Genome-Wide Association Studies of ARIA From the Aducanumab Phase 3 ENGAGE and EMERGE Studies

Aducanumab阶段3 Engage and Emerge研究中ARIA的全基因组关联研究

Amyloid-related imaging abnormalities (ARIA) were the most common adverse events reported in the phase 3 ENGAGE and EMERGE trials of aducanumab, an anti-amyloid monoclonal antibody. APOE ε4 carrier status has been shown to increase risk of ARIA in prior trials of aducanumab and other anti-amyloid therapies; however, the remainder of the human genome has not been evaluated for ARIA risk factors. Therefore, we sought to determine in a hypothesis-free manner whether genetic variants beyond APOE influence risk of ARIA in aducanumab-treated patients. We identified a strong, genome-wide significant association between APOE and risk of ARIA. Future, larger studies may be better powered to detect associations beyond APOE. These findings indicate that APOE is the strongest genetic risk factor of ARIA incidence, with implications for patient management and risk-benefit treatment decisions.

淀粉样蛋白相关成像异常(ARIA)是在抗淀粉样单抗Aducanumab的3期Engage and Emerge试验中报告的最常见的不良事件。在之前的阿杜卡努单抗和其他抗淀粉样蛋白治疗的试验中，已经证明载脂蛋白ε4携带者状态会增加ARIA的风险；然而，人类基因组的其余部分还没有被评估ARIA的风险因素。因此，我们试图以一种无假设的方式确定APOE以外的基因变异是否会影响阿杜卡那单抗治疗患者发生ARIA的风险。我们发现载脂蛋白E和ARIA风险之间在全基因组范围内有很强的显著相关性。未来，更大规模的研究可能会更好地发现APOE以外的关联。这些发现表明，载脂蛋白E是ARIA发病率最强的遗传风险因素，对患者管理和风险-收益治疗决策有影响。

REF: Loomis SJ, Miller R, Castrillo-Viguera C, et al. Genome-Wide Association Studies of ARIA From the Aducanumab Phase 3 ENGAGE and EMERGE Studies. Neurology. 2024;102(3):e207919. doi:10.1212/WNL.0000000000207919 PMID: 38165296

Characteristics, Prevalence, and Clinical Relevance of Juxtacortical Paramagnetic Rims in Patients With Multiple Sclerosis

多发性硬化患者皮质旁顺磁性边缘的特征、患病率和临床相关性

A subgroup of patients with multiple sclerosis (MS) presents focal paramagnetic rims at the border between cortex and white matter (juxtacortical paramagnetic rims [JPRs]). We investigated the presence of this finding in our in vivo MS cohort and explored its potential clinical relevance. Moreover, we exploited postmortem MRI of fixed whole MS brains to (1) detect those rims and (2) investigate their histologic correlation. JPRs are a novel potential MRI biomarker of focal cortical demyelination, which seems related to global cortical pathology and might be useful for diagnostic and stratification purposes in a clinical setting.

多发性硬化症(MS)患者的一个亚组表现为皮质和白质交界处的局灶性顺磁边缘(伴侧皮质顺磁边缘[JPR])。我们调查了这一发现在我们的活体多发性硬化症队列中的存在，并探索了其潜在的临床相关性。此外，我们利用固定的整个MS脑的死后MRI来(1)检测这些边缘和(2)研究它们的组织学相关性。JPR是一种新的潜在的局灶性皮质脱髓鞘的MRI生物标志物，它似乎与整体皮质病理有关，并可能在临床环境下用于诊断和分层。

REF: Galbusera R, Bahn E, Weigel M, et al. Characteristics, Prevalence, and Clinical Relevance of Juxtacortical Paramagnetic Rims in Patients With Multiple Sclerosis. Neurology. 2024;102(3):e207966. doi:10.1212/WNL.0000000000207966 PMID: 38165297

EEG Correlates in the 3 Variants of Primary Progressive Aphasia

原发性进行性失语三种变异型的脑电相关性研究

The 3 clinical presentations of primary progressive aphasia (PPA) reflect heterogenous neuropathology, which is difficult to be recognized in vivo. Resting-state (RS) EEG is promising for the investigation of brain electrical substrates in neurodegenerative conditions. In this study, we aim to explore EEG cortical sources in the characterization of the 3 variants of PPA. EEG findings in patients with PPA suggest that lvPPA-related pathology is associated with a characteristic disruption of the cortical electrical activity, which might help in the differential diagnosis from svPPA and nfvPPA. EEG connectivity was disrupted in all PPA variants, with distinct findings in disease-specific PPA groups.

原发性进行性失语(PPA)的3种临床表现反映了异质性的神经病理，在体内很难识别。静息状态脑电(RS-EEG)在神经退行性疾病的脑电基础研究中具有广阔的应用前景。在这项研究中，我们旨在探索脑电皮质来源的特征的三个变异体的PPA。PPA患者的EEG结果提示，LvPPA相关病理与皮质电活动的特征性紊乱有关，这可能有助于与svPPA和nfvPPA的鉴别诊断。在所有PPA变种中，脑电连接都被破坏，在疾病特异性PPA组中有不同的发现。

REF: Cecchetti G, Basaia S, Canu E, et al. EEG Correlates in the 3 Variants of Primary Progressive Aphasia. Neurology. 2024;102(3):e207993. doi:10.1212/WNL.0000000000207993 PMID: 38165298

Teaching Video NeuroImage: Status Epilepticus Manifesting as Belly Dancing Secondary to Subdural Hematoma

教学视频神经影像：硬膜下血肿继发肚皮舞表现的癫痫持续状态

A 74-year-old man developed involuntary rhythmic contractions of his left abdomen, after drainage of a chronic right frontoparietal subdural hematoma (Figure). These movements had electroencephalographic correlation with periodic lateralized discharges over the right posterior quadrant (Video 1, Figure) and were classified as clonic abdominal seizures. Clonic abdominal seizures are a rare clinical finding in patients with seizure disorders. The symptomatogenic zone most commonly localizes to the contralateral paracentral frontoparietal region.1 Possible etiologies include primary brain tumors, brain metastasis, CNS infections, cortical dysplasia, stroke, and postsurgical complications.1,2 Clonic abdominal seizures are infrequent, but should be suspected in patients with rhythmic and regular contractions of the hemiabdominal wall in the context of a contralateral cerebral structural lesion.

74岁男性，慢性右额顶叶硬膜下血肿引流后，出现左腹部不自主节律性收缩(图)。这些运动与右后象限的周期性偏侧放电有脑电相关性(视频1，图)，被归类为阵挛腹性发作。阵发性腹部癫痫在癫痫患者中是一种罕见的临床表现。症状区最常位于对侧额顶叶中央旁1。可能的病因包括原发脑肿瘤、脑转移、中枢神经系统感染、皮质发育不良、中风和术后并发症。1、2阵发性腹痛发作并不常见，但在对侧大脑结构损害的情况下，应怀疑有节律性和规律性半腹壁收缩的患者。

REF: Hurtado-Bedoya JD, Valencia-Enciso N, Espinosa-Jovel C. Teaching Video NeuroImage: Status Epilepticus Manifesting as Belly Dancing Secondary to Subdural Hematoma. Neurology. 2024;102(3):e208057. doi:10.1212/WNL.0000000000208057 PMID: 38165300

Partially Reversible FLAIR Hyperintensity Along the Brainstem Surface in Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy

自身免疫性胶质纤维酸性蛋白星形细胞病沿脑干表面部分可逆性FLAIR高信号

A 41-year-old woman presented with headache, fever, irritability, and confusion. She developed a coma after admission. MRI of the brain revealed periventricular and deep white matter lesions. Fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging hyperintensity along the brainstem surface was observed (Figure 1), considered a rare but characteristic finding in leptomeningeal carcinomatosis from lung cancer.1,2 However, serum tumor markers, CSF cytopathology, contrast-enhanced high-resolution chest CT, and whole-body PET were negative. Antiglial fibrillary acidic protein antibodies (cell-based assay) were positive in serum and CSF. After receiving intravenous methylprednisolone and immunoglobulin, the symptoms improved significantly. Repeated MRI of the brain showed partial resolution of the lesions (Figure 2). The lesions were possibly induced by immune-mediated intramyelinic edema.

一位41岁女性患者出现头痛、发烧、易怒和神志不清的症状。她在入院后出现昏迷。脑部核磁共振显示脑室周围和深部白质病变。可观察到沿脑干表面的液体衰减反转恢复(FLAIR)和弥散加权成像高信号(图1)，这被认为是肺癌软脑膜癌病罕见但具有特征性的表现。1，2然而，血清肿瘤标志物，脑脊液细胞病理学，增强高分辨率胸部CT和全身PET均为阴性。抗胶质纤维酸性蛋白抗体(细胞法)在血清和脑脊液中呈阳性。静脉注射甲基强的松龙和免疫球蛋白后，症状明显改善。重复的脑部MRI显示病变部分消退(图2)。这些损害可能是由免疫介导的髓内水肿引起的。

REF: Wu J, Guo K, Liu J. Partially Reversible FLAIR Hyperintensity Along the Brainstem Surface in Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy. Neurology. 2024;102(3):e208064. doi:10.1212/WNL.0000000000208064 PMID: 38165301

Teaching Video NeuroImage: Isolated Undulating Tongue Hyperkinesia Following a Basilar Stroke

教学视频神经影像：基底动脉卒中后孤立性波状舌象亢进

An 82-year-old man with a history of hypertension and coronary revascularization presented with sudden-onset right hemiparesis and disorientation lasting 5 hours. On admission, he was intubated because of gasping and a Glasgow Coma Scale of 3. Hemorrhagic stroke was suspected, but ruled out by the initial head CT, which revealed old cerebellar lacunae. The following day, the comatose, now unsedated patient exhibited tetraparesis; fixed, nonreactive pupils; and corneal reflex, but no oculocephalic reflex. Rhythmic undulating tongue movements without palatal or limb involvement were first observed (Video 1). EEG revealed no epileptiform activity. Follow-up head CT showed acute ischemic lesions in the thalamocapsular region, midbrain, and pons while angiotomography revealed distal basilar artery occlusion (Figure). Involuntary tongue movements, though rare, have been associated with various conditions such as stroke, trauma, and epilepsy.1,2 These movements may result from disinhibition within the inhibitory reticular formation projecting to hypoglossal neurons, suggesting the pontine reticular formation as a central pacemaker.2.

一位82岁男性患者，有高血压和冠状动脉血运重建的病史，表现为突然发作的右侧偏瘫和持续5小时的定向障碍。入院时，他因喘息和格拉斯哥昏迷评分为3分而被插管。出血性中风被怀疑，但最初的头部CT显示旧的小脑陷窝排除了他的可能性。第二天，昏迷不醒的病人出现了四肢瘫痪，瞳孔固定，无反应，角膜反射，但没有眼头反射。首次观察到舌头有节奏的波动运动，而不涉及腭部或四肢(视频1)。脑电检查未发现癫痫样活动。随访头颅CT显示丘脑囊区、中脑和桥脑的急性缺血性病变，而血管断层摄影显示远端基底动脉闭塞(图)。不随意的舌头运动虽然罕见，但与中风、创伤和癫痫等各种情况有关。1.这些运动可能是由于投射到舌下神经元的抑制性网状结构内的去抑制导致的，这表明桥脑网状结构是一种中枢起搏器。

REF: Santos DA, Costa FO, Dourado HN, Ferreira JA, Castro-Lima H. Teaching Video NeuroImage: Isolated Undulating Tongue Hyperkinesia Following a Basilar Stroke. Neurology. 2024;102(3):e208079. doi:10.1212/WNL.0000000000208079 PMID: 38165302

Right Brain: The Strangeness of a Good Diagnosis

右脑：一个好的诊断的奇怪之处

Coffee, black with a spritz of milk. I enjoyed routine, and today was no different. We were on the 12th floor of the "tower", as our hospital is lovingly called. It was my second year of residency, and I was charged with admissions to our neurological ward. Sighing with the expectation of a long day, I walked over to our patients. The first was a woman in her sixties. She complained of trouble swallowing for the past 2 months that was getting worse. She was otherwise healthy. Asked about her social background, she looked over to her husband with an impish grin and replied: "happily married for almost thirty years." Physical examination was next. There was no apparent muscle weakness, but, strangely enough, the Babinski sign was clearly positive. Looking at her tongue, I noticed a single, delicate strain of muscle twitching. It was subtle, but impossible to miss. The twitching was adamant. It was not rhythmic, but it was unrelenting. I could not help but stare, and eventually, the patient closed her mouth, looking at me puzzled. I did not make the connection at first. But, walking back to our room, I realized that the concert of neurological dysfunction was spelling out the diagnosis. I caught myself feeling excited despite my knowledge of the potential outcome. Reporting my findings to my consultant, I remember him saying: "Sure sounds like amyotrophic lateral sclerosis, but we still have to complete our work-up." And so we did, dutifully.

加牛奶的黑咖啡。我喜欢例行公事，今天也没什么不同。我们在医院被亲切地称为“塔楼”的12层。这是我实习的第二年，我被指控要进入我们的神经科病房。带着漫长的一天的期待，我叹了口气，走到我们的病人面前。第一个是一位60多岁的妇女。她抱怨说，在过去的两个月里，吞咽困难的情况正在恶化。除此之外，她还很健康。当被问及她的社会背景时，她调皮地笑着看着她的丈夫，回答说：“幸福的婚姻已经有近30年了。”体检紧随其后。没有明显的肌肉无力，但奇怪的是，巴宾斯基的征兆显然是积极的。看着她的舌头，我注意到一块微妙的肌肉在抽搐。这是微妙的，但不可能错过。抽搐是顽固的。它不是有节奏的，但它是无情的。我忍不住瞪了她一眼，最后，病人闭上了嘴，疑惑地看着我。一开始我没有把它联系起来。但是，走回我们的房间，我意识到神经功能障碍的音乐会正在详细说明诊断。尽管我知道可能的结果，但我还是感到兴奋。在向我的顾问汇报我的研究结果时，我记得他说：“听起来确实像是肌萎缩侧索硬化症，但我们还得完成我们的检查。”我们照做了，尽职尽责。

REF: Nelke C. Right Brain: The Strangeness of a Good Diagnosis. Neurology. 2024;102(3):e208103. doi:10.1212/WNL.0000000000208103 PMID: 38165299

Cognitive and Functional Change Over Time in Cognitively Healthy Individuals According to Alzheimer Disease Biomarker-Defined Subgroups

根据阿尔茨海默病生物标记物定义的亚组，认知健康个体的认知和功能随时间的变化

It is unclear to what extent cognitive outcome measures are sensitive to capture decline in Alzheimer disease (AD) prevention trials. We aimed to analyze the sensitivity to changes over time of a range of neuropsychological tests in several cognitively unimpaired, biomarker-defined patient groups. In conclusion, functional, composite, and neuropsychological outcome measures across all cognitive domains detect changes over time in various biomarker-defined groups, with changes being most evident among individuals with more AD pathology. AD prevention trials should use sufficiently long follow-up duration and/or more sensitive outcome measures to optimally capture subtle cognitive changes over time.

目前尚不清楚认知结果测量在多大程度上对阿尔茨海默病(AD)预防试验中的捕获下降敏感。我们的目标是在几个认知正常、生物标记物定义的患者组中分析一系列神经心理测试随时间变化的敏感性。总而言之，所有认知域的功能、复合和神经心理学结果测量可以检测到不同生物标记物定义的组随时间的变化，其中变化在AD病理程度较高的个体中最为明显。AD预防试验应使用足够长的随访持续时间和/或更敏感的结果测量，以最佳地捕捉随时间推移的微妙认知变化。

REF: Dubbelman MA, Hendriksen HMA, Harrison JE, et al. Cognitive and Functional Change Over Time in Cognitively Healthy Individuals According to Alzheimer Disease Biomarker-Defined Subgroups. Neurology. 2024;102(2):e207978. doi:10.1212/WNL.0000000000207978 PMID: 38165338

Comparative Risk of Major Congenital Malformations With Antiseizure Medication Combinations vs Valproate Monotherapy in Pregnancy

妊娠期联合应用抗癫痫药物与单用丙戊酸盐治疗重大先天畸形的风险比较

Valproate should be avoided in pregnancy, but it is the most effective drug for generalized epilepsies. Alternative treatment may require combinations of other drugs. Our objectives were to describe first trimester use of antiseizure medication (ASM) combinations that are relevant alternatives to valproate and determine whether specific combinations were associated with a lower risk of major congenital malformations (MCM) compared with valproate monotherapy. Lamotrigine-levetiracetam duotherapy in first trimester was associated with a 60% lower risk of MCM than valproate monotherapy, while lamotrigine-topiramate was not associated with a reduced risk. Duotherapy with lamotrigine and levetiracetam may be favored to treat epilepsy in people with childbearing potential compared with valproate regarding MCM, but whether this combination is as effective as valproate remains to be determined.

丙戊酸盐应避免在怀孕期间，但它是最有效的药物全身性癫痫。替代治疗可能需要其他药物的组合。我们的目的是描述作为丙戊酸盐相关替代品的抗癫痫药物（ASM）复方制剂在妊娠早期的使用情况，并确定与丙戊酸盐单药治疗相比，特定复方制剂是否与较低的主要先天性畸形（MCM）风险相关。与丙戊酸盐单药治疗相比，妊娠早期拉莫三嗪-左乙拉西坦二联治疗的MCM风险降低60%，而拉莫三嗪-托吡酯与风险降低无关。在MCM方面，与丙戊酸盐相比，拉莫三嗪和左乙拉西坦联合治疗可能更有利于治疗有生育能力人群的癫痫，但该联合治疗是否与丙戊酸盐一样有效仍有待确定。

REF: Cohen JM, Alvestad S, Suarez EA, et al. Comparative Risk of Major Congenital Malformations With Antiseizure Medication Combinations vs Valproate Monotherapy in Pregnancy. Neurology. 2024;102(2):e207996. doi:10.1212/WNL.0000000000207996 PMID: 38165339