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Spreading depolarization triggers pro- and anti-inflammatory signalling: a potential link to headache 扩展去极化触发促炎和抗炎信号:与头痛的潜在联系
IF 14.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-17 DOI: 10.1093/brain/awaf015
Zeynep Kaya, Nevin Belder, Melike Sever-Bahçekapılı, Şefik Evren Erdener, Buket Dönmez-Demir, Canan Bağcı, Merve Nur Köroğlu, Kaya Bilguvar, Turgay Dalkara
Cortical spreading depolarization (CSD), the neurophysiological event believed to underlie aura, may trigger migraine headaches through inflammatory signaling that originates in neurons and spreads to the meninges via astrocytes. Increasing evidence from studies on rodents and migraine patients supports this hypothesis. The transition from pro-inflammatory to anti-inflammatory mechanisms is crucial for resolving inflammation. However, the resolution of inflammation in the context of CSD and migraine headaches remains poorly understood. This study aims to elucidate the progression of post-CSD inflammatory signaling and its resolution in neurons, astrocytes, and microglia in mouse brains. CSD was triggered optogenetically or by pinprick. HMGB1 release, caspase-1 activation, and cell-specific activation of NF-κB pairs, along with ensuing transcriptomic changes, were evaluated using immunofluorescence, Western blotting, co-immunoprecipitation, FRET analysis, and cell-specific transcriptomics. Our findings indicate that after the initial burst, HMGB1 release from neurons ceased, and caspase-1 activation, which peaked 1-hour post-CSD, diminished within 3-5 hours. This suggests that pro-inflammatory stimuli driving inflammatory signaling decreased within hours after CSD. Pro-inflammatory NF-κB p65:p50 pairs, along with anti-inflammatory cRel:p65 pairs, were detected in astrocyte nuclei shortly after CSD. However, 24 hours post-CSD, the former had disappeared while the latter persisted, indicating a shift from pro-inflammatory to anti-inflammatory activity in astrocytes. Pathway analysis of cell-specific transcriptomic data confirmed NF-κB-related pro-inflammatory transcription in astrocytes 1-hour post-CSD, while no such activity was observed in neurons. Detailed transcriptomic analysis with Bayesian cell proportion reconstruction revealed that microglia exhibited transcriptional changes trending towards an anti-inflammatory profile, along with upregulation of several chemokines and cytokines (e.g., TNF). This suggests that microglia may play a role in supporting the inflammatory responses in astrocytes through the release of these mediators. The upregulation of genes involved in chemotaxis (e.g., Ccl3) and spine pruning (e.g., C1q) in microglia implies that microglia may contribute to synaptic repair, while inflammatory signaling in astrocytes could potentially modulate meningeal nociceptor activity through an extensive astrocyte endfeet syncytium abutting subarachnoid and perivascular spaces although direct evidence remains incomplete. This nuanced understanding of the inflammatory response in CNS cell types highlights the intricate cellular interactions and responses to CSD. Following a single CSD, distinct transcriptomic responses occur in neurons, astrocytes, and microglia, driving inflammatory and anti-inflammatory responses, potentially contributing to headache initiation and resolution.
皮层扩张性去极化(CSD),一种被认为是先兆基础的神经生理事件,可能通过炎症信号引发偏头痛,炎症信号起源于神经元,通过星形胶质细胞扩散到脑膜。对啮齿动物和偏头痛患者的研究越来越多的证据支持这一假设。从促炎到抗炎机制的转变是解决炎症的关键。然而,在CSD和偏头痛的背景下,炎症的解决仍然知之甚少。本研究旨在阐明小鼠脑内神经元、星形胶质细胞和小胶质细胞中csd后炎症信号的进展及其分解。CSD通过光遗传学或针刺触发。利用免疫荧光、Western blotting、共免疫沉淀、FRET分析和细胞特异性转录组学来评估HMGB1释放、caspase-1激活和NF-κB对的细胞特异性激活,以及随后的转录组学变化。我们的研究结果表明,在初始爆发后,神经元中HMGB1的释放停止,caspase-1的激活在csd后1小时达到峰值,在3-5小时内减弱。这表明促炎刺激驱动炎症信号在CSD后数小时内减少。促炎NF-κB p65:p50对和抗炎cRel:p65对在CSD后星形胶质细胞核中被检测到。然而,csd后24小时,前者消失,而后者持续存在,表明星形胶质细胞的活性从促炎向抗炎转变。细胞特异性转录组数据的通路分析证实,csd后1小时星形胶质细胞中存在NF-κ b相关的促炎转录,而神经元中没有观察到这种活性。贝叶斯细胞比例重建的详细转录组学分析显示,小胶质细胞的转录变化倾向于抗炎,同时一些趋化因子和细胞因子(如TNF)上调。这表明小胶质细胞可能通过释放这些介质在星形胶质细胞中支持炎症反应中发挥作用。参与小胶质细胞趋化性(如Ccl3)和脊柱修剪(如C1q)的基因上调表明,小胶质细胞可能有助于突触修复,而星形胶质细胞中的炎症信号可能通过广泛的星形胶质细胞终足合胞体邻近蛛网膜下腔和血管周围间隙调节脑膜伤害受体活性,尽管直接证据尚不完整。这种对中枢神经系统细胞类型炎症反应的细致理解强调了复杂的细胞相互作用和对CSD的反应。单一CSD发生后,不同的转录组反应发生在神经元、星形胶质细胞和小胶质细胞中,驱动炎症和抗炎反应,可能有助于头痛的发生和消退。
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引用次数: 0
The association of seizure control with neuropathology in dementia 痴呆患者癫痫控制与神经病理学的关系
IF 14.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-16 DOI: 10.1093/brain/awaf017
Ifrah Zawar, Aleksander Luniewski, Rithvik Gundlapalli, Carol Manning, Prachi Parikh, Jaideep Kapur, Mark Quigg
Seizures in people with dementia (PWD) are associated with faster cognitive decline and worse clinical outcomes. However, the relationship between ongoing seizure activity and postmortem neuropathology in PWD remains unexplored. We compared post-mortem findings in PWD with active, remote, and no seizures using multicentre data from 39 Alzheimer’s Disease Centres from 2005 to 2021. PWD were grouped by seizure status into active (seizures over the preceding one year), remote (prior seizures but none in the preceding year), and no seizures (controls). Baseline demographics, cognition, mortality, and postmortem findings of primary and contributing(co-pathologies) Alzheimer’s Disease(AD), Frontotemporal lobar degeneration(FTD), Lewy body, vascular pathologies and neurodegeneration were compared among the groups using Pearson’s Chi-squared test, fisher’s exact test, t-test, and ANOVA tests. Of 10,474 deceased PWD, active seizure participants suffered the highest mortality among the groups(proportion deceased among the groups: active=56%remote=35%, controls=34%, p<0.001). Among 6085 (58.1% of deceased) who underwent autopsy, 294 had active, 151 had remote, and 5640 had no seizures. PWD and active seizures died at a younger age (Active=75.8, remote=77.9, controls: 80.8 years, p <0.001) and had more severe dementia (CDR-Global: active=2.36, remote=1.90, controls=1.69, p<0.001). In post hoc analyses, those with primary postmortem diagnosis of AD with active seizures had more severe and later stages of AD pathology and ATN (amyloid, tau, and neurodegeneration) as evidenced by Braak stage for neurofibrillary(tau) degeneration and CERAD score density of neuritic(amyloid) plaques than remote seizure participants and controls. Active seizure participants had more neurodegeneration, evidenced by cerebral atrophy, hippocampal atrophy, and locus coeruleus hypopigmentation than controls. Among participants with primary postmortem diagnosis of non-AD, in posthoc analyses, active seizure participants had worse AD co-pathology evidenced by higher Braak stages than remote seizures and controls and a higher thal phase of beta-amyloid plaques than controls. Neurodegeneration (cerebral/hippocampal atrophy) and LC hypopigmentation were comparable among the groups. In both primary postmortem AD and non-AD diagnoses, FTD (co)pathology was less prevalent among active seizure participants than controls, while vascular pathology, Circle of Willis atherosclerosis, Lewy body pathology, lobar atrophy, and substantia nigra hypopigmentation were comparable among the three groups. This study shows that active, compared to remote seizures, are associated with earlier death and postmortem evidence of more severe ATN pathology. Active seizures are associated with more advanced AD pathology in AD and worse AD co-pathology in non-AD dementias. Therefore, clinicians should be vigilant in detecting ongoing seizures as this could reflect a worse prognosis in PWD.
痴呆症(PWD)患者的癫痫发作与认知能力下降更快和临床结果更差有关。然而,在PWD中持续的癫痫活动和死后神经病理之间的关系仍未被探索。我们使用来自39个阿尔茨海默病中心2005年至2021年的多中心数据,比较了PWD与主动、远程和无癫痫发作的尸检结果。根据癫痫发作状态将PWD分为活动性(过去一年内有癫痫发作)、远程性(过去一年内无癫痫发作)和无癫痫发作(对照组)。使用Pearson卡方检验、fisher精确检验、t检验和ANOVA检验比较各组间阿尔茨海默病(AD)、额颞叶变性(FTD)、路易体、血管病变和神经变性的基线人口统计学、认知、死亡率和尸检结果。在10,474名死亡的PWD患者中,活动性癫痫发作参与者的死亡率在各组中最高(组中死亡比例:活动性=56%,远程=35%,对照组=34%,p<0.001)。在6085名(58.1%的死者)接受尸检的患者中,294人有活动性癫痫发作,151人有远程癫痫发作,5640人没有癫痫发作。PWD和活动性癫痫发作患者死亡年龄较轻(主动=75.8,远程=77.9,对照组:80.8岁,p<0.001),且痴呆更严重(CDR-Global:主动=2.36,远程=1.90,对照组=1.69,p<0.001)。在事后分析中,与远程癫痫发作参与者和对照组相比,那些初步死后诊断为AD并伴有活动性癫痫发作的患者有更严重和更晚的AD病理和ATN(淀粉样蛋白、tau蛋白和神经变性),这可以通过神经原纤维(tau)变性的Braak分期和神经性(淀粉样蛋白)斑块的CERAD评分密度来证明。与对照组相比,活动性癫痫发作参与者有更多的神经退行性变,表现为脑萎缩、海马萎缩和蓝斑色素减退。在初步死后诊断为非阿尔茨海默病的参与者中,在死后分析中,活动性癫痫发作参与者的阿尔茨海默病共病理更严重,其Braak期高于远程癫痫发作和对照组,β -淀粉样斑块的thal期高于对照组。神经退行性变(脑/海马萎缩)和LC色素沉着在组间具有可比性。在原发性死后阿尔茨海默病和非阿尔茨海默病诊断中,FTD (co)病理在活动性癫痫发作参与者中的患病率低于对照组,而血管病理、威利斯动脉粥样硬化圈、路易体病理、脑叶萎缩和黑质色素沉着在三组之间具有可比性。这项研究表明,与远端癫痫发作相比,活动性癫痫发作与早期死亡和尸检证据更严重的ATN病理有关。活动性癫痫发作与阿尔茨海默氏症中更严重的阿尔茨海默氏症病理和非阿尔茨海默氏症中更严重的阿尔茨海默氏症共病理相关。因此,临床医生应该警惕发现持续的癫痫发作,因为这可能反映了PWD的预后较差。
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引用次数: 0
APOE4 impact on soluble and insoluble tau pathology is mostly influenced by amyloid-beta APOE4对可溶性和不可溶性tau蛋白病理的影响主要受淀粉样蛋白- β的影响
IF 14.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-16 DOI: 10.1093/brain/awaf016
Claudia Cicognola, Gemma Salvadó, Ruben Smith, Sebastian Palmqvist, Erik Stomrud, Tobey Betthauser, Sterling Johnson, Shorena Janelidze, Niklas Mattsson-Carlgren, Oskar Hansson, Alexa Pichet Binette
The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). While APOE4 is strongly associated with amyloid-beta (Aβ), its relationship with tau accumulation is less understood. Studies evaluating the role of APOE4 on tau accumulation showed conflicting results, particularly regarding the independence of these associations from Aβ load. In this study, we examined three independent longitudinal cohorts (BioFINDER-1, BioFINDER-2 and WRAP) in which participants had cross-sectional and longitudinal measures of tau tangles (tau-PET; temporal meta-ROI and entorhinal) or soluble p-tau (p-tau217), Aβ-PET and APOE genotype. The study included a total of 1370 cognitively unimpaired (CU) and 449 mild cognitive impairment (MCI) subjects, followed longitudinally with tau-PET and p-tau217. APOE4 carriers accounted for 40.2-50% of the cohorts. Different linear regressions (cross-sectional) and linear mixed-effect models (longitudinal) with tau measures as outcomes were fitted to test the effect of APOE4 as independent predictor, as well as in combination with baseline Aβ load (including interaction). All models included age, sex and cognitive status as covariates. We found no independent effects of the APOE4 carriership on insoluble tau in either cohort (BioFINDER-2 or WRAP), both on cross-sectional and longitudinal tau-PET in the temporal meta-ROI, when Aβ was present in the model (p=0.531-0.949). Aβ alone was the best predictor of insoluble tau accumulation, with no interaction between APOE4 and Aβ on tau-PET. In BioFINDER-2, there was a significant interaction between APOE4 and Aβ (b=0.166, p&lt;0.001) in the entorhinal cortex at baseline. However, the interaction was not present in WRAP PET. No independent effects of the APOE4 carriership on baseline (p=0.683-0.708) and longitudinal (p=0.188-0.570) soluble p-tau217 were observed when Aβ was included in the model in BioFINDER-1 and WRAP. Similarly, no interaction between APOE4 and Aβ on soluble p-tau217 was observed. Mediation analysis revealed that Aβ load fully mediated most associations between APOE4 and tau (46-112%, either cross-sectional or longitudinal tau-PET or soluble p-tau217). In the largest cohort (BioFINDER-2), looking at APOE4 groups by number of ε4 alleles, we found an interaction between APOE4 homozygotes and Aβ on tau-PET levels at baseline and over time in the temporal meta-ROI, while in the entorhinal cortex this effect was observed only at baseline. In conclusion, although APOE4 is strongly associated with Aβ aggregation, it seems to be minimally associated with longitudinal changes in soluble or insoluble p-tau levels at a given level of Aβ pathology, confirming the primacy of Aβ in driving tau pathology.
APOE4等位基因是散发性阿尔茨海默病(AD)最强的遗传危险因素。虽然APOE4与淀粉样蛋白β (Aβ)密切相关,但其与tau蛋白积累的关系尚不清楚。评估APOE4在tau积累中的作用的研究显示了相互矛盾的结果,特别是关于这些关联与Aβ负荷的独立性。在这项研究中,我们检查了三个独立的纵向队列(BioFINDER-1, BioFINDER-2和WRAP),其中参与者有tau缠结(tau- pet;颞元roi和内嗅)或可溶性p-tau (p-tau217), Aβ-PET和APOE基因型。该研究包括1370名认知未受损(CU)和449名轻度认知障碍(MCI)受试者,纵向随访tau-PET和p-tau217。APOE4携带者占40.2-50%。采用不同的线性回归(横截面)和线性混合效应模型(纵向),以tau测量为结果,检验APOE4作为独立预测因子的影响,以及与基线Aβ负荷(包括相互作用)的结合。所有模型均包括年龄、性别和认知状态作为协变量。我们发现APOE4携带者对两个队列(BioFINDER-2或WRAP)中的不溶性tau蛋白没有独立影响,当模型中存在Aβ时,APOE4携带者对时间元roi的横断面和纵向tau- pet都没有独立影响(p=0.531-0.949)。Aβ单独是不溶性tau积累的最佳预测因子,APOE4和Aβ在tau- pet上没有相互作用。在BioFINDER-2中,APOE4与a β在基线时存在显著的相互作用(b=0.166, p amp;lt;0.001)。然而,WRAP PET中不存在这种相互作用。当在BioFINDER-1和WRAP中加入Aβ时,APOE4携带者对基线(p=0.683-0.708)和纵向(p=0.188-0.570)可溶性p-tau217没有独立的影响。同样,APOE4和Aβ在可溶性p-tau217上也没有相互作用。中介分析显示,Aβ负载完全介导了APOE4和tau之间的大部分关联(46-112%,无论是横断面还是纵向tau- pet或可溶性p-tau217)。在最大的队列(BioFINDER-2)中,通过ε4等位基因的数量来观察APOE4组,我们发现APOE4纯合子与Aβ在基线和时间上的tau-PET水平之间存在相互作用,而在内嗅皮层中,这种作用仅在基线时观察到。综上所述,尽管APOE4与a β聚集密切相关,但在给定的a β病理水平下,它似乎与可溶性或不可溶性p-tau水平的纵向变化关系不大,证实了a β在驱动tau病理中的首要作用。
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引用次数: 0
N-methyl-d-aspartate receptor hypofunction causes recurrent and transient failures of perceptual inference n -甲基-d-天冬氨酸受体功能低下导致反复和短暂的知觉推理失败
IF 14.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-16 DOI: 10.1093/brain/awaf011
Veith Weilnhammer, Marcus Rothkirch, Deniz Yilmaz, Merve Fritsch, Lena Esther Ptasczynski, Katrin Reichenbach, Lukas Rödiger, Philip Corlett, Philipp Sterzer
Perception integrates external sensory signals with internal predictions that reflect prior knowledge about the world. Previous research suggests that this integration is governed by slow alternations between an external mode, driven by sensory signals, and an internal mode, shaped by prior knowledge. Using a double-blind, placebo-controlled, cross-over experiment in healthy human participants, we investigated the effects of the N-Methyl-D-aspartate receptor (NMDAR) antagonist S-ketamine on the balance between external and internal modes. We found that S-ketamine causes a shift of perception toward the external mode. A case-control study revealed that individuals with paranoid Scz, a disorder repeatedly associated with NMDAR hypofunction, spend more time in the external mode. This NMDAR-dependent increase in the external mode suggests that the symptoms of schizophrenia are caused by recurring dissociations of perception from prior knowledge about the world.
感知将外部感官信号与反映对世界先验知识的内部预测结合起来。先前的研究表明,这种整合是由由感官信号驱动的外部模式和由先验知识形成的内部模式之间的缓慢交替控制的。采用双盲、安慰剂对照、交叉实验,研究了n -甲基- d -天冬氨酸受体(NMDAR)拮抗剂s-氯胺酮对内外部模式平衡的影响。我们发现s -氯胺酮导致感知转向外部模式。一项病例对照研究显示,患有偏执型Scz(一种反复与NMDAR功能减退相关的疾病)的个体在外部模式下花费的时间更多。这种依赖于nmdar的外部模式的增加表明,精神分裂症的症状是由对世界的先验知识的感知反复分离引起的。
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引用次数: 0
Intrinsic neuronal resilience as a tool for therapeutic discovery. 内在神经弹性作为治疗发现的工具。
IF 14.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-15 DOI: 10.1093/brain/awaf010
Stefania Corti,Eva Hedlund
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引用次数: 0
Anterior-temporal network hyperconnectivity is key to Alzheimer's disease: from ageing to dementia 前颞叶网络超连通性是阿尔茨海默病的关键:从衰老到痴呆
IF 14.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-15 DOI: 10.1093/brain/awaf008
Léa Chauveau, Brigitte Landeau, Sophie Dautricourt, Anne-Laure Turpin, Marion Delarue, Oriane Hébert, Vincent de La Sayette, Gaël Chételat, Robin de Flores
Curing Alzheimer’s disease remains hampered by an incomplete understanding of its pathophysiology and progression. Exploring dysfunction in medial temporal lobe networks, particularly the anterior-temporal (AT) and posterior-medial (PM) systems, may provide key insights, as these networks exhibit functional connectivity alterations along the entire Alzheimer’s continuum, potentially influencing disease propagation. However, the specific changes in each network and their clinical relevance across stages are not yet fully understood. This requires considering commonly used biomarkers, clinical progression, individual variability, and age confounds. Here, we leveraged monocentric longitudinal data from 261 participants spanning the adult lifespan and the Alzheimer’s continuum. The sample included cognitively unimpaired adults aged 19 to 85 years (n = 209; eight out of 64 older adults over 60 were Aβ-positive) and Aβ-positive patients fulfilling diagnostic criteria for mild cognitive impairment (MCI, n = 26; 18 progressed to Alzheimer-dementia within seven years) or Alzheimer’s type dementia (n = 26). Participants underwent structural and resting-state functional (f) MRI, florbetapir and FDG-PET, and global cognitive assessments, with up to three visits over a maximum period of 47 months. Network connectivity was assessed using seed-based analyses with the perirhinal and parahippocampal cortices as seeds, within data-driven masks reflecting the AT and PM networks. Generalized additive and linear mixed models were run to assess age-specific effects and Alzheimer’s-related alterations. In this context, we explored various markers of pathological and clinical severity, including cerebral amyloid uptake, glucose metabolism, hippocampal volume, global cognition, diagnostic staging, and time to dementia onset. Our findings revealed distinct patterns of connectivity linked to normal aging or Alzheimer’s disease. Advancing age throughout adulthood was associated with lower PM connectivity and more subtle changes in AT connectivity, while Alzheimer’s disease was characterised by AT hyperconnectivity without global changes in PM connectivity. Specifically, AT connectivity was higher in MCI and Alzheimer-dementia patients compared to older controls and was positively associated with amyloid burden, glucose hypometabolism, hippocampal atrophy, and global cognitive deficits in older adults, ranging from unimpaired to demented. Additionally, higher AT connectivity correlated with faster progression to Alzheimer-dementia in MCI patients. This comprehensive approach allowed to reveal that excessive connectivity within the AT network is intrinsically linked to the pathological and clinical progression of Alzheimer’s disease. These insights may guide future research to better understand cascading events leading to the disease and hold promise for developing prognostic tools and therapeutic interventions targeting these specific network alterations.
治疗阿尔茨海默病仍然阻碍了对其病理生理和进展的不完全理解。探索内侧颞叶网络的功能障碍,特别是前颞叶(AT)和后内侧(PM)系统,可能会提供关键的见解,因为这些网络在整个阿尔茨海默病连续体中表现出功能连接的改变,可能会影响疾病的传播。然而,每个网络的具体变化及其在不同阶段的临床相关性尚不完全清楚。这需要考虑常用的生物标志物、临床进展、个体差异和年龄混杂。在这里,我们利用了261名参与者的单中心纵向数据,这些参与者跨越了成年寿命和阿尔茨海默氏症的连续体。样本包括19至85岁的认知功能正常的成年人(n = 209;64名60岁以上老年人中有8名a β阳性,a β阳性患者符合轻度认知障碍的诊断标准(MCI, n = 26;18例在7年内发展为阿尔茨海默痴呆)或阿尔茨海默型痴呆(n = 26)。参与者接受了结构和静息状态功能(f) MRI, florbetapir和FDG-PET以及整体认知评估,在最长47个月的时间内最多进行了三次访问。网络连通性评估使用基于种子的分析,以周围皮层和海马体旁皮层为种子,在数据驱动的面具内反映AT和PM网络。使用广义加性和线性混合模型来评估年龄特异性效应和阿尔茨海默病相关的改变。在此背景下,我们探讨了病理和临床严重程度的各种标志物,包括脑淀粉样蛋白摄取、葡萄糖代谢、海马体积、整体认知、诊断分期和痴呆发病时间。我们的发现揭示了与正常衰老或阿尔茨海默病相关的独特连接模式。随着年龄的增长,整个成年期的PM连通性降低,AT连通性发生更细微的变化,而阿尔茨海默病的特征是AT超连通性,而PM连通性没有全局变化。具体而言,MCI和阿尔茨海默痴呆症患者的AT连通性高于老年对照组,并且与淀粉样蛋白负担、葡萄糖低代谢、海马萎缩和老年人(从未受损到痴呆)的整体认知缺陷呈正相关。此外,在MCI患者中,较高的AT连通性与更快的阿尔茨海默病进展相关。这种综合方法揭示了AT网络中的过度连接与阿尔茨海默病的病理和临床进展具有内在联系。这些见解可能会指导未来的研究,以更好地了解导致疾病的级联事件,并有望开发针对这些特定网络改变的预后工具和治疗干预措施。
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引用次数: 0
Artificial intelligence models using F-wave responses predict amyotrophic lateral sclerosis 使用f波反应的人工智能模型预测肌萎缩侧索硬化症
IF 14.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-13 DOI: 10.1093/brain/awaf014
Jennifer M Martinez-Thompson, Kevin A Mazurek, Carolina Parra Cantu, Elie Naddaf, Venkatsampath Gogineni, Hugo Botha, David T Jones, Ruple S Laughlin, Leland Barnard, Nathan P Staff
Nerve conduction F-wave studies contain critical information about subclinical motor dysfunction which may be used to diagnose patients with amyotrophic lateral sclerosis (ALS). However, F-wave responses are highly variable in morphology, making waveform interpretation challenging. Artificial Intelligence techniques can extract time-frequency features to provide new insights into ALS diagnosis and prognosis. A retrospective analysis was performed on F-wave responses from 46,802 patients. Discrete wavelet transforms were applied to time-series waveform responses after stimulating ulnar, median, fibular, and tibial nerves. Wavelet coefficient statistics, onset age, sex, and BMI were features for training a Gradient Boosting Machine model on 40,095 (5,329 diagnosed with motor neuron disease). Model performance was tested on responses from 689 ALS patients meeting Gold Coast criteria and 689 age- and sex-matched controls. An exploratory analysis examined model performance on cohorts of patients with inclusion body myositis (IBM), cervical radiculopathy, lumbar radiculopathy, or peripheral neuropathy which can mimic ALS symptoms. Factors affecting survival were estimated through cox proportional hazards regression. The model trained using wavelet-features on the full waveform had 90% recall, 87% precision, and 88% accuracy. Similar model performance was measured using features only from the M-Wave or F-Wave. Classification probabilities for ALS patients were statistically different from the diagnoses mimicking ALS symptoms (p&lt;0.001, ANOVA, Tukey’s post-hoc), Higher model classification probabilities of ALS, older age at onset, and family history of ALS alone or with frontotemporal dementia were factors decreasing survival. Longer diagnostic delay and upper limb onset site were factors increasing survival. Model scores two standard deviations below the mean had 4 months increased survival (two standard deviations below had 3 months decreased survival). Artificial intelligence techniques extracted important information from F-wave responses to estimate a patient’s likelihood of ALS and their survival risks. Although the model can make predictions at specific decision threshold as presented here, the true strength of such a model lies in its ability to provide probabilities about whether a patient is likely to have ALS compared to other mimicking diagnoses such as IBM, cervical or lumbar radiculopathy, or peripheral neuropathy. These probabilities provide clinicians with additional information they can use to make the final diagnosis with greater confidence and precision. Integrating such a model into the clinical workflow could help clinicians diagnose ALS sooner and manage treatment based on estimated survival, which may improve outcomes and patients’ quality of life.
神经传导 F 波研究包含亚临床运动功能障碍的重要信息,可用于诊断肌萎缩侧索硬化症(ALS)患者。然而,F 波反应在形态上变化很大,因此波形解读具有挑战性。人工智能技术可以提取时间频率特性,为肌萎缩侧索硬化症的诊断和预后提供新的见解。我们对 46802 名患者的 F 波反应进行了回顾性分析。在刺激尺神经、正中神经、腓神经和胫神经后,对时间序列波形响应进行离散小波变换。小波系数统计、发病年龄、性别和体重指数是对 40,095 人(5,329 人确诊为运动神经元疾病)进行梯度提升机模型训练的特征。对 689 名符合黄金海岸标准的 ALS 患者和 689 名年龄和性别匹配的对照者的反应进行了模型性能测试。一项探索性分析检验了模型在患有包涵体肌炎 (IBM)、颈椎病、腰椎病或周围神经病变(可模仿 ALS 症状)的患者群中的表现。影响存活率的因素通过 cox 比例危险回归进行估计。使用完整波形的小波特征训练的模型具有 90% 的召回率、87% 的精确率和 88% 的准确率。仅使用 M 波或 F 波的特征也能测出类似的模型性能。ALS患者的分类概率与模仿ALS症状的诊断结果存在统计学差异(p&lt;0.001,方差分析,Tukey's post-hoc),较高的ALS模型分类概率、较高的发病年龄以及单独或伴有额颞叶痴呆的ALS家族史是降低存活率的因素。而较长的诊断延迟和上肢发病部位则是提高存活率的因素。模型得分低于平均值两个标准差,生存期会延长 4 个月(低于两个标准差,生存期会缩短 3 个月)。人工智能技术从 F 波反应中提取了重要信息,以估计患者患 ALS 的可能性及其生存风险。虽然该模型可以在特定的决策阈值(如本文所述)上进行预测,但这种模型的真正优势在于它能够提供患者是否有可能患有 ALS 的概率,而不是其他模仿诊断,如 IBM、颈椎或腰椎病或周围神经病变。这些概率为临床医生提供了额外的信息,他们可以利用这些信息更有把握、更准确地做出最终诊断。将这样一个模型整合到临床工作流程中,可以帮助临床医生更快地诊断出 ALS,并根据估计的存活率进行治疗,从而改善治疗效果和患者的生活质量。
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引用次数: 0
Visual feature processing in a large stroke cohort: evidence against modular organization. 大卒中队列的视觉特征处理:反对模块化组织的证据。
IF 10.6 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-13 DOI: 10.1093/brain/awaf009
Selma Lugtmeijer, Aleksandra M Sobolewska, Edward H F de Haan, H Steven Scholte

Mid-level visual processing represents a crucial stage between basic sensory input and higher-level object recognition. The conventional model posits that fundamental visual qualities like color and motion are processed in specialized, retinotopic brain regions (e.g., V4 for color, MT/V5 for motion). Using atlas-based lesion-symptom mapping and disconnectome maps in a cohort of 307 ischemic stroke patients, we examined the neuroanatomical correlates underlying the processing of eight mid-level visual qualities. Contrary to the standard model's predictions, our results did not reveal consistent relationships between processing impairments and damage to traditionally associated brain regions. While we validated our methodology by confirming the established relationship between visual field defects and damage to primary visual areas (V1, V2, and V3), we found no reliable evidence linking processing deficits to specific regions in the posterior brain. These findings challenge the traditional modular view of visual processing and suggest that mid-level visual processing may be more distributed across neural networks than previously thought. This supports alternative models where visual maps represent constellations of co-occurring information rather than specific qualities.

中级视觉处理是介于基本感官输入和高级物体识别之间的关键阶段。传统模型认为,基本的视觉品质,如颜色和运动,是在专门的视网膜定位大脑区域处理的(例如,V4负责颜色,MT/V5负责运动)。通过对307例缺血性卒中患者的基于图谱的病变症状作图和断连组作图,我们研究了8种中等水平视觉质量加工背后的神经解剖学相关性。与标准模型的预测相反,我们的结果并没有揭示处理障碍与传统相关大脑区域损伤之间的一致关系。虽然我们通过确认视野缺陷与初级视觉区域(V1、V2和V3)损伤之间的既定关系来验证我们的方法,但我们没有发现将加工缺陷与大脑后部特定区域联系起来的可靠证据。这些发现挑战了传统的视觉处理模块化观点,并表明中级视觉处理可能比以前认为的更分散在神经网络中。这支持替代模型,其中可视地图表示共同发生的信息的星座,而不是特定的质量。
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引用次数: 0
Lesion correlates of impaired acoustic-phonetic perception after unilateral left hemisphere stroke. 单侧左脑卒中后声音感知受损的病变相关性研究。
IF 10.6 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-10 DOI: 10.1093/brain/awae417
Jeffrey R Binder, Anna Freiberg, Joseph Heffernan, Mónica Geraldo-Chica, Diane S Book, Sara B Pillay

Acoustic-phonetic perception refers to the ability to perceive and discriminate between speech sounds. Acquired impairment of acoustic-phonetic perception is known historically as "pure word deafness" and typically follows bilateral lesions of the cortical auditory system. The extent to which this deficit occurs after unilateral left hemisphere damage and the critical left hemisphere areas involved are not well defined. We tested acoustic-phonetic perception in 73 individuals with chronic left hemisphere stroke and performed multivariate lesion-symptom mapping incorporating controls for non-specific task confounds, pure tone hearing loss, response bias, and lesion size. Separate analyses examined place of articulation, manner of articulation, voicing, and vowel discriminations. Overlap of the lesion map with transcallosal pathways linking left and right temporal lobes was examined using a probabilistic diffusion tensor tractography map of these pathways obtained from a healthy control cohort. Compared to an age- and education-matched control sample, 18% of the patients had impaired acoustic-phonetic perception overall, with 44% impaired on voicing, 26% on manner, 15% on place, and 14% on vowel discrimination. Lesion-symptom mapping revealed the most critical areas to be the transverse temporal gyrus (TTG) and adjacent medial belt cortex, the acoustic radiation, and the posterior superior temporal sulcus (pSTS). There were notable differences between lesion correlates for the different types of discrimination, with place discrimination linked to medial TTG, vowel discrimination to lateral TTG and planum temporale, manner discrimination to posterior planum temporale, and voicing discrimination to pSTS. Overlap of the main lesion map with transcallosal temporal lobe pathways was minor but included a deep white matter component at the base of the middle and inferior temporal gyri. The extent of overlap between individual lesions and the transcallosal pathway map was not correlated with acoustic-phonetic perception. The results add further evidence that acoustic-phonetic impairments, particularly impairments of voicing perception, are relatively common after unilateral left temporal lobe damage, and they clarify the lesion correlates of these deficits. Differences between the lesion maps for the discrimination types likely reflect differential reliance on spectral versus temporal analysis for these discriminations.

语音感知是指感知和区分语音的能力。在历史上,获得性语音感知障碍被称为“纯粹的文字耳聋”,通常伴随着双侧皮质听觉系统的损伤。单侧左半球损伤后这种缺陷发生的程度和涉及的关键左半球区域还没有很好的定义。我们测试了73名慢性左半球中风患者的声学-语音感知,并进行了多变量病变-症状映射,包括非特异性任务混淆、纯音听力损失、反应偏差和病变大小的控制。单独的分析检查了发音的位置、发音的方式、发音和元音的区分。使用从健康对照队列中获得的这些通路的概率扩散张量神经束造影图,检查了病变图与连接左右颞叶的经胼胝体通路的重叠。与年龄和受教育程度相匹配的对照样本相比,18%的患者总体上有语音感知受损,其中44%的患者发声受损,26%的患者举止受损,15%的患者位置受损,14%的患者元音辨别受损。病变症状图谱显示,最关键的区域是颞横回(TTG)和邻近的内侧带皮层、声辐射和颞后上沟(pSTS)。在不同类型的病灶相关中,位置歧视与TTG内侧相关,元音歧视与TTG外侧和颞平面相关,方式歧视与颞后平面相关,语音歧视与pSTS相关。主要病变图与经胼胝体颞叶通路的重叠较少,但包括颞中下回底部的深部白质成分。个别病变与经胼胝体通路图的重叠程度与声学-语音感知无关。研究结果进一步证明,单侧左颞叶损伤后,语音障碍,特别是声音感知障碍相对常见,并阐明了这些缺陷的病变相关性。区分类型的病变图之间的差异可能反映了这些区分对光谱与时间分析的不同依赖。
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引用次数: 0
Different factors underlie mild and severe forms of spinal muscular atrophy 不同的因素导致轻度和重度的脊髓性肌萎缩
IF 14.5 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-10 DOI: 10.1093/brain/awaf012
Eric W Ottesen, Ravindra N Singh
This scientific commentary refers to ‘The systemic complexity of a monogenic disease: the molecular network of spinal muscular atrophy’ by Tapken et al. (https://doi.org/10.1093/brain/awae272).
这篇科学评论引用了Tapken等人的“单基因疾病的系统复杂性:脊髓性肌萎缩的分子网络”(https://doi.org/10.1093/brain/awae272)。
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引用次数: 0
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