AI in Neurology: Everything, Everywhere, All at Once Part 3: Surveillance, Synthesis, Simulation, and Systems

神经学中的人工智能：无处不在、全面覆盖 第三部分：监测、整合、模拟与系统

This final part 3 review builds on the practical applications discussed in part 2 and explores how artificial intelligence (AI) is transforming data management, neurological education, and neurological care across large healthcare networks and datasets. The review also highlights AI's role in real-world and synthetic data, digital twins, and innovative clinical trial designs, such as in silico and adaptive trials. The review emphasizes AI's ability to drive continuous improvements in care and discovery through comparative effectiveness research and learning health systems. The global healthcare implications discussed here tie back to earlier discussions on human-AI collaboration and precision care, underscoring the neurological sciences' responsibility to adopt AI advances judiciously, while managing their ethical, economic, and environmental impacts.

这第三部分也是最后一部分的综述基于第二部分所讨论的实际应用，探讨了人工智能（AI）如何在大型医疗网络和数据集范围内改变数据管理、神经科学教育和神经科护理。该综述还着重介绍了人工智能在真实世界数据和合成数据、数字孪生以及创新临床试验设计（如计算机模拟试验和适应性试验）中的作用。综述强调了人工智能通过比较效果研究和学习型医疗系统推动护理和研究持续改进的能力。这里讨论的全球医疗影响与之前关于人机协作和精准护理的讨论相呼应，强调了神经科学领域有责任审慎采用人工智能的进步成果，同时管理其在伦理、经济和环境方面的影响。

REF: Rizzo M. AI in Neurology: Everything, Everywhere, All at Once Part 3: Surveillance, Synthesis, Simulation, and Systems. Ann Neurol. 2025;98(4):651-667. doi:10.1002/ana.27230 PMID: 40135538 PMCID: PMC12447850

The Scale of Neurodegeneration in Moderate-to-Severe Traumatic Brain Injury: A Systematic Review of Longitudinal Studies

中重度创伤性脑损伤的神经退行性病变程度：纵向研究的系统评价

Although moderate-to-severe traumatic brain injury (msTBI) was once considered a static neural event following resolution of acute injuries, numerous studies now demonstrate progressive losses to volume and white matter integrity in the months and years postinjury, leading to a paradigm shift in our understanding. These findings have yet to be synthesized. Therefore, our objective was to assimilate longitudinal studies of chronic msTBI to better elucidate the scale and timelines of neurodegeneration, regions of vulnerability, and ongoing gaps in the literature. Gaps in our understanding include mechanisms of degeneration, whether progressive losses remain constant or attenuate with time, and how patterns vary by region. Longitudinal research with 3 timepoints, standardized reporting, and additional outcome modalities (eg, functional magnetic resonance imaging [fMRI], and blood biomarkers) would refine our understanding and inform treatment research.

尽管中重度创伤性脑损伤（msTBI）曾被认为是急性损伤痊愈后的一种静止性神经事件，但如今大量研究表明，在受伤后的数月和数年里，脑容量和白质完整性会持续下降，这使得我们的认知发生了范式转变。这些研究结果尚未得到整合。因此，我们的目标是整合慢性中重度创伤性脑损伤的纵向研究，以更好地阐明神经退行性变的程度和时间线、易损区域以及现有文献中存在的空白。我们认知上的空白包括退变机制、进行性损伤是会随时间保持恒定还是会减轻，以及不同区域的变化模式有何差异。开展具有三个时间点的纵向研究、进行标准化报告并采用更多的结局评估方式（如功能磁共振成像[fMRI]和血液生物标志物），将有助于我们深化认知，并为治疗研究提供参考。

REF: Sharma B, Monteiro L, Changoor A, Colella B, Green R. The Scale of Neurodegeneration in Moderate-to-Severe Traumatic Brain Injury: A Systematic Review of Longitudinal Studies. Ann Neurol. 2025;98(4):668-681. doi:10.1002/ana.27279 PMID: 40519138 PMCID: PMC12542324

Blood α-Synuclein Separates Parkinson's Disease from Dementia with Lewy Bodies

血液α-突触核蛋白可区分帕金森病与路易体痴呆

Aggregation of misfolded α-synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBDs), including Parkinson's disease (PD), and dementia with Lewy bodies (DLB) disease. Although evidence exists for aSyn "strains," conformations with distinct biological properties, biomarkers for PD versus DLB are lacking. Here, we used monoclonal antibodies selective for two different in vitro aSyn species - termed strain A and B - to evaluate human brain tissue, cerebrospinal fluid (CSF), and plasma. Our findings suggest that circulating plasma aSyn strains may impact LBD clinical presentation, particularly cognition. The enrichment of these aSyn species in plasma but not CSF also suggests a potential source outside the brain.

大脑内错误折叠的α-突触核蛋白（aSyn）聚集是路易体病（LBDs）的病理标志，路易体病包括帕金森病（PD）和路易体痴呆（DLB）。尽管有证据表明存在具有不同生物学特性构象的aSyn “毒株”，但目前缺乏区分PD和DLB的生物标志物。在此，我们使用对两种不同体外aSyn种类（称为毒株A和毒株B）具有选择性的单克隆抗体来评估人脑组织、脑脊液（CSF）和血浆。我们的研究结果表明，循环血浆中的aSyn毒株可能会影响LBD的临床表现，尤其是认知功能。这些aSyn种类在血浆而非脑脊液中富集，这也提示其可能来源于脑外。

REF: Kannarkat GT, Zack R, Skrinak RT, et al. Blood α-Synuclein Separates Parkinson's Disease from Dementia with Lewy Bodies. Ann Neurol. 2025;98(4):682-698. doi:10.1002/ana.27288 PMID: 40521808 PMCID: PMC12262490

α-Synuclein-Related Mitochondria-Nrf2 Dysfunction in Parkinson's Disease Olfactory Mucosa

帕金森病嗅黏膜中与α-突触核蛋白相关的线粒体 - 核因子 E2 相关因子 2 功能障碍

The objective of this study was to outline the dynamics of the mitochondrial network and cytoprotective response in patients with Parkinson's disease (PD)-derived olfactory mucosa neurons (ONs) at different disease stages. Human-derived ONs may recapitulate PD pathogenic milestones, exhibiting stage-specific interactions among α-synuclein oligomers, mitochondrial metabolism, and cytoprotective response. These findings highlighted mitochondrial dysfunction as a primary target for therapeutic interventions and a potential axis for the biological stratification of patients. Moreover, they supported the translational value of ONs, as a source of biomarkers or models, which is critical in the current changing paradigm of PD toward a biological-based approach.

本研究的目的是阐述不同疾病阶段帕金森病（PD）患者来源的嗅黏膜神经元（ONs）中线粒体网络的动态变化和细胞保护反应。人源ONs可能重现PD的致病关键节点，表现出α-突触核蛋白寡聚体、线粒体代谢和细胞保护反应之间的阶段特异性相互作用。这些发现强调了线粒体功能障碍是治疗干预的主要靶点，也是患者生物学分层的潜在轴。此外，这些发现支持了将ONs作为生物标志物来源或模型的转化价值，这在当前PD向基于生物学方法转变的范式中至关重要。

REF: Maftei D, Di Certo MG, Maurizi R, et al. α-Synuclein-Related Mitochondria-Nrf2 Dysfunction in Parkinson's Disease Olfactory Mucosa. Ann Neurol. 2025;98(4):699-710. doi:10.1002/ana.27292 PMID: 40503742

Deep Brain Stimulation for VPS16-Related Dystonia: A Multicenter Study

VPS16 相关肌张力障碍的脑深部电刺激治疗：一项多中心研究

The objective was to evaluate the effects of deep brain stimulation (DBS) in an international cohort of patients with VPS16-related dystonia. DBS was an effective treatment for three-quarters of patients with pathogenic VPS16 variants in our cohort. Mean motor improvement was most pronounced at the 1-year FU, but persisted at the last FU despite disease progression.

目的是评估深部脑刺激（DBS）对国际VPS16相关肌张力障碍患者队列的疗效。在我们的队列中，DBS对四分之三携带致病性VPS16变异的患者是一种有效的治疗方法。运动功能的平均改善在1年随访时最为显著，但尽管疾病进展，在最后一次随访时仍持续存在。

REF: Svorenova T, Romito LM, Kaymak A, et al. Deep Brain Stimulation for VPS16-Related Dystonia: A Multicenter Study. Ann Neurol. 2025;98(4):711-725. doi:10.1002/ana.27290 PMID: 40539388 PMCID: PMC12542321

Chronic Striatal Cholinergic Interneuron Excitation Causes Cerebral Palsy-Related Dystonic Behavior in Mice

慢性纹状体胆碱能中间神经元兴奋导致小鼠出现与脑瘫相关的肌张力障碍行为

Mouse models of genetic dystonias have demonstrated abnormal striatal cholinergic interneuron excitability, but do not consistently demonstrate subjective dystonic features. To determine whether striatal cholinergic interneuron excitation can cause potentially dystonic motor behaviors, we first determined features correlated specifically with dystonia severity in people and then determined whether these features emerged in mice following striatal cholinergic interneuron excitation. We demonstrate that leg adduction variability correlates with leg dystonia severity in people with cerebral palsy and that chronic, but not acute, striatal cholinergic interneuron excitation can cause leg adduction variability in mice. These results support targeting striatal cholinergic interneurons for dystonia drug development and demonstrate the potential value of using quantifiable leg adduction metrics to study dystonia pathophysiology.

遗传性肌张力障碍的小鼠模型已显示出纹状体胆碱能中间神经元兴奋性异常，但并非始终能表现出主观的肌张力障碍特征。为了确定纹状体胆碱能中间神经元兴奋是否会导致潜在的肌张力障碍性运动行为，我们首先确定了与人类肌张力障碍严重程度具体相关的特征，然后确定在纹状体胆碱能中间神经元兴奋后，这些特征是否会在小鼠身上出现。我们发现，在脑瘫患者中，腿部内收变异性与腿部肌张力障碍的严重程度相关，并且慢性（而非急性）的纹状体胆碱能中间神经元兴奋可导致小鼠出现腿部内收变异性。这些结果支持将纹状体胆碱能中间神经元作为肌张力障碍药物研发的靶点，并证明了使用可量化的腿部内收指标来研究肌张力障碍病理生理学的潜在价值。

REF: Gemperli K, Lu X, Chintalapati K, et al. Chronic Striatal Cholinergic Interneuron Excitation Causes Cerebral Palsy-Related Dystonic Behavior in Mice. Ann Neurol. 2025;98(4):726-740. doi:10.1002/ana.27299 PMID: 40607765

The Relationship between Rest Tremor and Underlying Lewy Pathology in Essential Tremor: A Clinical-Pathological Study of 201 Cases

特发性震颤中静止性震颤与潜在路易体病理改变的关系：一项201例临床病理研究

Prospective studies demonstrated that essential tremor is a risk factor for Parkinson's disease. Identifying clinical markers for conversion from essential tremor to essential tremor-Parkinson's disease would be of considerable value. Rest tremor can be present in advanced essential tremor and may be a harbinger of conversion. We examined (1) the brain distribution and severity of Lewy pathology and (2) whether patients met pathologically based criteria for Lewy body disease in relation to (1) the presence and severity of isolated rest tremor and (2) the diagnosis of essential tremor-Parkinson's disease during life. In clinical practice, isolated rest tremor should be viewed as a finding that is associated with increased odds of Parkinson's disease but not, in the large majority of cases, indicative of underlying Lewy body disease. Our quantitative data can be conveyed to patients to provide prognostic information in discussions of risk stratification.

前瞻性研究表明，特发性震颤是帕金森病的一个危险因素。确定特发性震颤向特发性震颤 - 帕金森病转变的临床标志物将具有重要价值。静止性震颤可出现在晚期特发性震颤中，可能是病情转变的先兆。我们研究了（1）路易体病理改变的脑部分布和严重程度，以及（2）患者是否符合基于病理的路易体病标准，同时关联（1）孤立性静止性震颤的有无和严重程度，以及（2）生前特发性震颤 - 帕金森病的诊断情况。在临床实践中，孤立性静止性震颤应被视为与帕金森病患病几率增加相关的表现，但在大多数情况下，并不提示存在潜在的路易体病。我们的量化数据可以传达给患者，以便在进行风险分层讨论时提供预后信息。

REF: Louis ED, Hernandez NC, Guy T, Faust PL. The Relationship between Rest Tremor and Underlying Lewy Pathology in Essential Tremor: A Clinical-Pathological Study of 201 Cases. Ann Neurol. 2025;98(4):741-749. doi:10.1002/ana.27302 PMID: 40521765 PMCID: PMC12542307

Clinical and Genetic Findings in a Chinese Cohort of Dentatorubral–Pallidoluysian Atrophy Patients

中国齿状核红核 - 苍白球路易体萎缩患者队列的临床和遗传学研究结果

Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, inherited neurodegenerative disorder caused by the expansion of cytosine-adenine-guanine repeats in ATN1. Most studies on DRPLA to date are limited to case reports. We aimed to provide a comprehensive summary of the clinical, genetic, biological, and magnetic resonance imaging characteristics of DRPLA using cross-sectional baseline data. This is the first DRPLA cohort study to comprehensively report clinical, genetic, cognitive, imaging, and plasma neurofilament light data. This study provides robust data to enhance our understanding of the overall features of DRPLA. We also propose clear definitions for the preclinical stage of DRPLA, and demonstrate the high diagnostic utility of plasma neurofilament light as a biomarker.

齿状核红核苍白球路易体萎缩症（DRPLA）是一种罕见的遗传性神经退行性疾病，由ATN1基因中胞嘧啶 - 腺嘌呤 - 鸟嘌呤重复序列扩增所致。迄今为止，大多数关于DRPLA的研究仅限于病例报告。我们旨在利用横断面基线数据全面总结DRPLA的临床、遗传、生物学和磁共振成像特征。这是第一项全面报告DRPLA临床、遗传、认知、影像学和血浆神经丝轻链数据的队列研究。本研究提供了可靠的数据，有助于我们更全面地了解DRPLA的整体特征。我们还为DRPLA的临床前期提出了明确的定义，并证实了血浆神经丝轻链作为生物标志物具有很高的诊断价值。

REF: Yuan RY, Chen YF, Lin W, et al. Clinical and Genetic Findings in a Chinese Cohort of Dentatorubral-Pallidoluysian Atrophy Patients. Ann Neurol. 2025;98(4):750-761. doi:10.1002/ana.27293 PMID: 40552560

Decoding the Clinical Features that Associate with Progression, Causes, and Outcomes in Patients with Suspected Rapidly Progressive Dementia

解析疑似快速进展性痴呆患者与疾病进展、病因及预后相关的临床特征

To determine the clinical features that identify patients with suspected rapidly progressive dementia (RPD) who will develop RPD. Selected clinical features may identify patients with suspected RPD who are likely to continue to decline. Early recognition of these features may improve diagnostic accuracy and inform prognosis.

确定能够识别疑似快速进展性痴呆（RPD）且将发展为RPD患者的临床特征。某些选定的临床特征可能有助于识别疑似RPD且病情可能持续恶化的患者。早期识别这些特征可能会提高诊断准确性并为判断预后提供依据。

REF: Piura YD, Satyadev N, Corriveau-Lecavalier N, et al. Decoding the Clinical Features that Associate with Progression, Causes, and Outcomes in Patients with Suspected Rapidly Progressive Dementia. Ann Neurol. 2025;98(4):764-776. doi:10.1002/ana.27297 PMID: 40539812 PMCID: PMC12283139