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Stroke remained the second leading cause of death globally in 2019. The antiplatelet drug clopidogrel is used to keep blood clots from forming in people who have experienced a stroke. Although most people find clopidogrel to be safe and beneficial, there is inevitably a range in how each patient responds. The review covers about Clopidogrel resistance in stroke patients, their risk factors and the methods to identify it. Clopidogrel resistance is characterized as the drug’s inability to prevent the target enzyme from acting. The prognosis of patients with ischemic stroke and the responsiveness to clopidogrel are significantly impacted by the various genetic polymorphism CYP2C19 genotypes. The two primary mutant alleles, CYP2C19 *2 and CYP2C19 *3, have been found to be the most prevalent genotypes. Better mRS scores six months after treatment showed a higher response rate in patients without these CYP2C19 variant alleles. Other factors are drug-drug interaction (proton pump inhibitors), demographics (age, sex, social history), comorbid conditions, etc. Blood samples for testing platelet reactivity were drawn one month after discharge from a peripheral blood sample. Several methods are used to identify the clopidogrel resistance. Some of them are ADP-Induced platelet aggregation, Platelet Reactivity Index VASP, Verify Now Assay, TEG Analyzer, Plasma microRNA-223. Drugs that are not prodrugs and whose metabolism is not dependent upon CYP2C19 can be selected as a superior alternative in case of CR. Ticagrelor is one such effective substitute. Proton pump inhibitors and clopidogrel should only be used concurrently in patients with reliable clinical indications.

Autoimmune autonomic disorders encompass a spectrum of disorders mediated by immune responses directed against the autonomic nervous system, including the peripheral and central autonomic pathways. While centrally mediated autoimmune autonomic disorders primarily can cause autonomic hyperactivity, peripherally mediated disorders are more common and can cause either locally confined or global autonomic failure. These disorders are often underrecognized owing to vague and varied clinical signs and symptoms. The discovery of specific autoantibodies in the past decade has caused a growing recognition of autoimmune causes for these disorders. The management is also complex, as these disorders often manifest with generalized symptoms, are difficult to diagnose, invoke challenges involving robust establishment of an autoimmune syndrome, and are rare. This article presents an overview of autonomic disorders that have a suspected autoimmune etiology, as well as recent advancements in their diagnosis and management.

Background and Objectives: To compare the cognitive functions and trait anxiety in patients diagnosed with relapsing–remitting multiple sclerosis (RRMS) to those of matched healthy controls (HCs). In addition, the study aims to investigate the correlations among cognitive functions, anxiety, depression, and quality of life (QOL) in this clinical population. Methods: The sample included RRMS patients (n = 21) and an equal number of age-, education-, and sex-matched HCs. Participants were assessed on the Indian version of the Wechsler Adult Intelligence Scale-IV, auditory and visual learning and memory, and visual–spatial construction and memory. RRMS patients were also assessed for levels of anxiety, depression, and their QOL. Comparative analyses between RRMS patients and HCs were carried out for neuropsychological assessments. Correlations among cognitive functions, anxiety, depression, and QOL in RRMS patients were examined. Results: RRMS patients showed significant deficits across various cognitive domains, including processing speed and verbal learning, compared to HCs (P < 0.05). In addition, they reported higher levels of trait anxiety compared to HCs (P < 0.01), along with moderate state anxiety and mild depression. A significant correlation among anxiety, depression, and QOL was observed in RRMS patients. Conclusions: This study highlights significant cognitive impairments and psychological distress experienced by RRMS individuals, underscoring the critical need for comprehensive care addressing both cognitive impairments and psychological distress to enhance QOL.

Background and Objectives: Sensory neuronopathies (SNNs) are a rare group of pure sensory disorders causing asymmetrical, multifocal pattern of sensory loss with distinct clinical and electrophysiological features. We aimed to study the clinical features and etiology and share the experience of treating SNN from our center. Methods: A prospective observational study was conducted over 3 years. Patients with predominant sensory complaints and electrophysiological evidence of neuropathy were evaluated. Possible/probable SNN was diagnosed using Camdessanch´e criteria. Detailed workup was done to determine the etiology and treatment given accordingly. Follow-up was done and response to treatment was assessed using modified Rankin Scale grading at 12 months. Results: Fourteen patients with SNN were studied. Two (14.3%) patients were diagnosed with Sjogren’s syndrome (SS-SNN), two (14.3%) with paraneoplastic syndrome, one (7.1%) with leprous ganglionitis, and nine (64.3%) were idiopathic sensory neuronopathy (I-SNN) cases. Improvement occurred in nine (64.3%), stability in three (21.4%), and worsening in two (14.3%) patients. Out of 11 SS-SNN and I-SNN patients, eight showed improvement on follow-up, seven with injection rituximab (RTX) and one with azathioprine. We found positive correlation between RTX treatment and improvement on follow-up (P = 0.0256). Six (66.66%) out of nine I-SNN patients had early initiation of immunotherapy, of which all improved. There was positive correlation between early treatment initiation time in I-SNN patients and improvement (P = 0.0119). Conclusions: Promising results were noted in SS-SNN and I-SNN patients with intensive treatment approach using RTX. Hit hard and early treatment approach is crucial for achieving improvement in sensory neuronopathies.

Optic neuritis (ON) is an inflammatory condition that affects the optic nerve and may be associated with various central nervous system demyelinating conditions, infectious diseases, and systemic autoimmune syndromes. This manuscript sheds light on the epidemiologic patterns and diverse clinical features of ON, emphasizing the importance of early detection and prompt treatment. Various studies have revealed geographic and ethnic variations across ON subtypes, which are likely related to the incidence and prevalence of co-associated disorders. Distinguishing ON subtypes may be challenging and requires use of paraclinical tools. Treatment strategies differ depending on the etiology, further highlighting the importance of accurately identifying specific ON subtypes in a timely manner.

Gema Martinez-Navarrete,1,2 Sergio Castaño-Castaño,3– 6 Miguel Morales-Navas,4 Francisco Nieto-Escámez,4,7 Fernando Sánchez-Santed,4 Eduardo Fernandez1,2 1Neuroprosthesis and Neuroengineering Research Group, Institute of Bioengineering (IB), University Miguel Hernández (UMH), Elche, 03020, Spain; 2Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza, Spain; 3Department Psychology, University of Oviedo, Plaza Feijoo S/N, Oviedo, 33003, Spain; 4Department of Psychology, University of Almería, Ctra. Sacramento S/N, La Cañada de San Urbano, Almería, 04120, Spain; 5Institute of Neurosciences of the Principality of Asturias (INEUROPA), Oviedo, Spain; 6Institute of Health Research of the Principality of Asturias (ISPA), Oviedo, Spain; 7Neuropsychological Evaluation and Rehabilitation Center (CERNEP), Ctra. Sacramento S/N, La Cañada de San Urbano, Almería, 04120, SpainCorrespondence: Gema Martinez-Navarrete, Department of Histology and Anatomy (Faculty of Medicine). Neuroengineering Biomedical Research Group, Institute of Bioengineering, University Miguel Hernandez, Elche, 03202, Spain, Email gema.martinezn@umh.es Sergio Castaño-Castaño, Department Psychology, University of Oviedo, Plaza Feijoo s/n, Asturias, 33003, Spain, Email castanosergio@uniovi.esPurpose: The impact of visual deprivation on retinal structure is widely debated. Experimental models, like monocular deprivation through lid suture, provide insights into the consequences of lacking visual experience during development. This deprivation delays primary visual cortex (CV1) maturation due to improper neural connection consolidation, which remains plastic beyond the critical period. However, few studies have used Optical Coherence Tomography (OCT) to investigate structural alterations in the retina of animal models following monocular deprivation. Instead, some studies have focused on the ganglion cell layer using post-mortem histological techniques in amblyopia models induced by monocular deprivation.Methods: In this study, we used Cliff test to assess stereoscopic vision and spectral domain optical coherence tomography (SD-OCT) to evaluate retinal changes in an in vivo model of visual deprivation treated with Transcranial Direct Current Stimulation (tDCS).Results: The depth perception test initially revealed differences between individuals with amblyopia and the control group. However, after 8 tDCS sessions, amblyopic subjects matched the control group’s performance, which remained stable Additionally, significant changes were observed in retinal structures post-tDCS treatment. Specifically, the thickness of the Nerve Fiber Layer + Ganglion Cell Layer + Inner Plexiform Layer (NFL+GCL+IPL) increased significantly in amblyopic eyes (p< 0.001). Moreover, significant retinal thickening, including the Nerve Fiber Layer + Ganglion Cell Layer + Inner Plexiform Layer (NFL+GCL+IPL) and the entire retina, was observed post-tDCS treatment (p< 0.05), highlighting the critical role of tDCS in ameliorating amblyopia. Additionally, treated animals exhibited reduced thickness in the Inner Nuclear Layer (INL) and Outer Nuclear Layer (ONL).Conclusion: tDCS treatment effectively restores amblyopic individuals’ stereoscopic vision, aligning their performance with controls, while impacting retinal structure, highlighting its potential in ameliorating amblyopia’s visual deficits. Keywords: amblyopia, monocular visual deprivation model, tDCS, stereoscopic vision, OCT

本文介绍了1例基于基因检测的后循环缺血介入治疗后抗血小板治疗的患者情况。该例患者为老年女性，基底动脉中段闭塞所致急性缺血性卒中，发病3 h内入院，给予静脉溶栓后桥接介入治疗，治疗后恢复较好（NIHSS评分从入院时的11分降至出院时的2分）。为个体化选择患者的抗血小板治疗方案，在介入治疗后进行细胞色素P450酶家族2亚家族C成员19（cytochrome P450 family 2 subfamily C member 19，CYP2C19）基因检测，显示为中间代谢型，提示患者可能存在氯吡格雷抵抗，选择替格瑞洛联合阿司匹林双联抗血小板方案进行3个月的抗血小板治疗，之后根据患者随访情况调整用药。出院后2个月随访时患者预后良好且未出现出血表现。 Abstract: This article described a case of a patient with antiplatelet therapy after interventional therapy for posterior circulation ischemia based on gene detection. The patient was an elderly female with acute ischemic stroke caused by middle segment occlusion of the basilar artery. She was admitted within 3 hours of onset and received intravenous thrombolysis followed by bridging interventional therapy. After treatment, the patient recovered well (NIHSS score decreased from 11 points at admission to 2 points at discharge). In order to individualize the selection of the patient’s antiplatelet therapy regimen, cytochrome P450 family 2 subfamily C member 19 (CYP2C19) gene detection was performed after interventional therapy, which showed an intermediate metabolism type, indicating that the patient may have clopidogrel resistance. Therefore, the dual antiplatelet therapy regimen of ticagrelor combined with aspirin was selected for 3 months for antiplatelet therapy, and then the medication was adjusted according to the patient’s follow-up. At two months of follow-up after discharge, the prognosis was good and there were no bleeding manifestations.

本文报道了一例老年女性院内卒中患者的临床诊疗过程。该患者于肛肠外科手术后2 d突发急性缺血性卒中，经影像学检查确诊为右侧颈内动脉起始部重度狭窄。在接受了1个月的卒中二级预防药物治疗后，择期行血管内治疗。术前该患者进行了快速细胞色素P450酶家族2亚家族C成员19（cytochrome P450 family 2 subfamily C member 19，CYP2C19）基因检测，结果为中间代谢型，提示应用氯吡格雷的效果可能不佳。基于这一检测结果调整抗血小板治疗方案，选择替格瑞洛联合阿司匹林作为替代治疗。治疗后，患者病情稳定，预后较好。本病例报道提示，在非轻型卒中患者中，快速CYP2C19基因检测可帮助选择抗血小板治疗策略，改善患者预后。 Abstract: This paper reported the clinical diagnosis and treatment process of an elderly female patient with in-hospital stroke. The patient suddenly developed acute ischemic stroke 2 days after an anorectal surgery and was diagnosed with severe stenosis at the origin of the right internal carotid artery by imaging examination. After one month of treatment with secondary prevention drugs for stroke, selective endovascular treatment was performed. The rapid detection of cytochrome P450 family 2 subfamily C member 19 (CYP2C19) gene before the operation showed that it was an intermediate metabolic type, suggesting that the effect of clopidogrel may be poor. Based on this result, the antiplatelet therapy regimen was adjusted and ticagrelor combined with aspirin was selected as a replacement therapy. After treatment, the patient’s condition was stable and the prognosis was good. This report suggests that rapid detection of the CYP2C19 gene can also be used to guide the selection of antiplatelet therapy strategies and improve outcomes in non-mild stroke patients.

目的 分析影响脑小血管病患者发生认知障碍的因素。 方法 回顾性选取（系统抽样）沧州市中心医院2020年1月—2022年5月收治的脑小血管病患者作为建模组，根据是否发生认知障碍分为无认知障碍组和认知障碍组。多因素logistic回归模型分析脑小血管病患者发生认知障碍的因素，于R3.6.3中构建预测脑小血管病认知障碍的列线图模型。另以建模组∶验证组=7∶3的方案收集2022年5月—2023年5月收治的脑小血管病患者为验证组，对构建的模型进行外部验证；绘制ROC曲线评价列线图模型在脑小血管病认知障碍风险评估中的区分度。 结果 本研究共纳入247例患者，建模组173例，验证组74例；建模组中61例（35.26%）存在认知障碍，验证组中24例（32.43%）存在认知障碍。多因素分析显示，CRP水平较高（OR 1.527，95%CI 1.271～1.834，P＜0.001）、高血压（OR 2.106，95%CI 1.044～4.248，P=0.037）、颈动脉粥样硬化（OR 3.917，95%CI 1.416～10.833，P=0.009）、高同型半胱氨酸血症（OR 3.220，95%CI 1.261～8.226，P=0.015）、脑白质损伤病变程度（OR 2.862，95%CI 1.496～5.475，P=0.001）是脑小血管病患者发生认知障碍的危险因素。ROC的AUC为0.834（95%CI 0.791～0.902，P＜0.001），提示列线图预测模型的区分度较好；校准曲线斜率≈1（χ2=4.388、P=0.820），提示列线图模型拟合效度较好。外部验证结果显示，ROC的AUC为0.845（95%CI 0.802～0.911，P＜0.001），校准曲线斜率接近1，拟合效度较好（χ2=6.042，P=0.302）。 结论 CRP、高血压、颈动脉粥样硬化、高同型半胱氨酸血症、脑白质损伤病变程度均可能导致脑小血管病患者发生认知障碍，基于以上指标构建的预测脑小血管病患者认知障碍发生风险的列线图模型具有较好的区分度和一致性。 Abstract: Objective To analyze the factors influencing cognitive impairment in patients with cerebral small vessel disease. Methods Patients with cerebral small vessel disease admitted to Cangzhou Central Hospital from January 2020 to May 2022 were retrospectively selected (systematic sampling) as the modeling group, and divided into the non-cognitive impairment group and the cognitive impairment group according to the occurrence of cognitive impairment. Multivariate logistic regression model was used to analyze the influencing factors of cognitive impairment in patients with cerebral small vessel disease. A nomogram model was constructed in R3.6.3 to predict cognitive impairment in cerebral small vessel disease. In addition, patients with cerebral small vessel disease admitted from May 2022 to May 2023 were collected as the validation group. The radio of the modeling group to the validation group is 7∶3. This validation group was used for external validation of the constructed model. The ROC curve was developed to evaluate the discrimination of the nomogram model in assessing cognitive impairment in cerebral small vessel disease. Results A total of 247 patients were included in this study, including 173 in the modeling group and 74 in the validation group. In the modeling group, 61 cases (35.26%) had cognitive impairment, while in the validation group, 24 cases (32.43%) had cognitive impairment. Multivariate analysis showed that high levels of CRP (OR 1.527, 95%CI 1.271-1.834, P＜0.001), hypertension (OR 2.106, 95%CI 1.044-4.248, P=0.037), carotid atherosclerosis (OR 3.917, 95%CI 1.416-10.833, P=0.009), hyperhomocysteinemia (OR 3.220, 95%CI 1.261-8.226, P=0.015), and the degree of white matter lesion (OR 2.862, 95%CI 1.496-5.475, P=0.001) were the risk factors for cognitive impairment in patients with cerebral small vessel disease. The AUC of ROC was 0.834 (95%CI 0.791-0.902, P

目的 评估普罗布考与阿托伐他汀钙联合治疗急性脑梗死（acute cerebral infarction，ACI）的疗效，以提供ACI的治疗参考方案。 方法 回顾性收集2018年1月—2023年9月在重庆市急救医疗中心就诊，发病24 h内住院的ACI患者资料。纳入患者需满足：接受了阿托伐他汀钙（20 mg，每晚1次）单药或联用普罗布考（0.5 mg，每日2次）调节血脂治疗，且治疗周期为3个月以上。根据是否联用普罗布考分为联合治疗组和对照组，比较两组治疗后神经功能（使用NIHSS评估）、神经功能结局（使用mRS评估）、生活能力（使用Barthel指数评估）以及血脂水平的差异。 结果 研究共入组102例患者，其中联合治疗组56例，对照组46例。两组的基线资料差异无统计学意义。治疗后14 d两组的NIHSS评分和血脂水平、治疗3个月后的血脂水平均较本组治疗前显著改善（均P

目的 评估不同供氧方式的高压氧治疗下，发病30 d内卒中术后患者经皮氧分压（transcutaneous oximetry，TcPO2）的变化。 方法 回顾性纳入2023年1月1日—2024年6月20日在高压氧科接受治疗的发病30 d内卒中术后患者，根据气道情况分为正常气道面罩加储气囊供氧（面罩组）和人工气道头罩供氧（头罩组）。高压氧治疗期间实时监测TcPO2，比较两种供氧方式下TcPO2变化。 结果 本研究共入选26例患者，面罩组和头罩组各13例。面罩组升压开始时TcPO2为（55.92±9.58）mmHg （1 mmHg=0.133 kPa），稳压吸氧阶段TcPO2平均值和最大值分别为（679.30±186.80）mmHg和（881.40±208.20）mmHg，减压结束TcPO2为（83.71±21.54）mmHg。头罩组升压开始时TcPO2为（62.92±14.84）mmHg，稳压吸氧阶段TcPO2平均值和最大值分别为（369.50±163.00）mmHg和（487.90±212.10）mmHg，减压结束TcPO2为（84.25±19.95）mmHg。面罩组稳压吸氧阶段TcPO2的平均值和最大值高于头罩组相应指标，差异有统计学意义（P

Abstract: Objective To investigate the effects of chitinase protein-40 (YKL-40) and cysteine proteolytic enzyme-1 (Caspase-1) levels and ASPECTS on the prognosis of patients with anterior circulation massive cerebral infarction (MCI) after interventional thrombectomy. Methods Data of 180 patients with anterior circulation MCI who received interventional thrombectomy in The First Hospital of Hebei Medical University from June 2020 to February 2023 were retrospectively analyzed. The patients were divided into the death group (41 cases) and the survival group (139 cases) according to the prognosis 3 months after interventional thrombectomy. Baseline data and YKL-40 and Caspase-1 levels before interventional thrombectomy were compared between the two groups. Cox regression analysis was used to explore the prognostic factors of interventional thrombectomy for MCI. ROC curve analysis was used to assess the efficacy of YKL-40 and Caspase-1 levels and ASPECTS in predicting the prognosis of patients with MCI after interventional thrombectomy. Results The age and infarct area of the death group were higher than those of the survival group, while the ASPECTS were lower (all P＜0.001). Serum YKL-40 level [(141.37±12.40) μg/L vs. (115.05±11.40) μg/L] and Caspase-1 level [(13.05±1.15) ng/L vs. (8.61±0.64) ng/L] in the death group were higher than those in the survival group (all P＜0.001). Cox regression analysis showed that large infarct area (HR 1.011, 95%CI 1.001-1.022), high YKL-40 level (HR 1.033, 95%CI 1.001-1.066), and high Caspase-1 level (HR 1.576, 95%CI 1.264-1.966) were independent risk factors for death after interventional thrombectomy of anterior circulation MCI, while the high ASPECTS (HR 0.887, 95%CI 0.794-0.991) was the protective factor for death after interventional thrombectomy of anterior circulation MCI. ROC curve analysis results showed that the combined prediction of serum YKL-40 and Caspase-1 levels and ASPECTS yielded a better predictive accuracy (AUC 0.940, 95%CI 0.890-0.990) than any of these three indexes alone in predicting death after interventional thrombectomy of anterior circulation MCI [the AUC was 0.869 (95%CI 0.806-0.933), 0.897 (95%CI 0.828-0.966), and 0.724 (95%CI 0.642-0.806), respectively]. Conclusions YKL-40 and Caspase-1 levels and ASPECTS were closely related to the prognosis of patients with anterior circulation MCI after interventional thrombectomy. Consequently, these indexes could be used as prognostic indicators.

Abstract: Objective To investigate the relationship between serum microRNA-874-3p (miR-874-3p), microRNA-181a-5p (miR-181a-5p), Wnt/β-catenin signaling pathway and neurological function prognosis in patients with acute ischemic stroke (AIS). Methods AIS patients who received intravenous thrombolytic therapy in Shenzhen Longhua District Central Hospital from March 2021 to December 2022 were prospectively included into the AIS group, and healthy subjects during the same period were selected into the control group. The relative expression levels of serum miR-874-3p, miR-181a-5p and peripheral blood mononuclear cell (PBMC) determination of Wnt/β-catenin were detected and compared between the two groups. Pearson correlation was used to analyze the correlation between the expression of miR-874-3p and miR-181a-5p in serum and the Wnt/β-catenin signaling pathway in AIS patients. All AIS patients were followed up for 3 months after discharge. Patients who completed follow-up were divided into the good neurological function prognosis group and the poor neurological function prognosis group based on the mRS score. The relative expression levels of miR-874-3p and miR-181a-5p were compared between the two groups. Multivariate logistic regression equation was used to analyze the factors affecting the prognosis of neurological function in AIS patients. Results In this study, 185 patients were included in the AIS group, with an average age of (62.8±7.3) years. The control group included 65 healthy subjects with an average age of (63.4±6.9) years. Compared with the control group, the relative expression levels of miR-874-3p in serum (1.02±0.21 vs. 1.46±0.23, P

Abstract: Objective To examine the effects of granulocyte colony-stimulating factor (G-CSF) treatment on the expression of transforming growth factor-α (TGF-α) in microglia and its neuroprotective effects in stroke after alcohol use disorder (AUD) in rats. Methods Male Sprague-Dawley rats were used to establish an AUD model using the double bottle method. Based on the AUD model, the focal cerebral ischemia model of middle cerebral artery occlusion (MCAO) was established using the thread embolism method. TGF-α small interfering RNA (siRNA) or negative control siRNA was injected into the lateral ventricle 24 h before MCAO. G-CSF was injected intraperitoneally l h after ischemia-reperfusion injury. Rats were randomly divided into the AUD group (18 rats), the AUD+MCAO group (18 rats), the AUD+MCAO+G-CSF group (18 rats), the AUD+MCAO+G-CSF+TGF-α siRNA group (18 rats), and the AUD+MCAO+G-CSF+control siRNA group (6 rats). Alcohol intake, changes in alcohol preference, and neurological function scores of the rats were recorded. The volume of cerebral infarction 24 h after MCAO was measured by 2,3,5-triphenyltetrazolium chloride staining. The number of positive cells of transmembrane protein 119 (TMEM119), a specific marker of microglia in the cerebral cortex of the ischemic side, and the G-CSF receptor (G-CSFR), and the protein expression of TGF-α were observed by immunofluorescence staining. The expression levels of TMEM119 and TGF-α protein in brain tissue of the ischemic side were detected by Western blot. Results Alcohol intake and alcohol preference of rats gradually increased with the increase of drinking time. G-CSFR was significantly expressed in microglia. Compared with the AUD group, the fluorescence intensity of TMEM119 protein and TGF-α protein in the AUD+MCAO group was significantly enhanced, and the number of positive cells increased. Compared with the AUD+MCAO group, the volume of infarction in the AUD+MCAO+G-CSF group was significantly reduced, and the symptoms of neurological impairment improved. The fluorescence intensity of TMEM119 protein was significantly weakened, and the number of positive cells decreased. The fluorescence intensity of TGF-α protein was significantly enhanced, and the number of positive cells increased. Volume of cerebral infarction increased and neurological deficits aggravated in the rats after lateral ventricle injection of TGF-α siRNA. Conclusions G-CSF plays an important brain protective effect in stroke after AUD by increasing the expression of TGF-α in microglia.

Abstract: Objective To explore the effects of penehyclidine hydrochloride (PHC) on the blood-brain barrier (BBB) and the expression of Rho associated coiled-coil containing protein kinase 2 (ROCK2), claudin 5 (CLDN5), and aquaporin-4 (AQP-4) in rats with intracerebral hemorrhage (ICH). Methods A total of 100 SD rats were divided into 20 rats/group as the sham group, the ICH group, the PHC-L group (1 mg/kg PHC), the PHC-M group (2 mg/kg PHC), and the PHC-H group (4 mg/kg PHC). The rat model of ICH was established by autologous blood (50 μL) injection method (except for the sham group). After successful modeling, the rats in the PHC-L, PHC-M, and PHC-H groups were intraperitoneally injected with the corresponding doses of PHC. The sham group and the ICH group were injected with an equal amount of 0.9% sodium chloride solution for 7 consecutive days, once a day. The Longa scoring method was used to score the neurological impairment in rats. A transmission electron microscope was used to observe the ultrastructure of BBB. The Evans blue (EB) method was used to evaluate the permeability of BBB and the water content in rat brain tissue was detected. Immunohistochemical staining and western blot were used to detect the expressions of ROCK2, CLDN5, and AQP-4 in brain tissue. Results Compared with the sham group, the neurological impairment score [0 score vs. (2.45±0.48) score], EB content [(9.75±1.01) μg/g vs. (32.07±3.22) μg/g], brain tissue water content [(77.21±0.33) % vs. (80.96±0.45) %], ROCK2 integrated optical density (IOD) [(1.02±0.14)×103 vs.(11.05±0.71)×103] and relative expression (0.39±0.03 vs. 1.43±0.24), AQP-4 IOD [(1.67±0.18)×103 vs. (10.85±0.58)×103] and relative expression (0.60±0.07 vs. 1.69±0.21) increased significantly in the ICH group, while the CLDN5 IOD [(10.83±0.64)×103 vs. (3.02±0.33)×103] and relative expression (1.53±0.20 vs. 0.42±0.06) decreased significantly. Compared with the ICH group, the PHC-L, PHC-M, and PHC-H groups reversed the trend of changes in the aforementioned indicators to varying degrees according to different doses of PHC. Conclusions PHC can ameliorate structural damage to the BBB in ICH rats, potentially through up-regulating the level of CLDN5 and inhibiting the expression of ROCK2 and AQP-4.

Abstract: Stroke is the leading cause of death and disability in Chinese residents, with ischemic stroke (IS) accounting for approximately 70% of stroke patients. In IS, cardioembolic stroke and embolic stroke of undetermined source account for 20%-30% and 30%-40%, respectively. Cardiac magnetic resonance (CMR) examination is an important adjunctive diagnostic tool, facilitating the identification of IS etiology while also revealing the novel pathogenesis. This article discussed the necessity of CMR examination in IS patients, the value of CMR examination techniques, and the indications for its application in IS patients. It also recommended the procedure of CMR examination for IS patients to provide better help for the diagnosis, treatment, and secondary prevention of IS.

Abstract: Stroke, as a neurological disease characterized by high disability and mortality rates, poses a significant threat to the long-term quality of life for patients. Effective neurofunctional rehabilitation measures can substantially mitigate the long-term disabilities induced by stroke. Motor relearning, a crucial mechanism in post-stroke rehabilitation, is heavily reliant on good sleep quality. However, stroke patients often suffer from sleep disorders, which have a non-negligible negative impact on rehabilitation outcomes. This paper delved into the bidirectional relationship and pathophysiological mechanisms between sleep disorders and stroke rehabilitation. It also reviewed the application and prospect of emerging technologies such as non-invasive/invasive brain stimulation, virtual reality therapy, wearable sleep tracking devices, and gene therapy in stroke patients with sleep disorders, aiming to provide new perspectives and effective methods for optimizing stroke rehabilitation strategies, so as to enhance the rehabilitation effects and quality of life for stroke patients.

Abstract: Intracerebral hemorrhage refers to bleeding caused by non-traumatic rupturing of blood vessels within the brain, which is a serious neurological disorder. Its main pathophysiological characteristics include massive bleeding and neuron death, which impair the neuroimmune system and severely affect the patient’s prognosis. Iron ion homeostasis is crucial for maintaining normal neurological function. However, following intracerebral hemorrhage, disrupted iron metabolism leads to iron accumulation in the brain. Excessive iron participates in neuroinflammatory responses by activating inflammatory signaling pathways and regulating the function of inflammatory cells, while neuroinflammatory cells also participate in regulating the transportation and storage of iron ions. The interaction between the two exacerbates neurol damage. This article reviews the progress of research on the correlation between neuroinflammation and brain iron metabolism after intracerebral hemorrhage, aiming to provide a reference for the clinical treatment of intracerebral hemorrhage.

Abstract: Ischemic brain injury comprises 87% of all brain injuries and typically results in severe functional impairments. Dopamine, the most abundant catecholamine neurotransmitter in the brain, is intimately linked with autonomous movement, emotion, sleep, cognition, and other critical functions. Following ischemic brain injury, patients have severe dysfunction of dopamine in the brain. Studies have demonstrated that dopamine receptor agonists, such as ropinirole, pramipexole, and piribedil, can mitigate brain injury through both receptor-dependent and non-receptor-dependent pathways. These agonists have significant improvements in functions including learning, memory, behavior, and consciousness. This article reviews the potential mechanisms of various dopamine receptor agonists in brain protection after ischemic brain injury.

Abstract: Directed acyclic graph (DAG) is a visualization tool to construct causal hypotheses in causal inference, which can be used to control confounding bias in observational studies by screening the minimal adjustment subsets that need to be adjusted through the backdoor criterion. However, existing studies lack standardization in drawing DAGs and the quality of DAGs used in the literature varies, which causes application dilemmas. The emergence of the ESC-DAGs method provides a standardized process for constructing DAGs. Based on the basic idea of systematic review, ESC-DAGs extensively searches relevant literature and divides the construction process into three phases: mapping, translation, and integration. Firstly, a saturated DAG is constructed based on each retrieved study. The directed edges are screened in the graph according to the Hill criterion and the potential outcome framework, and finally, all the retained directed edges are integrated into one DAG. The ESC-DAGs method makes full use of the literature information and the expertise of researchers. It provides a reasonable and feasible criterion for applying DAGs, which has important guiding significance. This article presents the content of the ESC-DAGs method and elucidates the specific process of constructing a DAG using an example from a clinical study on stroke.

Abstract: Objective To explore the application effect of the “organ system-based, disease-centric” multidisciplinary integrated teaching model in the teaching of cerebrovascular diseases for five-year clinical medicine undergraduate students. Methods Two classes of five-year clinical medicine undergraduate students of grade 2019 studying in Beijing Luhe Hospital, Capital Medical University from March to May 2023 were selected as the research objects. They were randomly divided into the experimental and control groups according to different teaching models. Both groups studied the chapter on cerebrovascular diseases. The control group was taught using the traditional teaching model, while the experimental group was taught using the “organ system-based, disease-centric” multidisciplinary integrated teaching model. The assessment indicators of teaching effect included students’ test scores, students’ evaluation of the classroom teaching quality, and the evaluation on the improvement of their ability. The teaching effect was evaluated after the completion of the teaching period. Results The theoretical assessment scores [(43.90±2.36) scores vs. (41.83±3.36) scores, P=0.008], practical assessment scores [(43.67±2.16) scores vs. (41.70±3.01) scores, P=0.005], and overall scores [(87.57±3.30) scores vs. (83.53±5.43) scores, P=0.001] of the experimental group were all higher than those of the control group. Additionally, the evaluation scores of the experimental group on the classroom teaching quality (including quality requirements and overall scores) and various dimensions of the improvement of their ability (such as classroom participation, cultivation of learning interest, expansion of clinical thinking, improvement of self-learning ability, and improvement of communication and teamwork skills) were higher than those of the control group. The differences were statistically significant (all P

抗栓治疗是预防急性缺血性卒中复发的关键手段。随着多组学研究的进展和越来越多影响药物安全性和有效性的相关基因被发现，药物基因组学在个体化治疗中的应用逐渐受到关注。本文阐述了药物基因组学在急性缺血性卒中患者抗栓治疗中的指导作用的研究进展，旨在挖掘通过基因检测优化药物选择与剂量调整的潜力。研究表明，氯吡格雷等药物的疗效因细胞色素P450酶家族2亚家族C成员19（cytochrome P450 family 2 subfamily C member 19，CYP2C19）基因多态性而异，携带CYP2C19*2或CYP2C19*3等功能缺失等位基因的患者对标准抗血小板治疗反应较差，不能有效降低卒中复发风险，但通过基因检测指导药物选择可以显著提高治疗效果。此外，心源性卒中患者目前常选择华法林或新型口服抗凝药作为主要的抗栓治疗选择。华法林的剂量效应与多个基因，如细胞色素P450酶家族2亚家族C成员9（cytochrome P450 family 2 subfamily C member 9，CYP2C9）和维生素K环氧化物还原酶C1（vitamin K epoxide reductase complex 1，VKORC1）的多态性密切相关。基因检测能够帮助医师个体化调整华法林剂量，减少出血或血栓事件的发生。综上所述，药物基因组学在急性缺血性卒中抗栓治疗中的应用为个体化治疗提供了新的思路，未来有望进一步提高治疗的安全性和有效性。 Abstract: Antithrombotic therapy is a key measure for preventing acute ischemic stroke recurrence. With the advancement of multi-omics research and the identification of more genes affecting drug safety and efficacy, pharmacogenomics is gaining attention for its role in individualized therapy. This paper reviews the progress of research on pharmacogenomics in guiding antithrombotic therapy for patients with acute ischemic stroke, aiming to elucidate the potential of gene detection in optimizing drug selection and dosage adjustments. Studies have shown that the efficacy of drugs like clopidogrel is modulated by polymorphisms in the cytochrome P450 family 2 subfamily C member 19 (CYP2C19) gene. Patients carrying loss-of-function alleles such as CYP2C19*2 or CYP2C19*3 demonstrate diminished responses to standard antiplatelet therapy and cannot effectively reduce the risk of stroke recurrence. However, gene detection can significantly improve treatment outcomes by guiding drug selection. Additionally, for patients with cardioembolic stroke, warfarin or novel oral anticoagulants are commonly used as primary antithrombotic treatment options. The dosage effects of warfarin are closely related to the polymorphisms in genes such as cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1). Gene detection can help physicians individualize warfarin dosing, reducing the occurrence of bleeding or thrombotic events. In conclusion, the application of pharmacogenomics in antithrombotic therapy for acute ischemic stroke provides a new idea for individualized therapy, with the potential to further improve the safety and efficacy in the future.

目的 分析不同民族缺血性卒中患者对基于快速细胞色素P450酶家族2亚家族C成员19 （cytochrome P450 family 2 subfamily C member 19，CYP2C19）基因检测指导抗血小板治疗方案的反应差异。 方法 前瞻性连续纳入2023年1—7月在南宁市第三人民医院住院治疗的汉族（对照组）和壮族（试验组）非心源性轻型缺血性卒中患者。所有患者在CYP2C19基因检测结果指导下进行抗血小板治疗：对于基因表型为氯吡格雷快代谢的患者，抗血小板药物选择硫酸氢氯吡格雷；对于中间代谢或慢代谢的患者，抗血小板药物选择阿司匹林肠溶片或替格瑞洛片。随访90 d，记录mRS评分、日常生活能力量表（activity of daily living scale，ADL）评分、NIHSS评分以及90 d缺血性卒中累积复发率。 结果 共纳入1036例缺血性卒中患者，对照组743例，CYP2C19基因检测结果显示，氯吡格雷快代谢、中间代谢、慢代谢型患者分别为299例（40.24%）、345例（46.43%）和99例（13.32%）。试验组293例，氯吡格雷快代谢、中间代谢、慢代谢型患者分别为107例（36.52%）、161例（54.95%）和25例（8.53%）。两组不同CYP2C19基因表型的比例差异无统计学意义。随访90 d，两组间的mRS评分、ADL评分、NIHSS评分差异无统计学意义。对照组和试验组的90 d缺血性卒中累积复发率分别为5.52%（41/743）和5.12%（15/293），差异无统计学意义。 结论 基于CYP2C19基因检测指导的抗血小板治疗在汉族和壮族的缺血性卒中患者人群中，预防缺血性卒中复发的效果相似。 Abstract: Objective To analyze the difference in response of antiplatelet therapy guided by cytochrome P450 family 2 subfamily C member 19 (CYP2C19) gene detection in ischemic stroke patients of different ethnic groups. Methods The prospective study consecutively included Han (the control group) and Zhuang (the experimental group) patients with non-cardiogenic mild ischemic stroke who were hospitalized for treatment at the Third People’s Hospital of Nanning from January to July 2023. All patients were administered antiplatelet therapy, with the choice of medication guided by CYP2C19 gene detection results. Fast metabolizers were given clopidogrel bisulfate, while intermediate or slow metabolizers were given enteric-coated aspirin or ticagrelor. A follow-up period of 90 days was established to record the mRS scores, activity of daily living scale (ADL) scores, NIHSS scores, and the cumulative recurrence rates of ischemic stroke at 90 days. Results A total of 1036 patients with ischemic stroke were included, with 743 in the control group. The results of the CYP2C19 gene detection showed that there were 299 (40.24%) fast metabolizers, 345 (46.43%) intermediate metabolizers, and 99 (13.32%) slow metabolizers of clopidogrel. In the experimental group, there were 293 patients, with 107 (36.52%) fast metabolizers, 161 (54.95%) intermediate metabolizers, and 25 (8.53%) slow metabolizers of clopidogrel. The differences in the proportion of different CYP2C19 genotypes between the two groups were not statistically significant. After a 90 days follow-up, there was no significant difference in mRS scores, ADL scores, and NIHSS scores between the two groups. The cumulative recurrence rates of ischemic stroke at 90 days for the control group and the experimental group were 5.52% (41/743) and 5.12% (15/293), respectively, with no statistically significant difference. Conclusions Antiplatelet therapy guided by CYP2C19 gene detection has similar effects in preventing the recurrence of ischemic stroke in Han and Zhuang patients.

Lihao Zhang,1 Yan Su,2 Qian Wang,1 Yan Wang,1 Yikun Guo1 1Department of Neurology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, People’s Republic of China; 2Department of Radiology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, People’s Republic of ChinaCorrespondence: Yikun Guo, Department of Neurology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, 68&num; Middle Gehu Road, Changzhou, Jiangsu Province, 213000, People’s Republic of China, Tel +86-519-81087079, Fax +86-519-81087711, Email guoyikun000@163.comObjective: To explore the role of white matter hyperintensities (WMH) in predicting early neurological deterioration (END) in patients with embolic stroke of undetermined source (ESUS) without reperfusion therapy.Methods: In a retrospective analysis, 111 acute ESUS patients not treated with reperfusion therapy were enrolled. WMH severity was evaluated using the Fazekas scale, with patients categorized into mild (Fazekas score ≤ 2) or moderate-to-severe (Fazekas score ≥ 3) WMH groups. Clinical data were compared between the groups, and END was monitored within 72 hours of hospital admission. The association between WMH and END was assessed using binary logistic regression.Results: Patients with moderate-to-severe WMH were significantly older (p = 0.001) and more likely to have a history of stroke (28.6% vs 10.5%, p = 0.017) compared to the mild WMH group. The END group (n=16) presented with higher baseline NIHSS scores and a greater prevalence of moderate-to-severe WMH (p < 0.05). Binary logistic regression identified moderate-to-severe WMH (OR = 4.012, 95% CI: 1.080– 14.906, p = 0.038), smoking (OR = 4.368, 95% CI: 1.171– 16.293, p = 0.028), and diabetes mellitus (OR = 3.986, 95% CI: 1.007– 15.789, p = 0.049) as independent predictors of END in ESUS patients.Conclusion: Moderate-to-severe WMH is an independent risk factor for END in ESUS patients not receiving reperfusion therapy, highlighting the importance of considering WMH in the clinical evaluation and management of stroke patients.Keywords: white matter hyperintensities, early neurological deterioration, embolic stroke of undetermined source, risk factors

Yanyan Lu,1,&ast; Qiang Wang,2,&ast; Xuzhen Liu,1 Shuzhan Gao,1 Sulin Ni,1 Jing Sun,1 Xijia Xu1 1Department of Psychiatry, the Affiliated Brain Hospital of Nanjing Medical University, Nanjing Brain Hospital, Nanjing, People’s Republic of China; 2Department of Medical Psychology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xijia Xu, Department of Psychiatry, the Affiliated Brain Hospital of Nanjing Medical University, Nanjing Brain Hospital, Nanjing, People’s Republic of China, Tel +86-13739192705, Email xuxijia@c-nbh.comPurpose: Acute and transient psychotic disorder (ATPD), a psychosis frequently diagnosed, can potentially evolve into chronic conditions like schizophrenia (SCZ) and other mental disorders. This study aimed to develop a predictive model based on clinical data to forecast the transition from ATPD to SCZ and to identify the predictive factors.Methods: According to the diagnostic criteria issued by the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10), 396 inpatients diagnosed with ATPD were collected in this study. The Cox proportional-hazards regression model was performed using demographic data, clinical characteristics, and inflammatory markers to identify independent predictors for subsequent diagnostic transition (SDT) to SCZ.Results: During the follow-up period, 43.69% (n = 173) of ATPD patients had their diagnoses revised to SCZ. The multivariate Cox regression analysis identified post-treatment monocyte count, post-treatment monocyte/lymphocyte ratio (MLR), and the presence of schizophreniform symptoms as significant predictors for the diagnostic revision. Time-dependent receiver operating characteristic (TimeROC) analyses were developed. The AUC value at the 5-year follow-up was 0.728 for combined predictors, 0.702 for post-treatment monocyte count, 0.764 for post-treatment MLR, and 0.535 for the presence of schizophreniform symptoms.Conclusion: The combined predictors had good predictive ability for the diagnostic transition from acute and transient psychotic disorder to schizophrenia.Keywords: acute and transient psychotic disorder, Schizophrenia, inflammation, subsequent-diagnostic-transition, monocyte count, monocyte–lymphocyte ratio

Peiling Zhou,1 Shiyu Peng,2 Sizhe Wen,1 Qinghui Lan,1 Yingyin Zhuang,1 Xuyan Li,1 Mengliang Shi,1,3 Changzheng Zhang1 1Guangdong Provincial Key Laboratory of Development and Education for Special Needs Children & School of Educational Sciences, Lingnan Normal University, Zhanjiang, 524048, People’s Republic of China; 2Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 3School of Education, South China Normal University, Guangzhou, 510631, People’s Republic of ChinaCorrespondence: Changzheng Zhang, School of Educational Sciences, Lingnan Normal University, 29 Cunjin Road, Zhanjiang, Guangdong Province, 524048, People’s Republic of China, Email neurozhang@163.com Mengliang Shi, School of Education, South China Normal University, 55 West Zhongshan Avenue, Shipai Street, Guangzhou, Guangdong Province, 510631, People’s Republic of China, Email 20240169@m.scnu.edu.cnAbstract: The cerebellum has long been implicated in the etiopathogenesis of autism spectrum disorder (ASD), and emerging evidence suggests a significant contribution by reciprocal neural circuits between the cerebellum and ventral tegmental area (VTA) in symptom expression. This review provides a concise overview of morphological and functional alterations in the cerebellum and VTA associated with ASD symptoms, primarily focusing on human studies while also integrating mechanistic insights from animal models. We propose that cerebello–VTA circuit dysfunctional is a major contributor to ASD symptoms and that these circuits are promising targets for drugs and therapeutic brain stimulation methods.Keywords: autism spectrum disorder, cerebellum, ventral tegmental area, neural circuit

Ayaka Shimada,1,2 Kenji Suda,1 Eri Nakano,1 Miho Tagawa,1 Manabu Miyata,1 Satoshi Kashii,1 Takuya Hinoda,3 Yasutaka Fushimi,3 Kimitoshi Kimura,4 Ryusei Nishigori,4 Sinyeob Ahn,5 John Grinstead,6 Akitaka Tsujikawa1 1Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan; 2Department of Ophthalmology, Shimane University Faculty of Medicine, Izumo, Shimane, Japan; 3Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan; 4Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan; 5MR Research and Development, Siemens Healthineers, San Francisco, CA, USA; 6MR Research and Development, Siemens Healthineers, Portland, OR, USACorrespondence: Kenji Suda, Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, 54 Shougoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan, Tel +81-75-751-3248, Fax +81-75-752-0933, Email qwm04525@kuhp.kyoto-u.ac.jpPurpose: To evaluate the use of delay alternating with nutation for tailored excitation-prepared T1-weighted turbo spin echo (DANTE T1-SPACE) imaging for diagnosing optic neuritis and to analyze its correlation with clinical findings before and after treatment.Patients and Methods: Patients diagnosed with optic neuritis or non-arteritic anterior ischemic optic neuropathy (NA-AION) were evaluated at the Ophthalmology Department of Kyoto University Hospital. All patients underwent magnetic resonance (MR) studies before treatment initiation and ophthalmic examinations before and after treatment. Three ophthalmologists independently reviewed the MR scans for abnormalities. The magnetic resonance imaging (MRI) assessments included post-contrast DANTE T1-SPACE, post-contrast volumetric interpolated breath-hold examination (VIBE), and short T1 inversion recovery (STIR) scans. The presence of abnormalities in each sequence was determined.Results: Of 36 eyes from 30 patients, 21 eyes from 17 patients were diagnosed with optic neuritis, and 15 eyes from 13 patients were diagnosed with NA-AION. DANTE T1-SPACE sequences showed better sensitivity for detecting optic neuritis than STIR sequences (100% vs 67%, p = 0.009). VIBE images did not confirm enhancement of lesions in some cases with optic neuritis. No differences were observed among the sequences for NA-AION. Lesion length evaluated by DANTE T1-SPACE sequences was associated with circumpapillary retinal nerve fiber layer thickness at the initial visit, eye pain, and the time interval from symptom onset to MRI scan.Conclusion: Contrast-enhanced DANTE T1-SPACE was better than other sequences of MRI for diagnosing optic neuritis.Keywords: Optic neuritis, magnetic resonance imaging, retinal nerve fiber layer, visual field test

Abstract Background Post-traumatic headache is a disabling secondary headache disorder often attributed to traumatic brain injury and affects millions of individuals worldwide. Few studies have been done on the treatment needs of these patients in emergency departments. The purpose was to compare the effectiveness of ketorolac intravenous versus acetaminophen intravenous in reducing headaches in patients following head trauma. Methods This was a semi-experimental study in which the participants were assigned two groups. In the acetaminophen intravenous group, 1 g acetaminophen and in the ketorolac intravenous group, 60 mg of this drug was injected. Statistical analysis was done with IBM SPSS statistical software version 21, and a P-value less than 0.05 was considered statistically significant. Results Among samples after 6 h from the injection, the pain score in the ketorolac intravenous group was less than the acetaminophen intravenous group (P = 0.006). Also, the pain reduction rate in the ketorolac intravenous group was more than the acetaminophen intravenous group from before the injection until 2 h after it (P = 0.01) and before injection until 6 h after it (P = 0.001). The frequency of drowsiness in 2 and 6 h after drug administration in the ketorolac intravenous group was lower than the acetaminophen intravenous group, which is significant in 2 h after drug administration (P = 0.038). The verbal analog scale score comparison for two groups 2 h before medicine administration with pain control score (P = 0.03) and 6 h with pethidine use control (P = 0.003) is significant. Conclusions According to this study, ketorolac’s intravenous effect on pain control is better than that of acetaminophen intravenous. With more samples, we can express the survey results more decisively in the future.

Abstract Background Variants of the gene triggering receptor expressed on myeloid cells-2 (TREM2) increase the risk of Alzheimer’s disease (AD) and other neurodegenerative disorders. Signaling by TREM2, an innate immune receptor expressed by microglia, is thought to enhance phagocytosis of amyloid beta (Aβ) and other damaged proteins, promote microglial proliferation, migration, and survival, and regulate inflammatory signaling. Thus, TREM2 activation has potential to alter the progression of AD. AL002 is an investigational, engineered, humanized monoclonal immunoglobulin G1 (IgG1) antibody designed to target TREM2. In AD mouse models, an AL002 murine variant has been previously shown to induce microglial proliferation and reduce filamentous Aβ plaques and neurite dystrophy. Methods Preclinical studies assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of AL002 in cynomolgus monkeys. INVOKE-1 (NCT03635047) was a first-in-human phase 1, randomized, placebo-controlled, double-blind study assessing the safety, tolerability, PK, and PD of AL002 administered as single ascending doses (SAD) in healthy volunteers. Results In cynomolgus monkeys, weekly intravenous injections of AL002 for 4 weeks were well tolerated, dose-dependently decreased soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) and total TREM2 in hippocampus and frontal cortex, and increased biomarkers of TREM2 signaling in CSF and brain. In the phase 1 study of 64 healthy volunteers, a single intravenous infusion of AL002 demonstrated brain target engagement based on a dose-dependent reduction of sTREM2 in CSF and parallel increases in biomarkers of TREM2 signaling and microglia recruitment. Single-dose AL002 showed central nervous system penetrance and was well tolerated, with no treatment-related serious adverse events over 12 weeks. Conclusions These findings support the continued clinical development of AL002 for AD and other neurodegenerative diseases in which TREM2 activation may be beneficial. AL002 is currently being tested in a phase 2, randomized, double-blind, placebo-controlled study in early AD. Trial registration Clinicaltrials.gov, NCT03635047. Registered on August 15, 2018, https://www.clinicaltrials.gov/study/NCT03635047 .

Abstract Behavioral variant frontotemporal dementia (bvFTD) is characterized by profound and early deficits in social cognition (SC) and executive functions (EF). To date it remains unclear whether deficits of the respective cognitive domains are based on the degeneration of distinct brain regions. In 103 patients with a diagnosis of bvFTD (possible/probable/definite: N = 40/58/5) from the frontotemporal lobar degeneration (FTLD) consortium Germany cohort (age 62.5±9.4 years, gender 38 female/65 male) we applied multimodal structural imaging, i.e. voxel-based morphometry, cortical thickness (CTH) and networks of structural covariance via source based morphometry. We cross-sectionally investigated associations with performance in a modified Reading the Mind in the Eyes Test (RMET; reflective of theory of mind - ToM) and five different tests reflective of EF (i.e. Hamasch-Five-Point Test, semantic and phonemic Fluency, Trail Making Test, Stroop interference). Finally, we investigated the conjunction of RMET correlates with functional networks commonly associated with SC respectively ToM and EF as extracted meta-analytically within the Neurosynth database. RMET performance was mainly associated with gray matter volume (GMV) and CTH within temporal and insular cortical regions and less within the prefrontal cortex (PFC), whereas EF performance was mainly associated with prefrontal regions (GMV and CTH). Overlap of RMET and EF associations was primarily located within the insula, adjacent subcortical structures (i.e. putamen) and the dorsolateral PFC (dlPFC). These patterns were more pronounced after adjustment for the respective other cognitive domain. Corroborative results were obtained in analyses of structural covariance networks. Overlap of RMET with meta-analytically extracted functional networks commonly associated with SC, ToM and EF was again primarily located within the temporal and insular region and the dlPFC. In addition, on a meta-analytical level, strong associations were found for temporal cortical RMET correlates with SC and ToM in particular. These data indicate a temporo-frontal dissociation of bvFTD related disturbances of ToM and EF, with atrophy of the anterior temporal lobe being critically involved in ToM deficits. The consistent overlap within the insular cortex may be attributable to the multimodal and integrative role of this region in socioemotional and cognitive processing.

Abstract Background Biomarkers of Alzheimer’s disease (AD) and mild cognitive impairment (MCI, or prodromal AD) are highly significant for early diagnosis, clinical trials and treatment outcome evaluations. Electroencephalography (EEG), being noninvasive and easily accessible, has recently been the center of focus. However, a comprehensive understanding of EEG in dementia is still needed. A primary objective of this study is to investigate which of the many EEG characteristics could effectively differentiate between individuals with AD or prodromal AD and healthy individuals. Methods We collected resting state EEG data from individuals with AD, prodromal AD, and normal cognition. Two distinct preprocessing pipelines were employed to study the reliability of the extracted measures across different datasets. We extracted 41 different EEG features. We have also developed a stand-alone software application package, Feature Analyzer, as a comprehensive toolbox for EEG analysis. This tool allows users to extract 41 EEG features spanning various domains, including complexity measures, wavelet features, spectral power ratios, and entropy measures. We performed statistical tests to investigate the differences in AD or prodromal AD from age-matched cognitively normal individuals based on the extracted EEG features, power spectral density (PSD), and EEG functional connectivity. Results Spectral power ratio measures such as theta/alpha and theta/beta power ratios showed significant differences between cognitively normal and AD individuals. Theta power was higher in AD, suggesting a slowing of oscillations in AD; however, the functional connectivity of the theta band was decreased in AD individuals. In contrast, we observed increased gamma/alpha power ratio, gamma power, and gamma functional connectivity in prodromal AD. Entropy and complexity measures after correcting for multiple electrode comparisons did not show differences in AD or prodromal AD groups. We thus catalogued AD and prodromal AD-specific EEG features. Conclusions Our findings reveal that the changes in power and connectivity in certain frequency bands of EEG differ in prodromal AD and AD. The spectral power, power ratios, and the functional connectivity of theta and gamma could be biomarkers for diagnosis of AD and prodromal AD, measure the treatment outcome, and possibly a target for brain stimulation.

Abstract Background Dementia preventive interventions targeting multiple modifiable risk factors are a promising approach. However, the impact of modifiable risk factors in the presence of beta-amyloid or phosphorylated-tau (p-tau) pathology is unclear. Methods The objective of the study was to examine the role of modifiable risk factors (vascular factors, depression, and smoking) in the progression to mild cognitive impairment (MCI) or dementia among 434 cognitively unimpaired (CU) and 611 individuals with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Vascular risk factors were summarized with the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score, dichotomized into higher versus lower risk. Depression and smoking (yes/no) were categorised according to medical history or current symptoms. Analyses were stratified by beta-amyloid negative (A-) and positive (A +), p-tau negative (T-) and positive (T +), or beta-amyloid and p-tau negative (A-T-) and positive (A + T +) biomarker status. Cox proportional hazard models were adjusted for age, sex, education, baseline MMSE score, baseline hippocampal volume and ApoE4 carrier status. Results Higher CAIDE score was associated with increased risk of progression to all-cause dementia in most MCI subgroups: adjusted hazard ratios (aHR) [95% CI] were 3.1 [1.43; 6.53] in the A- subgroup, 1.7 [1.20–2.27] in T + , 2.6 [1.06–6.59] in A-T-, and 1.6 [1.15–2.22] in the A + T + subgroup. Smoking (yes/no) was associated with increased dementia aHR in the A + MCI subgroup: 1.6 [1.07–2.34]. Depression increased dementia aHR in the T + MCI subgroup: 1.5 [1.06–2.02]. No significant associations were found in the CU biomarker subgroups. Conclusion Addressing modifiable risk factors carries an important potential for reducing the risk of dementia even after the onset of Alzheimer's pathology. Knowledge of biomarker status can further optimize prevention strategies.

Abstract Background Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease. Three new drugs for AD based on monoclonal antibodies against the amyloid-β peptide (Aβ) have recently been approved because they favor the reduction of the burden of senile plaque in the AD patient’s brain. Nonetheless, both drugs have very limited applicability and benefits and show several side effects. These limitations invite us to find alternative strategies for treating patients with AD. Here, we explored whether tissue-nonspecific alkaline phosphatase (TNAP), an ectoenzyme upregulated in the brain of AD patients and whose inhibition has beneficial effects on tau-induced pathology, is also efficient in reducing senile plaque burden. Methods To evaluate whether TNAP may reduce cerebral senile plaque loading and Aβ-related toxicity, we use both pharmacological and genetic approaches. We analyze postmortem samples from human AD patients, APP/PS1 mice (a mouse model that mimics amyloid pathology observed in AD patients) treated or not with TNAP inhibitors, and the newly generated transgenic mouse line, TNAP-deficient APP/PS1 mice. Results For the first time, we describe that genetic or pharmacological blockade of TNAP effectively reduces senile plaque burden by promoting its clearance, which leads to amelioration of cognitive impairment caused by Aβ-induced toxicity. These beneficial effects of TNAP inhibition occur concomitantly with higher microglial recruitment toward the senile plaque and increased microglial phagocytic capacity of Aβ by a mechanism involving metalloprotease-depending osteopontin processing. In addition, we also found that TNAP blockade favors LRP1-mediated transport of Aβ through the BBB. Conclusions Here, we have shown that TNAP inhibition effectively reduces brain senile plaque burden and associated behavioral defects. Furthermore, given that we had previously reported that TNAP blockade also ameliorates Tau-induced neurotoxicity and increases lifespan of P301S tauopathy mouse model, we can state that TNAP blockade may be a novel and efficient therapy for treating patients with AD.

Abstract Background Blood-derived mitochondrial DNA copy number (mtDNA-CN) is a proxy measurement of mitochondrial function in the peripheral and central systems. Abnormal mtDNA-CN not only indicates impaired mtDNA replication and transcription machinery but also dysregulated biological processes such as energy and lipid metabolism. However, the relationship between mtDNA-CN and Alzheimer disease (AD) is unclear. Methods We performed two-sample Mendelian randomization (MR) using publicly available summary statistics from GWAS for mtDNA-CN and AD to investigate the causal relationship between mtDNA-CN and AD. We estimated mtDNA-CN using whole-genome sequence data from blood and brain samples of 13,799 individuals from the Alzheimer’s Disease Sequencing Project. Linear and Cox proportional hazards models adjusting for age, sex, and study phase were used to assess the association of mtDNA-CN with AD. The association of AD biomarkers and serum metabolites with mtDNA-CN in blood was evaluated in Alzheimer’s Disease Neuroimaging Initiative using linear regression. We conducted a causal mediation analysis to test the natural indirect effects of mtDNA-CN change on AD risk through the significantly associated biomarkers and metabolites. Results MR analysis suggested a causal relationship between decreased blood-derived mtDNA-CN and increased risk of AD (OR = 0.68; P = 0.013). Survival analysis showed that decreased mtDNA-CN was significantly associated with higher risk of conversion from mild cognitive impairment to AD (HR = 0.80; P = 0.002). We also identified significant associations of mtDNA-CN with brain FDG-PET (β = 0.103; P = 0.022), amyloid-PET (β = 0.117; P = 0.034), CSF amyloid-β (Aβ) 42/40 (β=-0.124; P = 0.017), CSF t-Tau (β = 0.128; P = 0.015), p-Tau (β = 0.140; P = 0.008), and plasma NFL (β=-0.124; P = 0.004) in females. Several lipid species, amino acids, biogenic amines in serum were also significantly associated with mtDNA-CN. Causal mediation analyses showed that about a third of the effect of mtDNA-CN on AD risk was mediated by plasma NFL (P = 0.009), and this effect was more significant in females (P

Abstract Although α-synuclein seed amplification assays (α-syn SAA) are promising, its sensitivity may be affected by heterogeneity among patients with Lewy body disease (LBD). We evaluated whether α-syn SAA sensitivity is affected by patient heterogeneity, using 123I-meta-iodobenzylguanidine (MIBG) cardiac scintigraphy in early drug-naïve patients. Thirty-four patients with clinically established or probable Parkinson’s disease (PD) and seven with dementia with Lewy bodies (DLB) or prodromal DLB were included. While 85.2% of patients with abnormal cardiac MIBG were α-syn SAA positive, only 14.3% were positive among those with normal scans. Logistic regression analysis showed that MIBG positivity was the only significant variable associated with α-syn SAA positivity (odds ratio 74.2 [95% confidence interval 6.1–909]). Although α-syn SAA is sensitive for LBD in patients with abnormal MIBG, the sensitivity may be lower in those with normal MIBG. Further studies are necessary to evaluate the association between patient heterogeneity and α-syn SAA sensitivity.

Abstract In this review, we summarize preclinical and clinical trials investigating innovative neuromodulatory approaches for Parkinson disease (PD) motor symptom management. We highlight the following technologies: temporal interference, nanoparticles for drug delivery, blood-brain barrier opening, gene therapy, optogenetics, upconversion nanoparticles, magnetothermal nanoparticles, magnetoelectric nanoparticles, ultrasound-responsive nanoparticles, and designer receptors exclusively activated by designer drugs. These studies establish the basis for novel and promising neuromodulatory treatments for PD motor symptoms.

Abstract Variants in GBA1 result in dysregulated sphingolipids. We investigated five CSF d18:1 sphingolipid species in a longitudinal multicenter cohort comprising people with Parkinson’s Disease and Dementia with Lewy bodies with and without GBA1 variants and healthy controls. We found no increase of sphingolipid species in heterozygous GBA1 variant participants and no effect on development of cognitive impairment. Thus, CSF d18:1 sphingolipids are not suitable as state markers in Parkinson’s Disease.

Abstract Cereblon (CRBN) is a substrate recruiter for CRL4CRBN E3 ubiquitin ligase system playing a plethora of pivotal roles for biological systems. Here, we identified DNAJB1 (DJ1) as endogenous substrate of CRBN and report how CRBN influences the aggregation and toxicity of alpha-synuclein (α-SYN) via modulation of DJ1. CRBN interferes with molecular activities of DJ1 in vitro, in cells, and in vivo resulting in a reduced disaggregation of α-SYN fibrils, increased formation of preformed fibrils (PFFs) of α-SYN, and high susceptibility of mice to MPTP and PFF-induced neurotoxicity. Depletion of Crbn improves the behavioral and biochemical responses of mice towards neurotoxic insult. Finally, we designed a peptide inhibitor to inhibit the recruitment of DJ1 to CRBN for ubiquitination, resulting in an enhanced supply of DJ1 to counteract the toxicity of aggregated α-SYN. Our data has important implications for development of CRBN-targeting therapies that could prevent or delay progression of neurodegenerative synucleinopathy.

Abstract Associations between the gut microbiota and Parkinson’s disease (PD) have been widely investigated. However, the replicable biomarkers for PD diagnosis across multiple populations remain elusive. Herein, we performed a meta-analysis to investigate the pivotal role of the gut microbiome in PD and its potential diagnostic implications. Six 16S rRNA gene amplicon sequence datasets from five independent studies were integrated, encompassing 550 PD and 456 healthy control samples. The analysis revealed significant alterations in microbial composition and alpha and beta diversity, emphasizing altered gut microbiota in PD. Specific microbial taxa, including Faecalibacterium, Roseburia, and Coprococcus_2, known as butyrate producers, were notably diminished in PD, potentially contributing to intestinal inflammation. Conversely, genera such as Akkermansia and Bilophila exhibited increased relative abundances. A network-based algorithm called NetMoss was utilized to identify potential biomarkers of PD. Afterwards, a classification model incorporating 11 optimized genera demonstrated high performance. Further functional analyses indicated enrichment in pathways related to neurodegeneration and metabolic pathways. These findings illuminate the intricate relationship between the gut microbiota and PD, offering insights into potential therapeutic interventions and personalized diagnostic strategies.

Abstract Alpha-synuclein (α-syn) inclusions in the brain are hallmarks of so-called Lewy body diseases. Lewy bodies contain mainly aggregated α-syn together with some other proteins. Monomeric α-syn lacks a well-defined three-dimensional structure, but it can aggregate into oligomeric and fibrillar amyloid species, which can be detected using specific antibodies. Here we investigate the aggregate specificity of monoclonal MJFR14-6-4-2 antibodies. We conclude that partial masking of epitope in unstructured monomer in combination with a high local concentration of epitopes is the main reason for MJFR14-6-4-2 selectivity towards aggregates. Based on the structural insight, we produced mutant α-syn that when fibrillated is unable to bind MJFR14-6-4-2. Using these fibrils as a tool for seeding cellular α-syn aggregation, provides superior signal/noise ratio for detection of cellular α-syn aggregates by MJFR14-6-4-2. Our data provide a molecular level understanding of specific recognition of toxic amyloid oligomers, which is critical for the development of inhibitors against synucleinopathies.

Abstract Deep brain stimulation (DBS) with electric field steering may avoid areas responsible for side effects. This prospective randomized cross-over trial compared omnidirectional (OS) and directional (DS) subthalamic DBS in 19 patients. Electromyographically measured rigidity was the primary outcome. Motor and non-motor scores were secondary outcomes. There were no significant differences between OS and DS. In the acute setting, both conditions improved motor scores compared to no stimulation. Motor symptoms improved after 3 weeks of OS relative to acute measurements, whereas they worsened under DS. The more ventral the active contact, and the less the motor improvement sweet spot was stimulated, the greater the benefit of DS over OS for executive function. Accurate OS of the dorsal subthalamic nucleus ensures motor and non-motor improvements. While DS can mitigate executive decline stemming from off-target stimulation, it may lead to worse motor outcomes. Larger, long-term studies are needed to confirm these findings. (Registration: subthalamic steering for therapy optimization in Parkinson’s Disease ClinicalTrials.gov: NCT03548506, 2018-06-06).

Abstract Mutations in GBA1 encoding the lysosomal enzyme β-glucocerebrosidase (GCase) are among the most prevalent genetic susceptibility factors for Parkinson’s disease (PD), with 10–30% of carriers developing the disease. To identify genetic modifiers contributing to the incomplete penetrance, we examined the effect of 1634 human transcription factors (TFs) on GCase activity in lysates of an engineered human glioblastoma line homozygous for the pathogenic GBA1 L444P variant. Using an arrayed CRISPR activation library, we uncovered 11 TFs as regulators of GCase activity. Among these, activation of MITF and TFEC increased lysosomal GCase activity in live cells, while activation of ONECUT2 and USF2 decreased it. While MITF, TFEC, and USF2 affected GBA1 transcription, ONECUT2 might control GCase trafficking. The effects of MITF, TFEC, and USF2 on lysosomal GCase activity were reproducible in iPSC-derived neurons from PD patients. Our study provides a systematic approach to identifying modulators of GCase activity and deepens our understanding of the mechanisms regulating GCase.

Abstract The impact of subthalamic nucleus (STN) deep brain stimulation (DBS) on neuropsychiatric fluctuations in Parkinson´s disease (PD) remains unclear. The Neuropsychiatric Fluctuations Scale (NFS) can help to fill this gap, directly measuring fluctuations between the OFF- and ON-medication conditions. The NFS provides NFS-plus (hyperdopaminergic) and NFS-minus (hypodopaminergic) sub-scores. Based on these, the NFS global scores express the overall magnitude of neuropsychiatric symptoms in both the OFF- and ON-medication states. The total fluctuation score (TFS) represents the difference between ON- vs. OFF-medication NFS global scores, thus assessing fluctuations amplitude. The NFS was used to evaluate changes in neuropsychiatric fluctuations between the OFF- and ON-medication conditions before and 1-year after bilateral STN-DBS in 45 PD patients (32 males; mean age, 61.3 ± 7.2 years; PD duration, 10.2 ± 3.0 years). After surgery, the amplitude of neuropsychiatric fluctuations was significantly reduced (p

Abstract The ability of serum biomarkers to predict the prognosis and response to deep-brain stimulation (DBS) therapy in Parkinson’s disease (PD) patients is promising. Here, we showed that NfL differed between healthy individuals and PD patients and that changes in NfL, GFAP, and BDNF occurred only transiently after DBS surgery. Therefore, subthalamic stimulation does not promote neurodegeneration, and these biomarkers do not serve as clinical improvement endpoints in PD DBS patients.

Abstract Genetic testing for Parkinson’s disease (PD) is infrequently performed due to perceptions of low utility. We investigated the personal utility in PD GENEration and how results lead to enrollment in additional research studies. Participants (n = 972) underwent genetic testing, results disclosure, genetic counseling, and completed a survey examining the perceived personal utility of their results and interest in participating in additional studies. Most participants found their genetic test results useful, including satisfying curiosity (81%), feeling good about helping the medical community (80%), and having information to share with family (77%). There were no significant differences in responses based on result type. Forty-five percent of participants expressed interest in participating in research studies; whereas 16% of participants confirmed enrollment. Our results suggest that participants find personal utility in genetic testing regardless of results. Although participants may be interested in enrolling in additional research, they may need support and resources.

Abstract Parkinson’s Disease (PD) is a prevalent, progressive neurodegenerative disease with motor and non-motor symptoms. Vagus Nerve Stimulation (VNS) has emerged as a potential therapeutic approach for PD, but published research on this topic varies widely. This scoping review maps existing literature on VNS for PD, highlighting stimulation methods, operational parameters, safety profiles, neurophysiological mechanisms, and clinical outcomes in human and animal models. Online databases were used to identify 788 papers published between 2013 and 2023, from which 17 publications on invasive and non-invasive VNS in PD were selected. Studies showed high variability in VNS parameters and study design. Evidence in animal models and human subjects suggests potential neurophysiological effects on PD-related pathology and motor function improvements. However, significant gaps in the literature remain. Future research should include rigorous reporting of study design, standardization of stimulation parameters, and larger sample sizes to ultimately facilitate translation of VNS into clinical practice.

Abstract Previous studies have established that rare biallelic SYNJ1 mutations cause autosomal recessive parkinsonism and Parkinson’s disease (PD). We analyzed 8165 PD cases, 818 early-onset-PD (EOPD, 20) in the Sac1 SYNJ1 domain and PD (Pfdr = 0.040). A meta-analysis of EOPD patients demonstrated an association between all rare heterozygous SYNJ1 variants and PD (Pfdr = 0.029).

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder marked by the loss of dopaminergic neurons in the substantia nigra. Despite progress, the pathogenesis remains unclear. Human midbrain organoids (hMLOs) have emerged as a promising model for studying PD, drug screening, and potential treatments. This review discusses the development of hMLOs, their application in PD research, and current challenges in organoid construction, highlighting possible optimization strategies.

Abstract To examine the association and modifiable risk factors between grip strength (GS) and Parkinson’s disease (PD) incidence considering genetic factors, a total of 411,648 individuals without PD at baseline from the UK Biobank were included. GS was measured by a hydraulic dynamometer. The polygenic risk score assessed the genetic predisposition. Multivariable Cox regression models were performed. During a median follow-up of 12.3 years, 2409 individuals developed PD. Compared with those with high GS, low-GS individuals had a 58.5% increased risk of PD (42.7%–76.1%), and 16.3% of this excess risk could be explained by adjusted risk factors. Low GS and high genetic predisposition contribute to the highest PD risk in an additive interaction. We observed that low GS was associated with higher PD incidence, particularly among individuals with high genetic predisposition. In addition to enhancing GS, interventions targeting risk factors (e.g., unhealthy lifestyles) might also reduce the excess risk.