Abnormal cerebellum connectivity patterns related to motor subtypes of Parkinson's disease.

Cerebellar dysfunction may substantially contribute to the clinical symptoms of Parkinson's disease (PD). The role of cerebellar subregions in tremors and gait disturbances in PD remains unknown. To investigate alterations in cerebellar subregion volumes and functional connectivity (FC), as well as FC between the dentate nucleus (DN) and ventral lateral posterior nucleus (VLp) of the thalamus, which are potentially involved in different PD motor subtypes. We conducted morphometric and resting-state functional connectivity analyses in various cerebellar subregions in 22 tremor-dominant (TD)-PD and 35 postural instability gait difficulty dominant (PIGD)-PD patients and 38 sex- and age-matched healthy controls (HCs). The volume and FC alterations in various cerebellar subregions and the neural correlates of these changes with the clinical severity scores were investigated. The PIGD-PD group showed greater FC between the right motor cerebellum (CBMm) and left postcentral gyrus than the HC group, and a higher FC was associated with less severe PIGD symptoms. In contrast, the TD-PD group had decreased FC between the right DN and left VLp compared with the PIGD-PD and HC groups, and lower FC was associated with worse TD symptoms. Furthermore, the PIGD-PD group had higher FC between the left DN and left inferior temporal gyrus than the TD-PD group. Morphometric analysis revealed that the TD-PD group showed a significantly higher volume of left CBMm than the HC group. Our findings point to differential alteration patterns in cerebellar subregions and offer a new perspective on the pathophysiology of motor subtypes of PD.

Novel heterozygous VPS13A pathogenic variants in chorea-neuroacanthocytosis: a case report.

BACKGROUND: Chorea-acanthocytosis (ChAc) is a rare hereditary autosomal recessive neurodegenerative disorder caused by pathogenic variants of the Vacuolar Protein Sorting 13 homolog A (VPS13A) gene. The variant spectrum of VPS13A has not been completely elucidated. This study reports two novel heterozygous VPS13A pathogenic variants in ChAc that expand the variant spectrum of VPS13A. CASE PRESENTATION: We described a case of a 29-year-old man with typical clinical manifestations of ChAc, including chorea, orofacial lingual dyskinesia, vocal tics, elevated serum biochemical indicators, increased acanthocytes in peripheral blood, and caudate nucleus atrophy. Next-generation sequencing revealed two heterozygous variants of VPS13A: a nonsense variant (NM_033305.2: c.8215G > T, p. Glu2739Ter) and a deletion variant in the exons 25-31. CONCLUSION: The identified nonsense variant gives rise to premature translation termination, while the deletion variant is expected to cause a significant in-frame deletion of amino acid residues in the encoded protein. Both variants are considered to be pathogenic and result in loss-of-function proteins. These findings have implications for the genetic counseling of patients with VPS13A variants.

Construction of a novel ursolic acid-based supramolecular gel for efficient removal of iodine from solution.

Pentacyclic triterpenes is a natural amphipathic product which possess a rigid backbone and several polar functional groups such as hydroxyl, carbonyl and carboxyl groups. The amphipathic character makes it easy to realize self-assemble into complex nano structure and therefore attract extensive attention due to the simple synthetic processes and renewable raw materials. Hence, a novel Ursolic acid-based hydrogel was prepared successfully via a simple self-assembly of triterpenoid derivative in methanol by capture water molecule in air. The resulting hydrogel show a porous morphology and good elasticity including strong heat resistance. Based on the characteristic above, the hydrogel showed a good iodine adsorption capacity and can removal 75.0% of the iodine from cyclohexane solution and 66.3% from aqueous solution within 36 h. Data analysis indicate that all the iodine adsorption process are dominated by chemisorption and belongs to the multi-site adsorption on heterogenous surfaces. In addition, the obtained hydrogel also possesses a good recyclability which can maintain more than 82% of its capacity after 5 cycles. The simple preparation method and easily available raw materials endow it a great potential in future pollutant treatment.

Egr2 contributes to age-dependent vulnerability to sevoflurane-induced cognitive deficits in mice.

Sevoflurane inhalation is prone to initiate cognitive deficits in infants. The early growth response-2 (Egr-2) gene is DNA-binding transcription factor, involving in cognitive function. In this study we explored the molecular mechanisms underlying the vulnerability to cognitive deficits after sevoflurane administration. Six-day-old (young) and 6-week-old (early adult) mice received anesthesia with 3% sevoflurane for 2 h daily for 3 days. We showed that multiple exposures of sevoflurane induced significant learning ability impairment in young but not early adult mice, assessed in Morris water maze test on postnatal days 65. The integrated differential expression analysis revealed distinct transcription responses of Egr family members in the hippocampus of the young and early adult mice after sevoflurane administration. Particularly, Egr2 was significantly upregulated after sevoflurane exposure only in young mice. Microinjection of Egr2 shRNA recombinant adeno-associated virus into the dentate gyrus alleviated sevoflurane-induced cognitive deficits, and abolished sevoflurane-induced dendritic spins loss and BDNF downregulation in young mice. On the contrary, microinjection of the Egr2 overexpression virus in the dentate gyrus aggravated learning ability impairment induced by sevoflurane in young mice but not early adult mice. Furthermore, we revealed that sevoflurane markedly upregulated the nuclear factors of activated T-cells NFATC1 and NFATC2 in young mice, which were involved in Egr2 regulation. In conclusion, Egr2 serves as a critical factor for age-dependent vulnerability to sevoflurane-induced cognitive deficits.

The related mechanism of complete Freund's adjuvant-induced chronic inflammation pain based on metabolomics analysis.

Chronic inflammation pain is a debilitating disease, and its mechanism still remains poorly understood. This study attempted to illuminate the metabolic mechanism of chronic inflammation pain induced by complete Freund's adjuvant (CFA) injection, especially at spinal level. The chronic inflammation pain model was established by CFA administration. Behavioral testing including mechanical allodynia and thermal hyperalgesia was performed. Meanwhile, a liquid chromatography-mass spectrometry-based metabolomics approach was applied to analyze potential metabolic biomarkers. The orthogonal partial least squares discrimination analysis mode was employed for determining metabolic changes, and a western blot was performed to detect the protein expression change. The results showed that 27 metabolites showed obviously abnormal expression and seven metabolic pathways were significantly enriched, comprising aminoacyl-tRNA biosynthesis, arginine and proline metabolism, histidine metabolism, purine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, glutathione metabolism, and phenylalanine metabolism. Meanwhile, the results showed that the expression of arginase I and nitric oxide levels were elevated in the CFA group compared with the control group, while the argininosuccinate synthetase and argininosuccinatelyase proteins were not significantly different between the groups. These findings demonstrate that metabolic changes of the spinal cord may be implicated in neurotransmitter release and pain conductivity following CFA administration.

Randomized controlled trials for comparison of laparoscopic versus conventional open catheter placement in peritoneal dialysis patients: a meta-analysis.

BACKGROUND: The application of laparoscopic catheterization technology in peritoneal dialysis (PD) patients has recently increased. However, the advantages and disadvantages of laparoscopic versus conventional open PD catheter placement are still controversial. The aim of this meta-analysis is to assess the complications of catheterization in PD patients and to provide a reference for choosing a PD-catheter placement technique in the clinic. METHODS: We searched numerous databases, including Embase, PubMed, CNKI and the Cochrane Library, for published randomized controlled trials (RCTs). RESULTS: Eight relevant studies (n = 646) were included in the meta-analysis. The pooled results showed a lower incidence of catheter migration (OR: 0.42, 95% CI: 0.19 to 0.90, P: 0.03) and catheter removal (OR: 0.41, 95% CI: 0.21 to 0.79, P: 0.008) but a higher incidence of bleeding (OR: 3.25, 95% CI: 1.18 to 8.97, P: 0.02) with a laparoscopic approach than with a conventional approach. There was no significant difference in the incidence of omentum adhesion (OR: 0.32, 95% CI: 0.05 to 2.10, P: 0.24), hernia (OR: 0.38, 95% CI: 0.09 to 1.68, P: 0.20), leakage (OR: 0.69, 95% CI: 0.38 to 1.26, P: 0.23), intestinal obstruction (OR: 0.96, 95% CI: 0.48 to 1.91, P: 0.90) or perforation (OR: 0.95, 95% CI: 0.06 to 15.42, P: 0.97). The statistical analysis showed no significant difference in early (OR: 0.44, 95% CI: 0.15 to 1.33, P: 0.15), late (OR: 0.89, 95% CI: 0.41 to 1.90, P: 0.76) or total (OR: 0.68, 95% CI: 0.42 to 1.12, P: 0.13) peritonitis infections between the 2 groups, and there are no no significant difference in early (OR: 0.39, 95% CI: 0.06 to 2.36, P: 0.30), late (OR: 1.35, 95% CI: 0.78 to 2.33, P: 0.16) or total (OR: 1.20, 95% CI: 0.71 to 2.02, P: 0.17) tunnel or exit-site infections between the 2 groups. CONCLUSION: Laparoscopic catheterization and conventional open catheter placement in PD patients have unique advantages, but laparoscopic PD catheterization may be superior to conventional open catheter placement. However, this conclusion needs to be confirmed with further large-sample-size, multi-centre, high-quality RCTs.

Gut microbiota regulates neuropathic pain: potential mechanisms and therapeutic strategy.

Neuropathic pain (NP) is a sustained and nonreversible condition characterized by long-term devastating physical and psychological damage. Therefore, it is urgent to identify an effective treatment for NP. Unfortunately, the precise pathogenesis of NP has not been elucidated. Currently, the microbiota-gut-brain axis has drawn increasing attention, and the emerging role of gut microbiota is investigated in numerous diseases including NP. Gut microbiota is considered as a pivotal regulator in immune, neural, endocrine, and metabolic signaling pathways, which participates in forming a complex network to affect the development of NP directly or indirectly. In this review, we conclude the current understanding of preclinical and clinical findings regarding the role of gut microbiota in NP and provide a novel therapeutic method for pain relief by medication and dietary interventions.

Hypotension and bradycardia, a serious adverse effect of piribedil, a case report and literature review.

BACKGROUND: Dopamine agonists (DAs) are efficacious for the treatment of motor and nonmotor symptoms in patients with Parkinson's disease (PD). The treatment of PD with DAs is often complicated by adverse drug reactions (ADRs) of dopaminergic and non-dopaminergic origins. The DA piribedil is widely used in Asian, European, and Latin American countries; therefore, its ADRs are pertinent to clinicians. Here we present a rare case of hypotension and bradycardia that is significantly related to the dosage of piribedil. CASE PRESENTATION: A middle-aged male, diagnosed with PD, received dopamine replacement with piribedil. When taking 50 mg piribedil daily dose, the patient didn't feel any discomfort. Two hours after taking 100 mg piribedil he presented with serious concomitant hypotension and bradycardia with a blood pressure (BP) reading of 85/48 mmHg and a heart rate (HR) of 45 beats/min when sitting. After taking 75 mg piribedil, the patient showed the same symptoms with BP reading at 70/45 mmHg and HR of 47 beats/min in the same position. Upon replacing treatment with pramipexole 0.125 mg, 0.25 mg, and 0.375 mg three times a day, no further cardiovascular effects persisted. CONCLUSIONS: No studies have previously reported the simultaneous observation of position-unrelated hypotension and bradycardia after taking small doses of piribedil. More studies are needed to explore the effects of DAs on BP and HR, especially piribedil. Piribedil is efficacious for the treatment of PD, but it is important to weigh the potential risk of hypotension and bradycardia against the clinical benefits of this drug.

[Study on phenotypic diversity and cluster analysis of Cistanche Herba in different populations in Xinjiang].

To intuitively understand the phenotypic diversity of intra-population and inter-population of the medicinal Cistanche Herba distributed in Xinjiang province, three species of Cistanche Herba were selected for the first time to be conducted to phenotypic observation and measurement from the morphological perspective, aiming to fill the gap in the morphological research concerning Cistanche Herba, and discuss about the relationship between the phenotypic variation and the host plants together with the geographical conditions, thus better understanding the speciation and evolutionary mechanism of Cistanche Herba and providing some scientific basis for the resource protection and germplasm breeding of Cistanche Herba. Based on sampling survey, a total of 118 well grown medicinal Cistanche samples from 17 Cistanche Herba distribution areas in Xinjiang province were selected, and various indexes were observed and measured. Besides, ANOVA and clustering analysis were conducted with 9 phenotypic quantity characters. The Cistanche Herba was plentiful in phenotypic variation. For detail, significant intra-population differences were observed in eight of the nine character indexes, and the intra-population differences were more obvious than those of inter-population. For each quantity character of the three species, the flower density possessed the maximal variable coefficient (71.1%) while the flower length was the minimum (15.9%). The phenotypic variation was also obvious among different populations. Specifically, the average variable coefficient of flower number was the maximal one (46.5%) and the flower length was the minimum one (10.0%). For different populations, the average variable coefficient of the D4 population was the maximal one (41.1%) and the S3 population was the minimum one (13.5%). According to the clustering analysis, all the samples of Cistanche Herba could be divided into three groups when the Euclidean distance was set at 15. The populations of S1, S3, D1, S2, D4, D6, D7 and D5 which distributed in the north of Xinjiang were clustered into one group, and the populations of D8, S4, D9, D2 and D3 that grown in east and central of Xinjiang were clustered into another group. The populations of C. deserticola and C. salsa could not be completely separated, but both of them were obviously differentiated from the T1, T3 and T2 populations of C. tubulosa. Besides, the C. deserticola and C. salsa displayed a patch distribution among different populations, and similar phenotypic characters were shared for each population. The research results of phenotype were consistent with that of molecular biology study of Cistanche Herba. The different phenotypic characters in different distribution areas were deduced to be arose from geographical isolation caused by mountains, which led to the specific genetic structure for each population of Cistanche Herba during the long-term adaptation and evolution. In conclusion, the current study showed the adaptation potency of Cistanche Herba exposed to different habitats.

Injection of Aß1-40 into hippocampus induced cognitive lesion associated with neuronal apoptosis and multiple gene expressions in the tree shrew.

Alzheimer's disease (AD) can incur significant health care costs to the patient, their families, and society; furthermore, effective treatments are limited, as the mechanisms of AD are not fully understood. This study utilized twelve adult male tree shrews (TS), which were randomly divided into PBS and amyloidbetapeptide1-40 (Aß1-40) groups. AD model was established via an intracerebroventricular (icv) injection of Aß1-40 after being incubated for 4 days at 37 °C. Behavioral, pathophysiological and molecular changes were evaluated by hippocampal-dependent tasks, magnetic resonance imaging (MRI), silver staining, hematoxylin-eosin (HE) staining, TUNEL assay and gene sequencing, respectively. At 4 weeks post-injection, as compared with the PBS group, in Aß1-40 injected animals: cognitive impairments happened, and the hippocampus had atrophied indicated by MRI findings; meanwhile, HE staining showed the cells of the CA3 and DG were significantly thinner and smaller. The average number of cells in the DG, but not the CA3, was also significantly reduced; furthermore, silver staining revealed neurotic plaques and neurofibrillary tangles (NFTs) in the hippocampi; TUNEL assay showed many cells exhibited apoptosis, which was associated with downregulated BCL-2/BCL-XL-associated death promoter (Bad), inhibitor of apoptosis protein (IAP), Cytochrome c (CytC) and upregulated tumor necrosis factor receptor 1 (TNF-R1); lastly, gene sequencing reported a total of 924 mobilized genes, among which 13 of the downregulated and 19 of the upregulated genes were common to the AD pathway. The present study not only established AD models in TS, but also reported on the underlying mechanism involved in neuronal apoptosis associated with multiple gene expression.

Soot nanoparticles promote ferroptosis in dopaminergic neurons via alteration of m6A RNA methylation in Parkinson's disease.

Soot nanoparticles (SNPs) are black carbon prevalent in atmospheric environment with significant impacts on public health, leading to neurodegenerative diseases including development of Parkinson's disease (PD). This study investigated the effects of SNPs exposure on PD symptoms, employing both in vivo and in vitro PD models. In the in vivo experiments, animal behavior assessments showed that SNPs exposure exacerbated motor and cognitive impairments in PD mice. Molecular biology techniques further unveiled that SNPs aggravated degeneration of dopaminergic neurons. In vitro experiments revealed that SNPs exposure intensified ferroptosis of PD cells by increasing reactive oxygen species and iron ion levels, while reducing glutathione levels and mitochondrial membrane potential. Sequencing tests indicated elevated N6-methyladenosine (m6A) alteration of the ferroptosis-related protein, acyl-CoA synthetase long chain family member 4 (ACSL4). This study demonstrates that SNPs may exacerbate the onset and progression of PD by recruiting YTH domain-containing family protein 1 (YTHDF1) protein, enhancing m6A methylation in the ACSL4 5'UTR, amplifying ACSL4 protein expression, and accelerating the ferroptosis process in dopaminergic neurons. These molecular mechanisms underlying SNPs exacerbation of PD development may provide crucial insights for formulating environmental safety regulations and potential therapeutic strategies addressing PD in populations residing in regions with varied air quality.

Brain network centrality and connectivity are associated with clinical subtypes and disease progression in Parkinson's disease.

To investigate brain network centrality and connectivity alterations in different Parkinson's disease (PD) clinical subtypes using resting-state functional magnetic resonance imaging (RS-fMRI), and to explore the correlation between baseline connectivity changes and the clinical progression. Ninety-two PD patients were enrolled at baseline, alongside 38 age- and sex-matched healthy controls. Of these, 85 PD patients underwent longitudinal assessments with a mean of 2.75 ± 0.59 years. Two-step cluster analysis integrating comprehensive motor and non-motor manifestations was performed to define PD subtypes. Degree centrality (DC) and secondary seed-based functional connectivity (FC) were applied to identify brain network centrality and connectivity changes among groups. Regression analysis was used to explore the correlation between baseline connectivity changes and clinical progression. Cluster analysis identified two main PD subtypes: mild PD and moderate PD. Two different subtypes within the mild PD were further identified: mild motor-predominant PD and mild-diffuse PD. Accordingly, the disrupted DC and seed-based FC in the left inferior frontal orbital gyrus and left superior occipital gyrus were severe in moderate PD. The DC and seed-based FC alterations in the right gyrus rectus and right postcentral gyrus were more severe in mild-diffuse PD than in mild motor-predominant PD. Moreover, disrupted DC were associated with clinical manifestations at baseline in patients with PD and predicted motor aspects progression over time. Our study suggested that brain network centrality and connectivity changes were different among PD subtypes. RS-fMRI holds promise to provide an objective assessment of subtype-related connectivity changes and predict disease progression in PD.

A profile of SGLT-2 inhibitors in hyponatremia: The evidence to date.

Hyponatremia is the most common electrolyte disorder in clinical practice, which may lead to life-threatening complications. Several lines of evidence suggest that hyponatremia is associated not only with significant increases in length of stay, cost, and financial burden, but also with increased morbidity and mortality. Hyponatremia is also considered to be a negative prognostic factor in patients with heart failure and cancer. Although multiple therapeutic methods are available for treating hyponatremia, most have some limitations, such as poor compliance, rapid correction of serum Na+, other negative side effects and high cost. Given these limitations, identifying novel therapies for hyponatremia is essential. Recent clinical studies have shown that SGLT-2 inhibitors (SGLT 2i) significantly increased serum Na+ levels and were well tolerated by patients who underwent this treatment. Therefore, oral administration of SGLT 2i appears to be an effective treatment for hyponatremia. This article will briefly review the etiology of hyponatremia and integrated control of sodium within the kidney, current therapies for hyponatremia, potential mechanisms and efficacy of SGLT 2i for hyponatremia, and the benefits in cardiovascular, cancer, and kidney disease by regulating sodium and water balance.

Diffusion along perivascular spaces provides evidence interlinking compromised glymphatic function with aging in Parkinson's disease.

AIMS: The aim of the study was to evaluate the glymphatic function and its related factors in patients with Parkinson's disease (PD) and patients with PD of different ages using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) method. METHODS: Medical records and imaging data of 93 patients with idiopathic PD and 42 age- and sex-matched healthy controls (HCs) were retrospectively reviewed and analyzed. The diffusivity along the perivascular spaces, projection fibers, and association fibers were calculated on diffusion tensor imaging (DTI) to acquire the analysis along the perivascular space (ALPS) index. RESULTS: PD patients exhibited a reduced ALPS index compared with the HCs. Negative correlations between the ALPS index and clinical information including age, age at disease onset, Parkinson's disease sleep scale 2nd version (PDSS-2) scores, and history of diabetes mellitus were revealed in the PD group. Besides, a negative correlation between the ALPS index and the severity of motor symptoms was identified in the subgroup aged 65 and above, rather than in the younger ones. CONCLUSIONS: The results demonstrate that reduced ALPS index, a potential noninvasive measure of compromised glymphatic activity, is involved in the pathophysiology of PD, especially in the aged ones and those with sleep disorders.

Cortical connectivity of cholinergic basal forebrain in Parkinson's disease with mild cognitive impairment.

Background: Cholinergic basal forebrain (BF) pathology is a hallmark of Parkinson's disease (PD) with mild cognitive impairment (PD-MCI). Assessment of functional connectivity (FC) of different cholinergic BF nuclei may deepen the understanding of PD-MCI pathogenesis. Methods: Seed-based FC analysis was performed with bilateral medial septal nucleus, the nucleus of the vertical limb of the diagonal band, nucleus of the horizontal limb of the diagonal band (Ch1-3), and the nucleus basalis of Meynert (NBM/Ch4) to explore the BF functional alterations in different frequency bands. Correlations between FC values of abnormal regions and scores of cognitive domains and depression in the PD group were also assessed. Results: For the right Ch4, in the conventional frequency band, the PD-MCI group exhibited lower FC values in the right middle cingulate and paracingulate gyri, middle frontal gyrus, left inferior parietal gyrus, and superior frontal gyrus compared with healthy controls (HC), and in the left calcarine fissure and surrounding cortex compared with PD with normal cognition (PD-NC). For the slow 4 subbands, the PD-MCI group showed significantly lower FC values in the left putamen, middle frontal gyrus, right middle frontal gyrus, and precuneus compared with HC, and in right middle frontal gyrus cingulate and paracingulate gyri compared with the PD-NC group. For the slow 5 subbands, the PD-MCI group showed increased FC values in the right calcarine fissure and surrounding cortex, and left cerebellum. For the left Ch1-3, FC values in the right middle cingulate and paracingulate gyri were lower in patients with PD-MCI than in the PD-NC group in slow 4 subbands. Furthermore, altered FC values in the cortical regions for Ch4 seed were possibly correlated with depression and different cognitive domain scores. Conclusions: The study identified an imbalanced association between different cholinergic BF nuclei and cortical regions in patients with PD-MCI, and showed that FC changes are frequency-specific, which may provide new insights into functional alterations within the cholinergic system in cognitive impairment associated with PD.

Associations between insomnia and large vessel occlusion acute ischemic stroke: An observational study.

OBJECTIVES: This study explored the association between insomnia and the clinical outcome of large vessel occlusion Acute Ischemic Stroke (AIS) and attempted to explore its potential mechanisms from the perspectives of inflammation and oxidative stress. METHODS: AIS patients who underwent endovascular treatment for large vessel occlusion at Binzhou Central Hospital from 2018 to 2022 (n = 508) were included. Patients were divided into an insomnia group and a non-insomnia group. Insomnia was judged by self-reported Athens Insomnia Scale score. Regression analysis was used to compare the differences in the 24-hour and 7-day National Institutes of Health Stroke Scale (NIHSS) score, Early Neurological Deterioration (END), early adverse event incidence, 90-day prognosis and mortality, and serum biomarkers levels. RESULTS: The incidence of insomnia in the study population was 39.6% (n = 144, insomnia group; n = 364, non-insomnia group). Compared with the non-insomnia group, a worse prognosis outcome (63% vs. 49%, adjusted rate ratio: 1.8, 95% Confidence Interval: 1.2-3.7; p = 0.016), higher 24-h and 7-day NIHSS score (17 [9-36] vs. 13 [5-20]; p = 0.024, and 11 [4‒24) vs. 8 [2‒14]; p = 0.031, respectively), higher END (24% vs. 15%, p = 0.022), and higher incidence of adverse events were observed in the insomnia group (79% vs. 59%, p = 0.010). The 90-day mortality was higher in the insomnia group than that in the non-insomnia group (22% vs. 17%), however, such a difference was not statistically significant. CONCLUSION: Insomnia is closely related to the clinical outcome of AIS with large vessel occlusion, and inflammation and oxidative stress mechanisms may be involved.

MAPKAPK2, a potential dynamic network biomarker of α-synuclein prior to its aggregation in PD patients.

One of the important pathological features of Parkinson's disease (PD) is the pathological aggregation of α-synuclein (α-Syn) in the substantia nigra. Preventing the aggregation of α-Syn has become a potential strategy for treating PD. However, the molecular mechanism of α-Syn aggregation is unclear. In this study, using the dynamic network biomarker (DNB) method, we first identified the critical time point when α-Syn undergoes pathological aggregation based on a SH-SY5Y cell model and found that DNB genes encode transcription factors that regulated target genes that were differentially expressed. Interestingly, we found that these DNB genes and their neighbouring genes were significantly enriched in the cellular senescence pathway and thus proposed that the DNB genes HSF1 and MAPKAPK2 regulate the expression of the neighbouring gene SERPINE1. Notably, in Gene Expression Omnibus (GEO) data obtained from substantia nigra, prefrontal cortex and peripheral blood samples, the expression level of MAPKAPK2 was significantly higher in PD patients than in healthy people, suggesting that MAPKAPK2 has potential as an early diagnostic biomarker of diseases related to pathological aggregation of α-Syn, such as PD. These findings provide new insights into the mechanisms underlying the pathological aggregation of α-Syn.

TREM2 Deficiency Aggravates NLRP3 Inflammasome Activation and Pyroptosis in MPTP-Induced Parkinson's Disease Mice and LPS-Induced BV2 Cells.

Microglia-mediated neuroinflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Triggering receptor expressed on myeloid cells 2 (TREM2) confers strong neuroprotective effects in PD by regulating the phenotype of microglia. Recent studies suggest that TREM2 regulates high glucose-induced microglial inflammation through the NLRP3 signaling pathway. This study aimed to investigate the effect of TREM2 on NLRP3 inflammasome activation and neuroinflammation in PD. Mice were injected with AAV-TREM2-shRNA into both sides of the substantia nigra using a stereotactic injection method, followed by intraperitoneal injection of MPTP to establish chronic PD mouse model. Behavioral assessments including the pole test and rotarod test were conducted to evaluate the effects of TREM2 deficiency on MPTP-induced motor dysfunction. Immunohistochemistry of TREM2 and tyrosine hydroxylase (TH), immunohistochemistry and immunofluorescence Iba1, Western blot of NLRP3 inflammasome and its downstream inflammatory factors IL-1ß and IL-18, and the key pyroptosis factors GSDMD and GSDMD-N were performed to explore the effect of TREM2 on NLRP3 inflammasome and neuroinflammation. In an in vitro experiment, lentivirus was used to interfere with the expression of TREM2 in BV2 microglia, and then lipopolysaccharide (LPS) and adenopterin nucleoside triphosphate (ATP) were used to stimulate inflammation to construct a cellular inflammation model. The expression differences of NLRP3 inflammasome and its components were detected by qPCR and Western blot. In vivo, TREM2 knockdown aggravated the loss of dopaminergic neuron and the decline of motor function. After TREM2 knockdown, the number of activated microglia was significantly increased, and the expression of cleaved caspase-1, NLRP3 inflammasome, IL-1ß, GSDMD, and GSDMD-N was increased. In vitro, TREM2 knockdown aggravated the inflammatory response of BV2 cells stimulated by LPS and promoted the activation of NLRP3 inflammasome through the NF-κB pathway. In addition, TREM2 knockdown also promoted the expression of TLR4/MyD88, an upstream factor of the NF-κB pathway. Our vivo and vitro data showed that TREM2 knockdown promoted NLRP3 inflammasome activation and downstream inflammatory response, promoted pyroptosis, and aggravated dopaminergic neuron loss. TREM2 acts as an anti-inflammatory in PD through the TLR4/MyD88/NF-κB pathway, which extends previous findings and supports the notion that TREM2 ameliorates neuroinflammation in PD.

Mitochondria-Related Ferroptosis Drives Cognitive Deficits in Neonatal Mice Following Sevoflurane Administration.

Multiple sevoflurane exposure may result in cognitive deficits in neonatal animals. This study attempted to investigate the potential mechanism of sevoflurane-induced neurotoxicity in developing hippocampus. Neonatal animals received sevoflurane anesthesia, then the behavioral tests and Golgi-Cox staining were employed to detect the effect of sevoflurane inhalation in adult mice. And the mitochondrial function was evaluated using MitoSOX staining, Fluo calcium indicators, mitochondrial permeability transition pore (mPTP) assay, and JC-1 probe after sevoflurane administration. Meanwhile, mitochondrial lipid hydroperoxide and ferroptosis were measured by MitoPeDPP and Mito-FerroGreen signals following sevoflurane exposure. Moreover, the ferroptosis and behavioral performance were assessed after deferiprone (DFP) treatment. The results showed that sevoflurane administration induced cognitive impairment accompanied by reducing dendritic length, density, and nodes. Additionally, sevoflurane exposure elevated mitochondrial ROS production and cytoplasm calcium levels, triggered the opening of mPTP, and decreased the mitochondrial membrane potential (MMP). However, supplement of elamipretide (SS-31) effectively reversed mitochondrial dysfunction. Mitochondrial lipid hydroperoxide production was increased after sevoflurane administration, whereas Fer-1 treatment reduced lipid hydroperoxide formation. Sevoflurane exposure induced mitochondrial iron overload, whereas Mito-Tempo treatment reduced iron accumulation. Prussian blue staining showed that the hippocampal iron deposition was apparently increased after sevoflurane inhalation. Additionally, the ferroptosis-related protein expression (including ACSL4, COX2, GPX4, and FTH1) was significantly changed, whereas DFP effectively suppressed ferroptosis and enhanced sevoflurane-induced behavioral malfunction. These findings demonstrated that sevoflurane administration elicited mitochondrial dysfunction and iron dyshomeostasis and eventually resulted in cognitive impairments, whereas protecting mitochondrial function and chelating neurotoxic iron effectively reversed these pathological processes.

Metabolite changes in prefrontal lobes and the anterior cingulate cortex correlate with processing speed and executive function in Parkinson disease patients.

Background: Processing speed and executive function can be impaired in patients with Parkinson disease (PD). However, the neural factors related to the slowdown in processing speed and dysexecutive function in PD are not completely understood. The objective of this study is to investigate the metabolic changes of the frontal and anterior cingulate cortex (ACC) through the use of 1H magnetic resonance spectroscopy and to explore the association between cognitive function and metabolic ratios. Methods: In this retrospective case-control study, we conducted neuropsychological assessments of executive function and information processing speed in healthy controls (HCs) and in patients with PD. Chemical information was obtained for the of N-acetyl-aspartate (NAA):creatine (Cr) ratio and the choline-containing compounds (Cho):Cr ratio within the bilateral prefrontal cortex and ACC. Using hierarchical multiple regression analysis, we analyzed the relationship between cognitive function and metabolic ratios in the bilateral prefrontal lobe and ACC in patients with PD. Results: In all, 59 patients with PD and 30 HCs were recruited. Patients with PD showed worse performance in executive function and processing speed compared with HCs (P<0.001). In patients with PD, the Cho:Cr ratios in the ACC (Z=2.20, P=0.028) and the right prefrontal cortex (t=2.16, P=0.034) were significantly increased. The hierarchical multiple regressions in patients with PD showed that the NAA:Cr ratio in the ACC correlated with the Stroop A completion times (P<0.05) and that the NAA:Cr ratio of the right prefrontal cortex correlated with the scores of the Wechsler Adult Intelligence Scale (WAIS)-Digit symbol test (P<0.05). Conclusions: Information processing speed and executive function are impaired in patients with PD. Neuronal integrity and membrane turnover in the ACC and the right prefrontal cortex may be important factors in the slowdown of the information processing speed in patients with PD.