Recurrent de-novo gain-of-function mutation in SPTLC2 confirms dysregulated sphingolipid production to cause juvenile amyotrophic lateral sclerosis

SPTLC2中反复出现的去新生功能获得突变证实鞘磷脂产生失调导致幼年型肌萎缩侧索硬化症

Amyotrophic lateral sclerosis (ALS) leads to paralysis and death by progressive degeneration of motor neurons. Recently, specific gain-of-function mutations in SPTLC1 were identified in patients with juvenile form of ALS. SPTLC2 encodes the second catalytic subunit of the serine-palmitoyltransferase (SPT) complex. Specific gain-of-function mutations in both core subunits affect the homoeostatic control of SPT. SPTLC2 represents a new Mendelian ALS gene, highlighting a key role of dysregulated sphingolipid synthesis in the pathogenesis of juvenile ALS. Given the direct interaction of SPTLC1 and SPTLC2, this knowledge might open new therapeutic avenues for motor neuron diseases.

肌萎缩侧索硬化症(ALS)通过运动神经元的进行性变性导致瘫痪和死亡。最近，在幼年型肌萎缩侧索硬化症患者中发现了SPTLC1特异的功能获得突变。SPTLC2编码丝氨酸-棕榈酰转移酶(SPT)复合体的第二催化亚基。两个核心亚单位中特定的功能增益突变会影响SPT的稳态控制。SPTLC2代表了孟德尔ALS的一个新基因，突显了鞘磷脂合成失调在青少年ALS发病机制中的关键作用。鉴于SPTLC1和SPTLC2的直接相互作用，这一认识可能会为运动神经元疾病的治疗开辟新的途径。

REF: Dohrn MF, Beijer D, Lone MA, et al. Recurrent de-novo gain-of-function mutation in SPTLC2 confirms dysregulated sphingolipid production to cause juvenile amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. Published online November 24, 2023. doi:10.1136/jnnp-2023-332130 PMID: 38041684

Pragmatic computerised perfusion diagnostics for non-convulsive status epilepticus: a prospective observational study

非惊厥性癫痫持续状态的实用化计算机灌注诊断：一项前瞻性观察研究

Non-convulsive status epilepticus (NCSE) is a time-dependent neurological disorder often misdiagnosed in the emergency setting. Electroencephalography (EEG) is often not available on a 24/7 basis, and Salzburg criteria may at times miss the diagnosis. Here, we tested the accuracy of hyperperfusion on CT perfusion imaging (CTP) in the identification of NCSE against Salzburg criteria, to define its potential role in a pragmatic diagnostic workflow. CTP hyperperfusion may be implemented in the emergency fast-track to rule out NCSE, given very high NPV. Further validation studies are needed to evaluate CTP application in real-world setting for NCSE codes.

非惊厥性癫痫持续状态(NCSE)是一种时效性神经系统疾病，在急诊时常被误诊。脑电(EEG)通常不是全天候的，Salzburg标准有时可能会遗漏诊断。在这里，我们根据Salzburg标准测试了CT灌注成像(CTP)在识别NCSE中的准确性，以确定其在实用诊断工作流程中的潜在作用。考虑到非常高的NPV，可以在急诊快速通道中实施CTP高灌注以排除NCSE。需要进一步的验证研究来评估CTP在NCSE代码的真实环境中的应用。

REF: Merli E, Romoli M, Galluzzo S, et al. Pragmatic computerised perfusion diagnostics for non-convulsive status epilepticus: a prospective observational study. J Neurol Neurosurg Psychiatry. Published online November 24, 2023. doi:10.1136/jnnp-2023-332152 PMID: 38041670

Recurrent de novo SPTLC2 variant causes childhood-onset amyotrophic lateral sclerosis (ALS) by excess sphingolipid synthesis

复发的SPTLC2变异通过鞘磷脂过度合成导致儿童期起病的肌萎缩侧索硬化症(ALS)

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motor neurons with varying ages of onset, progression and pathomechanisms. Monogenic childhood-onset ALS, although rare, forms an important subgroup of ALS. We recently reported specific SPTLC1 variants resulting in sphingolipid overproduction as a cause for juvenile ALS. Here, we report six patients from six independent families with a recurrent, de novo, heterozygous variant in SPTLC2 c.778G>A [p.Glu260Lys] manifesting with juvenile ALS. SPTLC2 is the second SPT-associated gene that underlies monogenic, juvenile ALS and further establishes alterations of sphingolipid metabolism in motor neuron disease pathogenesis. Our findings also have important therapeutic implications: serine supplementation must be avoided in SPT-associated ALS, as it is expected to drive pathogenesis further.

肌萎缩侧索硬化症(ALS)是一种发生、发展和发病机制不同的上下运动神经元的神经退行性疾病。单基因儿童期起病的肌萎缩侧索硬化症虽然罕见，但却是肌萎缩侧索硬化症的重要亚群。我们最近报道了导致鞘磷脂过度产生的特定SPTLC1变异是青少年ALS的一个原因。在这里，我们报告了来自六个独立家系的六名患者，他们在SPTLC2C.778G>A[p.Glu260Lys]中出现了一个复发的、从头开始的杂合子变异，表现为青少年ALS。SPTLC2是第二个SPT相关基因，它是单基因青少年ALS的基础，并进一步确立了运动神经元病发病机制中鞘磷脂代谢的改变。我们的发现还具有重要的治疗意义：在SPT相关的ALS中必须避免补充丝氨酸，因为它有望进一步推动发病。

REF: Syeda SB, Lone MA, Mohassel P, et al. Recurrent de novo SPTLC2 variant causes childhood-onset amyotrophic lateral sclerosis (ALS) by excess sphingolipid synthesis. J Neurol Neurosurg Psychiatry. Published online November 24, 2023. doi:10.1136/jnnp-2023-332132 PMID: 38041679

Predictive value of retinal atrophy for cognitive decline across disease duration in multiple sclerosis

视网膜萎缩对多发性硬化症患者跨病程认知功能下降的预测价值

We investigated the association between changes in retinal thickness and cognition in people with MS (PwMS), exploring the predictive value of optical coherence tomography (OCT) markers of neuroaxonal damage for global cognitive decline at different periods of disease. The progressive retinal thinning is related to cognitive decline, indicating that cognitive dysfunction is a late manifestation of accumulated neuroaxonal damage. Quantifying the pRFNL aids in identifying individuals at risk of cognitive dysfunction.

进行性视网膜变薄与认知功能下降有关，提示认知功能障碍是神经轴突损伤累积性的晚期表现。量化pRFNL有助于识别有认知功能障碍风险的个体。

REF: Alba-Arbalat S, Solana E, Lopez-Soley E, et al. Predictive value of retinal atrophy for cognitive decline across disease duration in multiple sclerosis. J Neurol Neurosurg Psychiatry. Published online November 21, 2023. doi:10.1136/jnnp-2023-332332 PMID: 37989566

Quantitative MRI outcome measures in CMT1A using automated lower limb muscle segmentation

使用自动下肢肌肉分割的CMT1A患者的定量MRI结果测量

Lower limb muscle magnetic resonance imaging (MRI) obtained fat fraction (FF) can detect disease progression in patients with Charcot-Marie-Tooth disease 1A (CMT1A). However, analysis is time-consuming and requires manual segmentation of lower limb muscles. We aimed to assess the responsiveness, efficiency and accuracy of acquiring FF MRI using an artificial intelligence-enabled automated segmentation technique. Using automated image segmentation for the first time in a longitudinal study in CMT, we have demonstrated that calf FF has similar responsiveness to previously published data, is efficient with minimal time needed for QC checks and is accurate with minimal corrections needed.

下肢肌肉磁共振成像（MRI）获得的脂肪分数（FF）可以检测Charcot-Marie-Tooth病1A（CMT 1A）患者的疾病进展。然而，分析是耗时的，并且需要对下肢肌肉进行手动分割。我们旨在评估使用人工智能自动分割技术获取FF MRI的响应性、效率和准确性。在CMT的纵向研究中首次使用自动图像分割，我们已经证明小牛FF对先前发表的数据具有相似的响应性，有效且QC检查所需时间最短，并且准确且所需校正最少。

REF: O'Donnell LF, Pipis M, Thornton JS, et al. Quantitative MRI outcome measures in CMT1A using automated lower limb muscle segmentation. J Neurol Neurosurg Psychiatry. Published online November 18, 2023. doi:10.1136/jnnp-2023-332454 PMID: 37979968

Evolution of brain MRI lesions in paediatric myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and its relevance to disease course

儿童髓鞘-少突胶质细胞糖蛋白抗体相关性疾病（MOGAD）脑MRI病变的演变及其与病程的相关性

Lesion resolution is often observed in children with myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and asymptomatic lesions are less commonly reported in MOGAD than in multiple sclerosis (MS). We aimed to evaluate brain MRI changes over time in paediatric MOGAD. The striking differences in lesion dynamics between MOGAD and MS suggest greater potential to repair. Early treatment with steroids and plasma exchange is associated with reduced likelihood of new lesions.

髓鞘少突胶质细胞糖蛋白抗体相关疾病(MOGAD)的儿童常可观察到病变的消退，而无症状病变在MOGAD中的报道比多发性硬化症(MS)少。我们的目标是评估儿童MOGAD患者随时间的脑MRI变化。MOGAD和MS在损伤动力学上的显著差异表明修复的潜力更大。早期使用类固醇和血浆置换治疗与降低新病变的可能性有关。

REF: Abdel-Mannan O, Champsas D, Tur C, et al. Evolution of brain MRI lesions in paediatric myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and its relevance to disease course. J Neurol Neurosurg Psychiatry. Published online November 18, 2023. doi:10.1136/jnnp-2023-332542 PMID: 37979966

Dementia prevention: the Mendelian randomisation perspective

痴呆症预防：孟德尔随机化视角

Understanding the causes of Alzheimer's disease and related dementias remains a challenge. Observational studies investigating dementia risk factors are limited by the pervasive issues of confounding, reverse causation and selection biases. Conducting randomised controlled trials for dementia prevention is often impractical due to the long prodromal phase and the inability to randomise many potential risk factors. In this essay, we introduce Mendelian randomisation as an alternative approach to examine factors that may prevent or delay Alzheimer's disease. Mendelian randomisation is a causal inference method that has successfully identified risk factors and treatments in various other fields. However, applying this method to dementia risk factors has yielded unexpected findings. Here, we consider five potential explanations and provide recommendations to enhance causal inference from Mendelian randomisation studies on dementia. By employing these strategies, we can better understand factors affecting dementia risk.

了解阿尔茨海默病和相关痴呆症的原因仍然是一个挑战。调查痴呆症危险因素的观察性研究受到混淆、反向因果关系和选择偏差等普遍问题的限制。进行预防痴呆症的随机对照试验通常是不切实际的，因为先兆阶段较长，而且无法随机化许多潜在的风险因素。在这篇文章中，我们引入孟德尔随机化作为一种替代方法来检查可能预防或延迟阿尔茨海默病的因素。孟德尔随机化是一种因果推断方法，它成功地识别了各种其他领域的风险因素和治疗方法。然而，将这种方法应用于痴呆症的危险因素，得到了意想不到的发现。在这里，我们考虑了五种可能的解释，并提供了建议，以加强孟德尔关于痴呆症的随机研究的因果推断。通过采用这些策略，我们可以更好地了解影响痴呆症风险的因素。

REF: Anderson EL, Davies NM, Korologou-Linden R, Kivimäki M. Dementia prevention: the Mendelian randomisation perspective. J Neurol Neurosurg Psychiatry. Published online November 15, 2023. doi:10.1136/jnnp-2023-332293 PMID: 37967935

Unravelling the influence of affective stimulation on functional neurological symptoms: a pilot experiment examining potential mechanisms

揭示情感刺激对功能性神经症状的影响：一项研究可能机制的先导性实验

Differences in affective processing have previously been shown in functional neurological disorder (FND); however, the mechanistic relevance is uncertain. We tested the hypotheses that highly arousing affective stimulation would result in elevated subjective functional neurological symptoms (FNS), and this would be associated with elevated autonomic reactivity. The possible influence of cognitive detachment was also explored. Emotionally significant events may exert an influence on FNS which is related to autonomic activation rather than altered subjective affect or perceived arousal. This influence may be modulated by cognitive detachment. Further work is needed to determine the relevance and neural bases of these processes in specific FND phenotypes.

情感加工的差异以前在功能性神经障碍(FND)中表现出来；然而，机制上的相关性还不确定。我们测试了高度唤醒情感刺激会导致主观功能性神经症状(FNS)升高的假设，这将与自主神经反应性升高有关。此外，本研究还探讨了认知超脱可能产生的影响。情绪上的重大事件可能会对FNS产生影响，这与自主神经激活有关，而不是改变的主观情绪或知觉唤醒。这种影响可能会受到认知超脱的影响。需要进一步的工作来确定这些过程在特定FND表型中的相关性和神经基础。

REF: Pick S, Millman LM, Ward E, et al. Unravelling the influence of affective stimulation on functional neurological symptoms: a pilot experiment examining potential mechanisms. J Neurol Neurosurg Psychiatry. Published online November 14, 2023. doi:10.1136/jnnp-2023-332364 PMID: 37963722

Serum biomarker levels predict disability progression in patients with primary progressive multiple sclerosis

血清生物标记物水平预测原发性进行性多发性硬化症患者的残疾进展

We aimed to investigate the potential of serum biomarker levels to predict disability progression in a multicentric real-world cohort of patients with primary progressive multiple sclerosis (PPMS). Levels of sNfL, sGFAP and sCHI3L1 are prognostic biomarkers associated with disability progression in patients with PPMS, being CHI3L1 findings less dependent on the inflammatory component associated with disease progression.

我们的目的是研究血清生物标志物水平预测原发性进展型多发性硬化症（PPMS）患者多中心真实世界队列中残疾进展的潜力。sNfL、sGFAP和sCHI3L1的水平是与PPMS患者的残疾进展相关的预后生物标志物，因为CHI3L1的发现较少依赖于与疾病进展相关的炎症组分。

REF: Fissolo N, Benkert P, Sastre-Garriga J, et al. Serum biomarker levels predict disability progression in patients with primary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. Published online November 8, 2023. doi:10.1136/jnnp-2023-332251 PMID: 37940409