Pragmatic Clinical Trials in Neurology

神经病学中的实用性临床试验

The need for pragmatic clinical trials evaluating therapeutic interventions in patients with neurological disease is continually increasing due to availability of multiple therapeutic interventions (comparative effectiveness), multifaceted approaches (multiple concurrent synergistic therapeutic interventions), and gaps in trial-specific and real-world population outcomes. Several designs for pragmatic trials are available, including individual randomized trials with pragmatic characteristics, cluster-randomized and non-randomized trials, and observational prospective cohort studies. Cluster trials may have parallel cluster and crossover (unidirectional, bidirectional, and alternating crossover) designs. There are unique aspects of consenting and data collection leveraging existing registries, electronic health records (EHRs), and claims data that make pragmatic trials most suited to study the effectiveness of therapeutic interventions in patients with neurological diseases in real-world settings.

由于有多种治疗干预手段可供选择（比较有效性）、采用多方面治疗方法（多种同时进行的协同治疗干预），以及试验特定人群和真实世界人群的结局存在差异，开展评估神经系统疾病患者治疗干预措施的实用性临床试验的需求持续增加。实用性试验有多种设计方案，包括具有实用性特征的个体随机试验、整群随机和非随机试验，以及观察性前瞻性队列研究。整群试验可采用平行整群设计和交叉设计（单向、双向和交替交叉）。利用现有的登记系统、电子健康记录（EHR）和保险理赔数据进行知情同意和数据收集有其独特之处，这使得实用性试验最适合在真实世界环境中研究神经系统疾病患者治疗干预措施的有效性。

REF: Qureshi AI, Bartlett-Esquilant G, Brown A, McClay J, Pasnoor M, Barohn RJ. Pragmatic Clinical Trials in Neurology. Ann Neurol. 2025;97(6):1022-1037. doi:10.1002/ana.27244 PMID: 40260697

Neuroimaging Predictors of Cognitive Resilience against Alzheimer's Disease Pathology

阿尔茨海默病病理认知弹性的神经影像学预测因子

Some individuals demonstrate greater cognitive resilience-the ability to maintain cognitive performance despite adverse brain-related changes-through as yet unknown mechanisms. We examined whether cortical thickness in several brain regions confers resilience against cognitive decline in amyloid-positive adults by moderating the effects of thinner cortex in Alzheimer's disease (AD)-related brain regions and of higher levels of tau. We identified 8 cortical regions that appear to confer cognitive resilience cross-sectionally and longitudinally in the face of established indicators of AD pathology. Brain regions fostering executive function may enable compensation in later memory performance and confer cognitive resilience against effects of phosphorylated tau and AD-related cortical changes. These "resilience" regions suggest the value of focusing on brain regions beyond only those determined to be AD-related and may partially explain variability in AD-related cognitive trajectories.

一些个体表现出更强的认知弹性，即尽管大脑出现了相关不良变化，但仍能维持认知表现的能力，其背后的机制尚不清楚。我们研究了几个大脑区域的皮质厚度是否能通过调节阿尔茨海默病（AD）相关脑区皮质变薄以及tau蛋白水平升高的影响，使淀粉样蛋白阳性的成年人对认知衰退产生抵抗力。我们确定了8个皮质区域，这些区域在面对已明确的AD病理指标时，在横断面和纵向研究中似乎都能赋予认知弹性。促进执行功能的脑区可能使个体在后期的记忆表现中实现代偿，并赋予个体对磷酸化tau蛋白和AD相关皮质变化影响的认知弹性。这些“弹性”区域表明，除了已确定与AD相关的脑区之外，关注其他脑区是有价值的，并且可能部分解释了AD相关认知轨迹的变异性。

REF: Williams ME, Fennema-Notestine C, Bell TR, et al. Neuroimaging Predictors of Cognitive Resilience against Alzheimer's Disease Pathology. Ann Neurol. 2025;97(6):1038-1050. doi:10.1002/ana.27186 PMID: 39891430 PMCID: PMC12081995

The Use of Antihypertensive Medication and In Vivo Alzheimer's Disease Pathology

降压药物的使用与体内阿尔茨海默病病理改变

We investigated whether the use of antihypertensive medication (AHM) is associated with in vivo Alzheimer's Disease (AD) pathologies in older adults with hypertension and examined if the effect differs by drug-class and blood-brain barrier (BBB) permeability of the drug. Our findings suggest that AHM use may be associated with lower Aβ burden in older adults with hypertension. Further studies exploring the underlying mechanism, particularly related to RASi, may provide insights into new therapeutic targets for AD.

我们研究了降压药物（AHM）的使用是否与老年高血压患者的体内阿尔茨海默病（AD）病理特征相关，并探讨了这种影响是否因药物类别和药物的血脑屏障（BBB）通透性而异。我们的研究结果表明，使用降压药物可能与老年高血压患者较低的β-淀粉样蛋白（Aβ）负荷相关。进一步探索潜在机制（尤其是与肾素-血管紧张素系统抑制剂（RASi）相关机制）的研究，可能会为AD的新治疗靶点提供见解。

REF: Keum M, Byun MS, Yi D, et al. The Use of Antihypertensive Medication and In Vivo Alzheimer's Disease Pathology. Ann Neurol. 2025;97(6):1051-1061. doi:10.1002/ana.27204 PMID: 39960250 PMCID: PMC12236095

UNC13A Polymorphism Influences Survival in Patients with Frontotemporal Dementia

UNC13A基因多态性影响额颞叶痴呆患者的生存情况

UNC13A (rs12608932-CC) is associated with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and shortens survival in ALS. We aim to describe the association for UNC13A and survival in FTD. We included 626 patients with FTD from Dutch memory clinics, including a subcohort of 150 patients with TDP-43 pathology. Survival analyses were performed using Cox proportional hazard models in a recessive manner. Homozygosity for rs12608932-C in UNC13A was associated with a shorter survival compared with other genotypes (hazard ratio [HR] = 1.28, 95% confidence interval [CI] = 1.02-1.60, p = 0.033), which has implications for patient counselling and trial design.

UNC13A（rs12608932 - CC）与肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）均相关，且会缩短ALS患者的生存期。我们旨在阐述UNC13A与FTD患者生存期的关联。我们纳入了来自荷兰记忆门诊的626例FTD患者，其中包括一个由150例有TDP - 43病理改变患者组成的亚组。采用Cox比例风险模型以隐性方式进行生存分析。与其他基因型相比，UNC13A中rs12608932 - C纯合子与较短的生存期相关（风险比[HR] = 1.28，95%置信区间[CI] = 1.02 - 1.60，p = 0.033），这对患者咨询和试验设计具有指导意义。

REF: Reus LM, Willemse SW, de Boer SCM, et al. UNC13A Polymorphism Influences Survival in Patients with Frontotemporal Dementia. Ann Neurol. 2025;97(6):1062-1066. doi:10.1002/ana.27245 PMID: 40214138 PMCID: PMC12082005

Neuropathological Evidence of Reduced Amyloid Beta and Neurofibrillary Tangles in Multiple Sclerosis Cortex

多发性硬化症皮质中β-淀粉样蛋白和神经原纤维缠结减少的神经病理学证据

Multiple sclerosis (MS) and Alzheimer's disease are neurodegenerative diseases with age-related disability accumulation. In MS, inflammation spans decades, whereas AD is characterized by Aβ plaques and neurofibrillary tangles (NFT). Few studies explore accumulation of amyloids in MS. We examined Aβ deposition and NFT density in temporal and frontal cortices from postmortem MS (n = 75) and control (n = 66) cases. Compared with controls, MS cases showed reduced Aβ, especially in those aged <65 years, and reduced NFT, notably in cases aged >65 years. Aβ deposition predicted greater NFT density both in MS cases and controls. MS-related factors may affect Aβ/NFT deposition and/or clearance, offering new therapeutic insights for both diseases.

多发性硬化症（MS）和阿尔茨海默病是与年龄相关的残疾累积性神经退行性疾病。在多发性硬化症中，炎症会持续数十年，而阿尔茨海默病的特征是β-淀粉样蛋白（Aβ）斑块和神经原纤维缠结（NFT）。很少有研究探索多发性硬化症中淀粉样蛋白的累积情况。我们检查了75例尸检多发性硬化症患者和66例对照者颞叶和额叶皮质中的Aβ沉积和NFT密度。与对照者相比，多发性硬化症患者的Aβ沉积减少，尤其是年龄小于65岁的患者；NFT减少，特别是年龄大于65岁的患者。Aβ沉积在多发性硬化症患者和对照者中均预示着更高的NFT密度。与多发性硬化症相关的因素可能会影响Aβ/NFT的沉积和/或清除，为这两种疾病提供了新的治疗思路。

REF: Pansieri J, Pisa M, Yee S, et al. Neuropathological Evidence of Reduced Amyloid Beta and Neurofibrillary Tangles in Multiple Sclerosis Cortex. Ann Neurol. 2025;97(6):1067-1073. doi:10.1002/ana.27231 PMID: 40195794 PMCID: PMC12082000

Accelerated Cellular Senescence in Progressive Multiple Sclerosis: A Histopathological Study

进行性多发性硬化中的细胞衰老加速：一项组织病理学研究

The neurodegenerative processes driving the build-up of disability in progressive multiple sclerosis (P-MS) have not been fully elucidated. Recent data link cellular senescence (CS) to neurodegeneration. We investigated for evidence of CS in P-MS and sought to determine its pattern. Our data indicates that CS primarily affects actively demyelinating gray and WMLs. A higher senescent cell load in P-MS is associated with faster disability progression and death.

推动进展型多发性硬化症（P - MS）残疾累积的神经退行性过程尚未完全阐明。近期数据将细胞衰老（CS）与神经退行性变联系起来。我们研究了P - MS中细胞衰老的证据，并试图确定其模式。我们的数据表明，细胞衰老主要影响正在发生脱髓鞘的灰质和白质病变。P - MS中较高的衰老细胞负荷与更快的残疾进展和死亡相关。

REF: Papadopoulos D, Magliozzi R, Bandiera S, et al. Accelerated Cellular Senescence in Progressive Multiple Sclerosis: A Histopathological Study. Ann Neurol. 2025;97(6):1074-1087. doi:10.1002/ana.27195 PMID: 39891488 PMCID: PMC12081997

Heparin-Binding Protein in Cerebrospinal Fluid as a Biomarker for Bacterial Meningitis: A Study of Diagnostic Accuracy

脑脊液中肝素结合蛋白作为细菌性脑膜炎生物标志物的诊断准确性研究

We aimed to evaluate the diagnostic accuracy of heparin-binding protein (HBP) in cerebrospinal fluid for the diagnosis of bacterial meningitis in patients with a suspected central nervous system infection. HBP can correctly distinguish bacterial meningitis from other disorders. It can be of additional value to current diagnostics in cases where CSF leukocyte count is relatively low, particularly when combined with CSF CRP.

我们旨在评估脑脊液中肝素结合蛋白（HBP）对疑似中枢神经系统感染患者细菌性脑膜炎的诊断准确性。HBP 能够正确区分细菌性脑膜炎与其他疾病。在脑脊液白细胞计数相对较低的情况下，尤其是与脑脊液 C 反应蛋白（CRP）联合检测时，HBP 对当前的诊断方法具有额外的价值。

REF: Olie SE, Staal SL, da Cruz Campos AC, et al. Heparin-Binding Protein in Cerebrospinal Fluid as a Biomarker for Bacterial Meningitis: A Study of Diagnostic Accuracy. Ann Neurol. 2025;97(6):1088-1095. doi:10.1002/ana.27193 PMID: 39868663 PMCID: PMC12082029

Nigral Neuroinflammation and Dopaminergic Neurons in Parkinson's Disease and Atypical Parkinsonisms

帕金森病和非典型帕金森综合征中的黑质神经炎症与多巴胺能神经元

To investigate the role of neuroinflammation in the substantia nigra pars compacta (SNc) across different parkinsonian disorders-Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA)-by examining SNc dopaminergic neuron counts, neuroinflammatory T cells, and microglial activity. The study reveals distinctive neuroinflammatory patterns in the SNc, with T cell-mediated inflammation prominent in PSP and microglia-mediated inflammation in PD. PSP and MSA show greater SNc dopaminergic neuron loss compared to PD. Increased neuroinflammatory response is seen in earlier disease stages, diminishing with greater neuron loss, which may inform disease progression understanding and therapeutic strategies.

通过检查黑质致密部（SNc）多巴胺能神经元数量、神经炎症性T细胞和小胶质细胞活性，研究神经炎症在不同帕金森综合征（帕金森病（PD）、进行性核上性麻痹（PSP）和多系统萎缩（MSA））的黑质致密部中所起的作用。该研究揭示了黑质致密部独特的神经炎症模式，在进行性核上性麻痹中T细胞介导的炎症较为突出，而在帕金森病中小胶质细胞介导的炎症较为显著。与帕金森病相比，进行性核上性麻痹和多系统萎缩的黑质致密部多巴胺能神经元丢失更为严重。在疾病早期可观察到神经炎症反应增强，随着神经元丢失增多，炎症反应减弱，这可能有助于了解疾病进展并指导治疗策略的制定。

REF: Backman EA, Gardberg M, Luntamo L, et al. Nigral Neuroinflammation and Dopaminergic Neurons in Parkinson's Disease and Atypical Parkinsonisms. Ann Neurol. 2025;97(6):1096-1109. doi:10.1002/ana.27202 PMID: 39918108

Validating the Accuracy of Parkinson's Disease Clinical Diagnosis: A UK Brain Bank Case–Control Study

验证帕金森病临床诊断的准确性：一项英国脑库病例对照研究

Despite diagnostic criteria refinements, Parkinson's disease (PD) clinical diagnosis still suffers from a not satisfying accuracy, with the post-mortem examination as the gold standard for diagnosis. Seminal clinicopathological series highlighted that a relevant number of patients alive-diagnosed with idiopathic PD have an alternative post-mortem diagnosis. We evaluated the diagnostic accuracy of PD comparing the in-vivo clinical diagnosis with the post-mortem diagnosis performed through the pathological examination in 2 groups. Our findings confirm a still significant diagnostic error and emphasize the need for more fine and homogeneous criteria to classify idiopathic Parkinson's patients correctly.

尽管诊断标准有所改进，但帕金森病（PD）的临床诊断准确性仍不尽人意，尸检检查是诊断的金标准。早期的临床病理系列研究表明，相当数量生前被诊断为特发性帕金森病的患者在尸检后有其他诊断。我们比较了两组患者的活体临床诊断与通过病理检查进行的尸检诊断，以评估帕金森病的诊断准确性。我们的研究结果证实，诊断误差仍然显著，并强调需要更精细、统一的标准来正确分类特发性帕金森病患者。

REF: di Biase L, Pecoraro PM, Di Lazzaro V. Validating the Accuracy of Parkinson's Disease Clinical Diagnosis: A UK Brain Bank Case-Control Study. Ann Neurol. 2025;97(6):1110-1121. doi:10.1002/ana.27190 PMID: 39871110 PMCID: PMC12082010