Neuronal intranuclear inclusion disease (NIID) is a rare, progressive neurodegenerative disorder currently diagnosed through invasive biopsies or genetic testing with ethnic limitations. Existing biomarkers from cerebrospinal fluid or plasma are not fully noninvasive, and no urine-based biomarker has been identified. There is an urgent need for a noninvasive, definitive diagnostic tool to distinguish NIID from other neurodegenerative diseases and healthy individuals. We developed a homogeneous digital immunoassay using two-color quantum dot (QD)-labeled antibodies to quantify p62 in urinary cell nuclei, achieving a detection limit of 47 fM. The assay demonstrated high selectivity and a wide dynamic range across three orders of magnitude. Analysis of urine samples from 10 NIID patients, 4 healthy controls, and 13 patients with other neurodegenerative disorders (myasthenia gravis, cerebral infarction, and Parkinson's disease) revealed that p62 levels were significantly elevated only in NIID patients. Spike recovery tests confirmed measurement accuracy (91%-106%), and p62 levels showed no correlation with disease stage in this limited cohort. This study introduces the first noninvasive urinary biomarker for NIID using a novel homogeneous digital immunoassay. The significantly elevated p62 levels specifically in NIID patients highlight its potential as a reliable, noninvasive diagnostic tool, enabling distinction from other neurodegenerative conditions and facilitating earlierand more accessible diagnosis.

Vascular parkinsonism (VP) and the postural instability and gait difficulty (PIGD) subtype of Parkinson’s disease (PD) exhibit similar gait characteristics. However, most research emphasizes lower-limb gait parameters, often neglecting the role of cognitive function in gait regulation. Therefore, this study investigates differences in cognitive-motor interactions between VP and PIGD to identifying specific gait biomarkers and develop a diagnostic model. We recruited 37 PIGD patients and 37 VP patients between year 2022 to 2024 and used wearable devices to record gait parameters during single-task and dual-task paradigms. Demographic and clinical data were collected from all participants. Statistical analysis was conducted using R software with P < 0.05 as statistically significance. Multiple gait parameters significantly difference between VP and PIGD groups under both single-task and dual-task paradigms. In both single-task and dual-task gait comparisons, significant differences were observed between VP and PIGD in walk speed, shank swing speed, gait speed, phase coordination index (PCI), and trunk sway maximum (P < 0.05). Corresponding dual-task costs (DTC) also showed significant differences (P < 0.05). ROC curve analysis indicated a good diagnostic performance when combining multiple gait parameters and their DTC with MoCA scores (AUC 0.838, 95

BackgroundNeuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder caused by GGC repeat expansions in NOTCH2NLC, leading to uN2CpolyG protein deposition. Although immune-mediated renal lesions have been described in NIID, the systemic immunoinflammatory profile associated with kidney injury and its relationship with genetic burden remain undefined. This study investigated peripheral immune alterations in NIID-related nephropathy and their correlation with repeat expansion size.MethodsThis multicenter retrospective study enrolled 150 genetically and pathologically confirmed NIID patients from nine tertiary hospitals (2019-2024). Using KDIGO criteria, patients were stratified into NIID with kidney injury (NIID-KD, n=100) and NIID with no kidney injury (NIID-ND, n=50) groups. Peripheral inflammatory markers were assessed in 110 patients, and 12 T-cell-related cytokines were measured in a subset of 35 patients. Multivariable analyses adjusting for disease duration were performed. GGC repeat numbers were quantified in 48 patients.ResultsAfter adjustment for disease duration, the NIID-KD group maintained significantly higher white blood cell counts, neutrophil counts, monocyte counts, and neutrophil-to-lymphocyte ratio compared to NIID-ND (all P < 0.05). Cytokine profiling revealed selectively elevated IL-6 levels in the NIID-KD group (P = 0.042), whereas IL-17 elevation did not persist after adjustment (P = 0.239). No significant difference in GGC repeat expansion size was observed between groups among genotyped patients.ConclusionNIID-associated kidney injury is characterized by a distinct immunoinflammatory signature with sustained neutrophilic and monocytic activation and IL-6 upregulation, suggesting involvement of innate immunity and IL-6-mediated inflammation in renal pathology. The absence of direct correlation between repeat expansion size and kidney involvement indicates that while genetic mutation confers disease susceptibility, acquired inflammatory mechanisms critically determine renal phenotype. These findings provide clinical evidence linking proteinopathy to innate immune activation in NIID.

We employed a novel method for collecting oral mucosal epithelial cells, an anagar-paraffin double-embedding technique for cell fixation in cytopathological processing. OMEC biopsy demonstrated a high diagnostic efficacy for NIID: H&E staining revealed inclusions in 60% (12/20) of patients, TEM confirmed them in 40% (8/20) of cases and immunofluorescence detected p62-positive aggregates in 9/20 (45%) and uN2CpolyG in 8/20 (40%) of cases, respectively. OMEC biopsy is a simple, noninvasive technique for detecting intranuclear inclusions in NIID, avoiding the need for invasive surgical procedures such as skin or labial gland biopsies.

Aims/Background Lipoprotein(a) [Lp(a)] has been implicated in cerebrovascular diseases and may contribute to cognitive decline. Thus, this study sought to assess cognitive impairment in ischemic stroke patients and its association with Lp(a). Methods This single-center cross-sectional study included 790 patients from the Affiliated Hospital of Xuzhou Medical University between January 2017 and December 2023, categorized into lower and higher Lp(a) groups based on the median Lp(a) levels. Logistic regression analysis, subgroup analysis, sensitivity analysis, receiver operating characteristic (ROC) curve analysis, and restricted cubic spline (RCS) analysis were conducted to explore the association between Lp(a) and cognitive impairment. Results The higher Lp(a) group showed a greater prevalence of cognitive impairment than the lower Lp(a) group (p < 0.001). After accounting for all potential influences, the risk of cognitive impairment was 1.735 times higher in the higher Lp(a) group than in the lower Lp(a) group (p = 0.001), and for each unit increase in Lp(a), the risk of cognitive impairment increased by 0.1% (p = 0.001). Subgroup analysis indicated that the significant association between Lp(a) and cognitive impairment remained stable in all subgroups except for the subgroup without hypertension (p < 0.05). Additionally, even after omitting those with prior stroke, higher Lp(a) levels remained independently linked to an increased risk of cognitive impairment (p < 0.05). ROC analysis revealed that Lp(a) had predictive value for cognitive impairment in the overall population, as well as in male and female patients (p < 0.05). In the multivariate-adjusted regression model, a linear relationship between Lp(a) and cognitive impairment risk was demonstrated by RCS analysis (p < 0.001, p nonlinear = 0.828). Conclusion Higher levels of Lp(a) are independently linked to a greater risk of cognitive impairment in stroke patients.

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease primarily diagnosed through diffusion-weighted imaging (DWI). However, the limitation of human visual interpretation and clinical experience can lead to inaccuracies in diagnosis. This research proposes a deep learning method based on cross self-supervision, alongside the construction of Co-ResNet50 and CO-ViT models for intelligent auxiliary diagnosis of NIID. This method uses self-supervised learning and effectively combines the characteristics of ResNet50 and ViT networks to improve the model’s feature extraction capabilities. The experiment preprocessed 249 DWI data and divided them into 204 training sets and 45 test sets. The results reveal that the CO-ResNet50 model has the best performance, with an accuracy of 95.49%, precision of 95.51%, recall of 95.44%, F1 score of 0.954 7, and AUC of 0.989 7. These findings underscore the model's potential to provide support for clinical NIID diagnosis.

Neuropathology and Applied NeurobiologyVolume 50, Issue 2 e12976 SHORT COMMUNICATION Immune system involvement in neuronal intranuclear inclusion disease Lei Bao, Lei Bao Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China Department of Neurology, Xuzhou Medical University, Xuzhou, ChinaSearch for more papers by this authorDandan Zuo, Dandan Zuo Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, ChinaSearch for more papers by this authorXiaoying Qu, Xiaoying Qu Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China Department of Neurology, Xuzhou Medical University, Xuzhou, ChinaSearch for more papers by this authorYingying Cui, Yingying Cui Department of Pathology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, ChinaSearch for more papers by this authorKeke Li, Keke Li Department of Radiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, ChinaSearch for more papers by this authorJing Dong, Jing Dong Department of Stomatology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, ChinaSearch for more papers by this authorRenjin Chen, Renjin Chen College of Life Sciences, Xuzhou Medical University, Xuzhou, ChinaSearch for more papers by this authorZunsheng Zhang, Corresponding Author Zunsheng Zhang [email protected] Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China Correspondence Guiyun Cui, Hao Chen, and Zunsheng Zhang, Department of Neurology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China. Email: [email protected], [email protected], and Email: [email protected]Search for more papers by this authorGuiyun Cui, Corresponding Author Guiyun Cui [email protected] orcid.org/0000-0001-9675-8497 Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China Correspondence Guiyun Cui, Hao Chen, and Zunsheng Zhang, Department of Neurology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China. Email: [email protected], [email protected], and Email: [email protected]Search for more papers by this authorHao Chen, Corresponding Author Hao Chen [email protected] Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China Correspondence Guiyun Cui, Hao Chen, and Zunsheng Zhang, Department of Neurology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China. Email: [email protected], [email protected], and Email: [email protected]Search for more papers by this author Lei Bao, Lei Bao Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China Department of Neurology, Xuzhou Medical University, Xuzhou, ChinaSearch for more papers by this authorDandan Zuo, Dandan Zuo Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, ChinaSearch for more papers by this authorXiaoying Qu, Xiaoying Qu Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China Department of Neurology, Xuzhou Medical University, Xuzhou, ChinaSearch for more papers by this authorYingying Cui, Yingying Cui Department of Pathology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, ChinaSearch for more papers by this authorKeke Li, Keke Li Department of Radiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, ChinaSearch for more papers by this authorJing Dong, Jing Dong Department of Stomatology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, ChinaSearch for more papers by this authorRenjin Chen, Renjin Chen College of Life Sciences, Xuzhou Medical University, Xuzhou, ChinaSearch for more papers by this authorZunsheng Zhang, Corresponding Author Zunsheng Zhang [email protected] Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China Correspondence Guiyun Cui, Hao Chen, and Zunsheng Zhang, Department of Neurology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China. Email: [email protected], [email protected], and Email: [email protected]Search for more papers by this authorGuiyun Cui, Corresponding Author Guiyun Cui [email protected] orcid.org/0000-0001-9675-8497 Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China Correspondence Guiyun Cui, Hao Chen, and Zunsheng Zhang, Department of Neurology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China. Email: [email protected], [email protected], and Email: [email protected]Search for more papers by this authorHao Chen, Corresponding Author Hao Chen [email protected] Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China Correspondence Guiyun Cui, Hao Chen, and Zunsheng Zhang, Department of Neurology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China. Email: [email protected], [email protected], and Email: [email protected]Search for more papers by this author First published: 04 April 2024 https://doi.org/10.1111/nan.12976 Lei Bao and Dandan Zuo contributed equally to this work. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat CONFLICT OF INTEREST STATEMENT The authors declare that they have no competing interests. Open Research DATA AVAILABILITY STATEMENT The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Supporting Information Filename Description nan12976-sup-0001-Supplementary_ Table S1.docxWord 2007 document , 14 KB Table S1. Overview of clinical information and manifestations in 32 NIID patients. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. REFERENCES 1Ishiura H, Shibata S, Yoshimura J, et al. Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease. 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CGG repeat expansion in NOTCH2NLC causes mitochondrial dysfunction and progressive neurodegeneration in Drosophila model. Proc Natl Acad Sci U S A. 2022; 119(41):e2208649119. doi:10.1073/pnas.2208649119 10.1073/pnas.2208649119 CASPubMedWeb of Science®Google Scholar Volume50, Issue2April 2024e12976 ReferencesRelatedInformation

OBJECTIVE:Neuronal precursor cells expressed developmentally down-regulated 4 (Nedd4) are believed to play a critical role in promoting the degradation of substrate proteins and are involved in numerous biological processes. However, the role of Nedd4 in intracerebral hemorrhage (ICH) remains unknown. This study aims to investigate the regulatory role of Nedd4 in the ICH model.METHODS:Male C57BL/6J mice were induced with ICH. Subsequently, the levels of glutathione peroxidase 4 (GPX4), malondialdehyde (MDA) concentration, iron content, mitochondrial morphology, as well as the expression of divalent metal transporter 1 (DMT1) and Nedd4 were assessed after ICH. Furthermore, the impact of Nedd4 overexpression was evaluated through analyses of hematoma area, ferroptosis, and neurobehavioral function. The mechanism underlying Nedd4-mediated degradation of DMT1 was elecidated using immunoprecipitation (IP) after ICH.RESULTS:Upon ICH, the level of DMT1 in the brain increased, but decreased when Nedd4 was overexpressed using Lentivirus, suggesting a negative correlation between Nedd4 and DMT1. Additionally, the degradation of DMT1 was inhibited after ICH. Furthermore, it was found that Nedd4 can interact with and ubiquitinate DMT1 at lysine residues 6, 69, and 277, facilitating the degradation of DMT1. Functional analysis indicated that overexpression of Nedd4 can alleviate ferroptosis and promote recovery following ICH.CONCLUSION:The results demonstrated that ferroptosis occurs via the Nedd4/DMT1 pathway during ICH, suggesting it potential as a valuable target to inhibit ferroptosis for the treatment of ICH.

Background and objectives The neutrophil-to-lymphocyte ratio (NLR) is a widely recognized marker of inflammation in peripheral blood. However, its specific role in neuronal intranuclear inclusion disease (NIID) has not been reported. This study aims to investigate the relationship between NIID and NLR. Methods A multicenter database was collected, including 157 NIID patients from seven hospitals (The Affiliated Hospital of Xuzhou Medical University, Yantai Yuhuangding Hospital, Tengzhou Central People's Hospital,The Affiliated Brain Hospital of Nanjing Medical University, Liaocheng People's Hospital,The Second Hospital of Shandong University, Inner Mongolia People's Hospital, Xuanwu Hospital Capital Medical University,The First Affiliated Hospital of USTC), along with 157 age- and gender-matched healthy control subjects. White blood cell counts (including neutrophils, lymphocytes, monocytes, eosinophils, and basophils) were obtained, and the NLR was calculated. Additionally, cognitive impairment was assessed using clinical evaluation scores. Results NIID patients exhibited significantly higher NLR values compared to the healthy control group (p < 0.001). The plasma NLR levels in NIID patients showed a weak positive correlation with disease duration (r = 0.219, p = 0.016). However, no significant correlations were found between NLR and age of onset or cognitive impairment (p > 0.05). Conclusion There is a significant association between NLR and NIID, suggesting a potential role of peripheral blood inflammation in the pathogenesis of NIID.

Neuronal intranuclear inclusion disease (NIID) is an underdiagnosed neurodegenerative disorder caused by pathogenic GGC expansions in NOTCH2NLC. However, an increasing number of reports of NOTCH2NLC GGC expansions in patients with Alzheimer disease, essential tremor, Parkinson disease, amyotrophic lateral sclerosis, and oculopharyngodistal myopathy have led to the proposal of a new concept known as NOTCH2NLC-related GGC repeat expansion disorders (NREDs). The majority of studies have mainly focused on screening for NOTCH2NLC GGC repeat variation in populations previously diagnosed with the associated disease, subsequently presenting it as a novel causative gene for the condition. These studies appear to be clinically relevant but do have their limitations because they may incorrectly regard the lack of MRI abnormalities as an exclusion criterion for NIID or overlook concomitant clinical presentations not typically observed in the associated diseases. Besides, in many instances within these reports, patients lack pathologic evidence or undergo long-term follow-up to conclusively rule out NIID. In this review, we will systematically review the research on NOTCH2NLC 5' untranslated region GGC repeat expansions and their association with related neurologic disorders, explaining the limitations of the relevant reports. Furthermore, we will integrate subsequent studies to further demonstrate that these patients actually experienced distinct clinical phenotypes of NIID.

Objectives: To investigate clinical manifestations and outcomes of patients with LGI1 autoimmune encephalitis. Methods: A total of 12 patients who were diagnosed with LGI1 autoimmune encephalitis were retrospectively analyzed between 2018 and 2022 at the Department of Neurology of the Affiliated Hospital of Xuzhou Medical University. Clinical characteristics, laboratory examinations, electroencephalograms, brain magnetic resonance images and prognosis were assessed. The clinical data were collected by searching through electronic medical records. Results: Among 12 patients, 8 were male and 4 were female. The average age at disease onset was 61.8 years (24-83). The most common clinical symptoms were seizures (n=10), cognitive dysfunction (n=8), and mental behavioral disorders (n=8). A total of 9 cases had hyponatremia. Brain MRI and electroencephalographic were abnormal in 7 patients each. All patients were treated with first line immunotherapy. Most patients responded well and 3 patients relapsed on follow-up. Conclusion: Characteristic features of LGI1 antibody encephalitis include subacute onset cognitive impairment, seizures, faciobrachial dystonic seizures (FBDS), and mental and behavioral abnormalities. Especially, FBDS and hyponatremia suggest LGI1-antibody encephalitis. Therefore, early identification and immunotherapy may prevent cognitive impairment and improve prognosis.

The expansion of GGC repeats within NOTCH2NLC leads to the translation of the uN2CpolyG protein, the primary pathogenic factor in neuronal intranuclear inclusion disease (NIID). This study aims to explore the deposition of uN2CpolyG as an amyloid in the vessel wall, leading to uN2CpolyG cerebral amyloid angiopathy (CAA)-related cerebral microbleeds (CMBs). A total of 97 patients with genetically confirmed NIID were enrolled in this study. We analyzed the presence of CMBs using susceptibility-weighted imaging sequences and compared general clinical information, cerebrovascular risk factors, stroke history, antiplatelet medication use, and MRI features between NIID patients with and without CMBs. We further performed hematoxylin and eosin (H&E), Perl's, Congo red, and Thioflavin S staining, ubiquitin, p62 and uN2CpolyG immunostaining on brain tissue obtained from four NIID patients. A total of 354 CMBs were detected among 41 patients with NIID, with nearly half located in the deep brain, one-third in the lobes, and approximately 20% in the infratentorial area. No significant differences in cerebrovascular disease risk factors or history of antiplatelet drug use were observed between patients with and without CMBs. However, patients with CMBs suffered a higher incidence of previous ischemic and hemorrhagic stroke events. This group also had a higher incidence of recent subcortical infarcts and a higher proportion of white matter lesions in the external capsule and temporal pole. Conversely, patients without CMBs showed higher detection of high signals at the corticomedullary junction on diffusion-weighted imaging and more pronounced brain atrophy. Haematoxylin and eosin staining showed blood vessel leakage and hemosiderin-laden macrophage clusters, and Prussian blue staining revealed brain tissue iron deposition. CMBs occurred more frequently in small vessels lacking intranuclear inclusions, and extensive degeneration of endothelial cells and smooth muscle fibres was observed mainly in vessels lacking inclusions. Congo red-positive amyloid deposition was observed in the cerebral vessels of NIID patients, with disordered filamentous fibres appearing under an electron microscope. Additionally, the co-localization of Thioflavin S-labeled amyloid and uN2CpolyG protein in the cerebral vascular walls of NIID patients further suggested that uN2CpolyG is the main pathogenic protein in this form of amyloid angiopathy. In conclusion, we reviewed patients with GGC repeat expansion of NOTCH2NLC from a novel perspective, providing initial clinical, neuroimaging, and pathological evidence suggesting that uN2CpolyG may contribute to a distinct type of CAA.

Neuronal intranuclear inclusion disease (NIID) is a rare but probably underdiagnosed neurodegenerative disorder due to pathogenic GGC expansions in the NOTCH2NLC gene. In this review, we summarize recent developments in the inheritance features, pathogenesis, and histopathologic and radiologic features of NIID that subvert the previous perceptions of NIID. GGC repeat sizes determine the age of onset and clinical phenotypes of NIID patients. Anticipation may be absent in NIID but paternal bias is observed in NIID pedigrees. Eosinophilic intranuclear inclusions in skin tissues once considered pathological hallmarks of NIID can also present in other GGC repeat diseases. Diffusion-weighted imaging (DWI) hyperintensity along the corticomedullary junction once considered the imaging hallmark of NIID can frequently be absent in muscle weakness and parkinsonism phenotype of NIID. Besides, DWI abnormalities can appear years after the onset of predominant symptoms and may even disappear completely with disease progression. Moreover, continuous reports of NOTCH2NLC GGC expansions in patients with other neurodegenerative diseases lead to the proposal of a new concept of NOTCH2NLC-related GGC repeat expansion disorders (NRED). However, by reviewing the previous literature, we point out the limitations of these studies and provide evidence that these patients are actually suffering from neurodegenerative phenotypes of NIID.

OBJECTIVE:Microglial polarization plays a critical role in neuroinflammation and may be a potential therapeutic target for ischemic stroke. This study was to explore the role and underlying molecular mechanism of Circular RNA PTP4A2 (circPTP4A2) in microglial polarization after ischemic stroke.METHODS:C57BL/6J mice underwent transient middle cerebral artery occlusion (tMCAO), while primary mouse microglia and BV2 microglial cells experienced oxygen glucose deprivation/reperfusion (OGD/R) to mimic ischemic conditions. CircPTP4A2 shRNA lentivirus and Colivelin were used to knock down circPTP4A2 and upregulate signal transducer and activator of transcription 3 (STAT3) phosphorylation, respectively. Microglial polarization was assessed using immunofluorescence staining and Western blot. RNA pull-down and RNA binding protein immunoprecipitation (RIP) were applied to detect the binding between circPTP4A2 and STAT3.RESULTS:The levels of circPTP4A2 were significantly increased in plasma and peri-infarct cortex in tMCAO mice. CircPTP4A2 knockdown reduced infarct volume, increased cortical cerebral blood flow (CBF), and attenuated neurological deficits. It also decreased pro-inflammatory factors levels in peri-infarct cortex and plasma, and increased anti-inflammatory factors concentrations 24 h post-stroke. In addition, circPTP4A2 knockdown suppressed M1 microglial polarization and promoted M2 microglial polarization in both tMCAO mice and OGD/R-induced BV2 microglial cells. Moreover, circPTP4A2 knockdown inhibited the phosphorylation of STAT3 induced by oxygen-glucose deprivation. In contrast, increased phosphorylation of STAT3 partly counteracted the effects of circPTP4A2 knockdown. RNA pull-down and RIP assays further certified the binding between circPTP4A2 and STAT3.CONCLUSION:These results revealed regulatory mechanisms of circPTP4A2 that stimulated neuroinflammation by driving STAT3-dependent microglial polarization in ischemic brain injury. CircPTP4A2 knockdown reduced cerebral ischemic injury and promoted microglial M2 polarization, which could be a novel therapeutic target for ischemic stroke.

BACKGROUND AND PURPOSE:Neuronal intranuclear inclusion disease (NIID) poses a diagnostic challenge because of its diverse clinical manifestations. Detection of intranuclear inclusions remains the primary diagnostic criterion for NIID. Skin biopsies have traditionally been used, but concerns exist regarding postoperative complications and scarring. We sought to investigate the diagnostic utility of labial salivary gland biopsy, a less invasive alternative. METHODS:This study included a total of 19 patients and 11 asymptomatic carriers who underwent labial gland biopsies, while 10 patients opted for skin biopsies. All these individuals were confirmed to have pathogenic GGC repeat expansions in the NOTCH2NLC gene. The control group comprised 20 individuals matched for age and sex, all with nonpathogenic GGC repeat expansions, and their labial gland tissue was sourced from oral surgery specimens. RESULTS:Labial gland biopsies proved to be a highly effective diagnostic method in detecting eosinophilic intranuclear inclusions in NIID patients. The inclusions showed positive staining for p62 and ubiquitin, confirming their pathological significance. The presence of uN2CpolyG protein in the labial gland tissue further supported the diagnosis. Importantly, all patients who underwent lip gland biopsy experienced fast wound healing without any noticeable scarring. In contrast, skin biopsies led to varying degrees of scarring and one instance of a localized infection. CONCLUSION:Labial salivary gland biopsy emerged as a minimally invasive, efficient diagnostic method for NIID, with rapid healing and excellent sensitivity.

Objective: The aim of this study is to investigate the value of p-tau181 and Aβ1-42 in serum in the diagnosis of neuronal intranuclear inclusion disease (NIID) and differential diagnosis with Parkinson's disease dementia (PDD), Alzheimer's disease (AD) and Vascular dementia (VD). Methods: We recruited 98 individuals: 16 with neuronal intranuclear inclusion disease dementia (NIID-D), 19 with AD, and 21 each for PDD patients, AD patients, and healthy controls (HC). Serum concentrations of p-tau181 and Aβ1-42 were measured using ELISA in five groups of people to compare the differences between the NIID group and the remaining groups and to analyze the correlation between p-tau181 and Aβ1-42 concentrations in patients with NIID and the correlation with MMSE scores. Results: Serum Aβ1-42 concentrations and Aβ1-42/P-tau181 ratio were significantly higher in NIID-D patients than in the rest of the groups (P < 0.001). The difference in serum concentrations of P-tau181 reached significance (P<0.05) between patients with NIID and those with VD and PDD. There was a positive correlation between Aβ1-42 and p-tau181 concentrations and a positive correlation between serum Aβ1-42/P-tau181 ratio and MMSE scores. Conclusions: The serum Aβ1-42 concentration and Aβ1-42/P-tau181 ratio are valuable for the diagnosis and differentiation of NIID.

Introduction/AimsHypernatremia myopathy is a rare disease often unrecognized by clinicians. This study aimed to present a case series of hypernatremic myopathy with an emphasis on profiling its clinical characteristics and exploring its pathogenesis. MethodsWe reviewed seven patients with hypernatremic myopathy and reported their demographic data, etiology, clinical manifestations, and laboratory and electrophysiological characteristics. A muscle biopsy was performed on one patient. ResultsAll patients had hypothalamic lesions as the cause of the hypernatremia including craniopharyngioma, germinoma, pituitary adenoma, Langerhans cell histiocytosis, and glioma. The clinical manifestations varied from mild weakness to complete paralysis. Myalgia and muscle cramps were also observed. Four of the patients had rhabdomyolysis on admission and developed acute kidney injury. All patients had markedly elevated serum creatine kinase (CK) and sodium levels. There was a significant positive correlation between serum sodium and CK levels. A high prevalence of hypopituitarism in different axes was observed in our study. Central hypogonadism (5 of 7), central hypothyroidism (3 of 7), and central diabetes insipidus (3 of 7) were the most common manifestations of hypothalamic dysfunction. Myopathic changes were observed on needle electromyography. The muscle biopsy of one patient showed diffuse necrotic fibers and scattered hypercontracted fibers with increased ragged red fibers. DiscussionHypernatremia myopathy should be considered in hypernatremic patients with muscle weakness and myalgia. Rhabdomyolysis frequently occurs and may lead to acute kidney injury in hypernatremia myopathy. Testing of hormone levels and performance of brain magnetic resonance imaging for possible hypothalamic lesions is strongly recommended.

Objective:To summarize the electrophysiological characteristics of neuronal intranuclear inclusion disease (NIID) and explore the value of electrophysiological examination in NIID auxiliary diagnosis.Methods:Twenty NIID patients diagnosed by pathological biopsy and genetic confirmation (15 were symptomatic, 5 were asymptomatic), admitted to Department of Neurology, Affiliated Hospital of Xuzhou Medical University from February 2020 to June 2022 were chosen. Peripheral motor/sensory nerve conduction, needle electromyography, F wave, repetitive electrical stimulation, skin sympathetic reflex (SSR), and tremor were analyzed. Peripheral nerve conduction and SSR parameters were compared between 15 patients with symptomatic NIID (symptomatic NIID group) and 11 age- and gender-matched normal control subjects (control group).Results:(1) All 15 patients with symptomatic NIID were with abnormal electrophysiological findings: 14 patients had abnormal peripheral nerve conduction, including 14 with slowed motor nerve conduction velocity (MCV), 4 with reduced composite muscle action potential (cMAP) wave amplitude, 12 with slowed sensory nerve conduction velocity (SCV), and 3 with reduced sensory nerve action potential (sNAP) wave amplitude, and overall slowed nerve conduction velocity and relatively preserved wave amplitude were noted; 4 patients had neurogenic lesions by needle electromyography; 13 patients had prolonged F-wave latency at varied degrees; 12 showed abnormal SSR; 4 exhibited synchronous tremor from 4.0 to 7.5 Hz. (2) In 5 patients with asymptomatic NIID, 3 had abnormal peripheral nerve conduction, including 3 with slowed MCV, 2 with slowed SCV, and 1 with reduced sNAP wave amplitude; 3 showed abnormal SSR. (3) Significant differences in MCV and SCV, some cMAP and sNAP amplitudes, and SSR latency and amplitude were noted in nerves of the upper and lower extremities between the symptomatic NIID group and control group ( P<0.05). Conclusion:Peripheral nerve damages are common in patients with NIID, especially myelin damage and autonomic nerve injury, and some patients may have electrophysiological abnormalities before clinical symptoms; therefore, peripheral nerve conduction and SSR can be recommended as auxiliary screening tools for NIID.

Objective To explore the clinical features and auxiliary examination of neuronal intranuclear inclusions（NIID）, in order to raise awareness toward the disease.Methods A total of 8 NIID patients who were admitted to Department of Neurology, the Affiliated Hospital of Xuzhou Medical University from January 2020 to January 2022, andpathologically and genetically diagnosed were enrolled. Their clinical, imaging and electrophysiological data were retrospective analyzed.Results For the patients enrolled, their clinical manifestations included cognitive impairment in six cases, episodic psychiatric symptoms in one case, limb weakness in two cases, sensory disturbance in one case, autonomic dysfunction in six cases, tremor in four cases, and ataxia in four cases. Magnetic resonance imaging（MRI） showed abnormally high signals of diffusion-weighted image（DWI） along the corticomedullary junction in all eight cases, with brain atrophy to various degree in six cases. According to electrophysiological results, there were abnormal nerve conduction in eight cases, including slowing of motor nerve conduction velocity in eight cases, decreases in motional amplitudein one case, slowing of sensory nerve conduction in seven cases, decreases in sensory amplitude in two cases, and abnormal sympathetic skin response in seven cases. Synchronized tremor（4-7 Hz） was detected in four cases.Conclusions The clinical manifestations of NIID are different, where both the central and peripheral nervous systems are involved. Cerebral MIR shows abnormally high signals along the corticomedullary junction. Electrophysiological results presents obvious peripheral myelin damage and autonomic nerve injury, with tremor in some pateints.

目的 探讨笑气滥用导致神经功能缺损的临床特点.方法 回顾性分析2例笑气滥用导致神经功能缺损患者的临床资料,并对相关文献资料进行复习.结果 1例以模拟格林-巴利综合征的症状发病,表现为四肢对称性的麻木无力,脊椎横断面T2WI显示颈髓后索倒"V"形高信号,EMG呈多发性周围神经脱髓鞘和轴索损伤.另1例以模拟急性脊髓炎症状起病,表现为双下肢无力伴小便潴留,EMG呈脊髓损害表现,但脊椎MRI未发现明显病灶.2例患者血同型半胱氨酸水平均明显升高,伴或不伴维生素B12缺乏,停止吸食笑气并补充维生素B12后症状逐渐好转.结论 当健康青年人出现维生素B12缺乏的神经系统症状,如表现为亚急性联合变性、周围神经病等,应考虑笑气中毒的可能.