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Background: Patients with Parkinson's disease (PD) suffer from serious quality of life problems. Diabetes has been demonstrated as an independent risk element for PD, aggravating its severity and accelerating its progression. There are currently no suitable biomarkers to reveal the impact of diabetes on PD. The purpose of our research was to study the impact of diabetes on PD using corneal confocal microscopy (CCM), a non‐invasive and objective test. Methods: Fourteen PD patients with diabetes (PD‐DM), 60 PD patients without diabetes (PD‐NDM), and 30 healthy controls (HC) were included in the study. The clinical symptoms of patients with PD were assessed using the Unified Parkinson's Disease Rating Scale‐3 (UPDRS‐3) and the Parkinson's Disease Autonomic Symptom Prognosis Scale (SCOPA‐AUT). Participants underwent CCM to quantify the corneal nerve fibres. Results: Corneal nerve fibre density (CNFD) and corneal nerve fibre length (CNFL) in patients with PD were lower than HC. Furthermore, CNFD in PD‐DM was lower than in PD‐NDM (P < 0.01). We also assessed the relationship between CCM parameters and clinical scores. CNFL and Hamilton anxiety (HAMA) have a negative correlation (r = −0.261, P = 0.032), but this study did not observe a significant correlation between CCM parameters and SCOPA‐AUT. Additionally, CNFD could distinguish PD‐DM from PD‐NDM, achieving an area under the curve of 75.06% (95% CI, 61.76%–88.36%). Conclusions: The CCM could be served as an objective and sensitive biomarker to investigate the impact of diabetes in PD. [ABSTRACT FROM AUTHOR]

Objective: Prior research has underscored the importance of sphingolipid metabolism in Parkinson's disease (PD) pathogenesis. Our objective was to explore the associations between plasma ceramide levels and PD patients with cognitive dysfunction (PD‐CD). Methods: We enrolled two study populations from Eastern China and the Parkinson's Progression Markers Initiative (PPMI), comprising 290 (100 HCs, 160 PDs, and 30 MSAs) and 429 (125 HCs and 304 PDs) participants, respectively. The plasma levels of ceramides (Cer 16:0, Cer 18:0, Cer 24:0, and Cer 24:1) were tested via HPLC–MS/MS analysis. Results: Compared with those in the HC group, the plasma levels of Cer 18:0, Cer 24:1, Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0 were higher in both the PD and MSA groups. Significant differences in the plasma levels of Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0 were observed among the PD‐NC (PD with normal cognition), PD‐MCI (PD with mild cognitive impairment), and PDD (PD dementia) groups, with the PDD group exhibiting the highest levels. PD patients with higher baseline levels of plasma ceramides (specifically, Cer 18:0, Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0) demonstrated accelerated cognitive decline compared with individuals who had lower baseline plasma ceramide levels during the 5‐year follow‐up period. A biomarker panel including Cer 18:0/Cer 24:0 and Cer 24:1/Cer 24:0 could effectively differentiate PD‐CD from PD‐NC with notable diagnostic accuracy. Conclusions: Our results indicate that plasma ceramide levels could potentially be used as diagnostic biomarkers for PD‐CD. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) is a heterogeneous condition that can precede various forms of dementia, including Alzheimer's disease (AD). Identifying MCI subjects who are at high risk of progressing to AD is of major clinical relevance. Enlarged perivascular spaces (EPVS) on MRI are linked to cognitive decline, but their predictive value for MCI to AD progression is unclear. Objective: This study aims to assess the predictive value of EPVS for MCI to AD progression and develop a predictive model combining EPVS grading with clinical and laboratory data to estimate conversion risk. Methods: We analyzed 358 patients with MCI from the ADNI database, consisting of 177 MCI-AD converters and 181 non-converters. The data collected included demographic information, imaging data (including perivascular spaces grade), clinical assessments, and laboratory test results. Variable selection was conducted using the Least Absolute Shrinkage and Selection Operator (LASSO) method, followed by logistic regression to develop predictive model. Results: In the univariate logistic regression analysis, both moderate (OR = 5.54, 95% CI [3.04–10.18]) and severe (OR = 25.04, 95% CI [10.07–62.23]) enlargements of the centrum semiovale perivascular space (CSO-PVS) were found to be strong predictors of disease progression. LASSO analyses yielded 12 variables, refined to six in the final model: APOE4 genotype, ADAS11 score, CSO-PVS grade, and volumes of entorhinal, fusiform, and midtemporal regions, with an AUC of 0.956 in the training and 0.912 in the validation cohort. Conclusions: Our predictive model, emphasizing EPVS assessment, provides clinicians with a practical tool for early detection and management of AD risk in MCI patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This article explores the involvement of the immune system in neuronal intranuclear inclusion disease (NIID), a progressive neurodegenerative disorder. The study found inflammatory cell infiltrates and eosinophilic intranuclear inclusions in various tissues of NIID patients, suggesting the systemic nature of the disease. Additionally, the presence of ubiquitin-positive intranuclear inclusions and uN2CpolyG protein aggregates in peripheral blood monocyte cells (PBMCs) of NIID patients may serve as potential biomarkers for diagnosis. The study highlights the need for further research to understand the immune system's role in NIID and improve clinical management strategies. [Extracted from the article]

Background: This study set out to investigate the relationship between serum neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), and various non‐motor symptoms (NMSs) in patients with Parkinson's disease (PD). Methods: The study included 37 healthy controls (HCs) and 51 PD patients. Clinical assessments of PD symptoms were conducted for all PD patients. The NMSS was utilised to evaluate the NMS burden (NMSB) in individuals. Based on the severity of NMSB, we further categorised the PD group into two subgroups: mild–moderate NMSB group and severe–very severe NMSB group. The amounts of NFL and GFAP in the serum were measured using an extremely sensitive single molecule array (Simoa) method. Statistical analyses were performed on the collected data using SPSS 26.0 and R (version 3.6.3). Results: Serum GFAP and NFL levels in the PD group with severe–very severe NMSB were significantly higher than those in the mild–moderate NMSB group (GFAP: P < 0.007; NFL: P < 0.009). Serum NFL and GFAP levels had positive correlations with NMSS total scores (GFAP: r = 0.326, P = 0.020; NFL: r = 0.318, P = 0.023) and multiple subdomains. The relationship between the attention/memory domains of NMSS and NFL levels is significantly positive (r = 0.283, P = 0.044). Similarly, the mood/apathy domains of NMSS are also significantly positively correlated with GFAP levels (r = 0.441, P = 0.001). Patients with emotional problems or cognitive impairment had higher GFAP or NFL levels, respectively. Furthermore, it has been demonstrated that NMSs play a mediating role in the quality of life of patients with PD. Moreover, the combination of NFL and GFAP has proven to be more effective than using a single component in identifying PD patients with severe–very severe NMSB. Conclusions: The severity of NMSs in PD patients, particularly cognitive and emotional symptoms, was found to be associated with the levels of serum NFL and GFAP. This study marks the first attempt to examine the connection between NMSs of PD and the simultaneous identification of NFL and GFAP levels. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]