和男性) 、实验室生物标志物 (如CSF限制性寡克隆带) 和神经放射学特征 (如脊髓、幕下或钆增强病变) 有关。

REF: Filippi M, Rocca MA. Radiologically isolated syndrome: knowns and unknowns. Lancet Neurol. 2023;22(11):978-979. doi:10.1016/S1474-4422(23)00362-9 PMID: 37839431

Global burden of spinal cord injury: future directions

脊髓损伤的全球负担: 未来方向

Findings from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) have provided valuable insight into the descriptive epidemiology of diseases and injuries for many countries over time. 1 GBD 2019 approximates incidence, prevalence, and years of life lived with disability (YLDs) for more than 350 unique diseases and injuries for 204 countries and territories from 1990 to 2019. 2 Among these diseases and injuries is spinal cord injury, a debilitating neurological condition that can result in lifelong disability and costly medical care, which has become a global health priority owing to the preventability of some injuries. GBD investigators have previously reported on the global, regional, and national burden of spinal cord injury from 1990 to 2016, 3 and since then, two articles have independently reported on changes in the incidence, prevalence, and YLDs for spinal cord injury using GBD 2019 data: one study by Ding and colleagues, 4 published in November, 2022, and a second by the GBD Spinal Cord Injuries Collaborators, published in The Lancet Neurology. 5 Both studies concluded that, despite increasing occurrence of spinal cord injury due to population growth and a shift in spinal cord injury towards older adults over time, overall age-standardised incidence, prevalence, and YLDs rates changed minimally between 1990 and 2019.

全球疾病，伤害和危险因素负担研究 (GBD) 的发现为许多国家随着时间的推移对疾病和伤害的描述性流行病学提供了宝贵的见解。1 GBD 2019近似于1990年至2019年204个国家和地区的350多种独特疾病和伤害的发病率，患病率和残疾寿命 (YLDs)。2在这些疾病和损伤中，脊髓损伤是一种使人衰弱的神经系统疾病，可能导致终身残疾和昂贵的医疗保健，由于某些损伤的可预防性，脊髓损伤已成为全球卫生优先事项。GBD研究人员以前曾报道过1990年至2016年的全球，地区和国家脊髓损伤负担3，从那时起，有两篇文章使用GBD 2019数据独立报道了脊髓损伤的发病率，患病率和yld的变化: Ding及其同事的一项研究，4发表于2022年11月，第二篇由GBD脊髓损伤合作者发表在《柳叶刀神经病学》上。5两项研究都得出结论，尽管随着时间的推移，由于人口增长和脊髓损伤向老年人转移，脊髓损伤的发生率不断增加，但总体年龄标准化发病率，患病率和YLDs率在1990年至2019之间变化很小。

REF: Crispo JAG, Kuramoto LK, Cragg JJ. Global burden of spinal cord injury: future directions. Lancet Neurol. 2023;22(11):976-978. doi:10.1016/S1474-4422(23)00366-6 PMID: 37863598