Glial growth factor 2 treatment alleviates ischemia and reperfusion-damaged integrity of the blood-brain barrier through decreasing Mfsd2a/caveolin-1-mediated transcellular and Pdlim5/YAP/TAZ-mediated paracellular permeability.

The impairment of blood-brain barrier (BBB) integrity is the pathological basis of hemorrhage transformation and vasogenic edema following thrombolysis and endovascular therapy. There is no approved drug in the clinic to reduce BBB damage after acute ischemic stroke (AIS). Glial growth factor 2 (GGF2), a recombinant version of neuregulin-1ß that can stimulates glial cell proliferation and differentiation, has been shown to alleviate free radical release from activated microglial cells. We previously found that activated microglia and proinflammatory factors could disrupt BBB after AIS. In this study we investigated the effects of GGF2 on AIS-induced BBB damage as well as the underlying mechanisms. Mouse middle cerebral artery occlusion model was established: mice received a 90-min ischemia and 22.5 h reperfusion (I/R), and were treated with GGF2 (2.5, 12.5, 50 ng/kg, i.v.) before the reperfusion. We showed that GGF2 treatment dose-dependently decreased I/R-induced BBB damage detected by Evans blue (EB) and immunoglobulin G (IgG) leakage, and tight junction protein occludin degradation. In addition, we found that GGF2 dose-dependently reversed AIS-induced upregulation of vesicular transcytosis increase, caveolin-1 (Cav-1) as well as downregulation of major facilitator superfamily domain containing 2a (Mfsd2a). Moreover, GGF2 decreased I/R-induced upregulation of PDZ and LIM domain protein 5 (Pdlim5), an adaptor protein that played an important role in BBB damage after AIS. In addition, GGF2 significantly alleviated I/R-induced reduction of YAP and TAZ, microglial cell activation and upregulation of inflammatory factors. Together, these results demonstrate that GGF2 treatment alleviates the I/R-compromised integrity of BBB by inhibiting Mfsd2a/Cav-1-mediated transcellular permeability and Pdlim5/YAP/TAZ-mediated paracellular permeability.

Application Value of Serum Neurofilament Light Protein for Disease Staging in Huntington's Disease.

BACKGROUND: Neurofilament light protein (NfL) has been proven to be a sensitive biomarker for Huntington's disease (HD). However, these studies did not include HD patients at advanced stages or with larger CAG repeats (>50), leading to a knowledge gap of the characteristics of NfL. METHODS: Serum NfL (sNfL) levels were quantified using an ultrasensitive immunoassay. Participants were assessed by clinical scales and 7.0 T magnetic resonance imaging. Longitudinal samples and clinical data were obtained. RESULTS: Baseline samples were available from 110 controls, 90 premanifest HD (pre-HD) and 137 HD individuals. We found levels of sNfL significantly increased in HD compared to pre-HD and controls (both P < 0.0001). The increase rates of sNfL were differed by CAG repeat lengths. However, there was no difference in sNfL levels in manifest HD from early to late stages. In addition, sNfL levels were associated with cognitive measures in pre-HD and manifest HD group, respectively. The increased levels of sNfL were also closely related to microstructural changes in white matter. In the longitudinal analysis, baseline sNfL did not correlate with subsequent clinical function decline. Random forest analysis revealed that sNfL had good power for predicting disease onset. CONCLUSIONS: Although sNfL levels are independent of disease stages in manifest HD, it is still an optimal indicator for predicting disease onset and has potential use as a surrogate biomarker of treatment effect in clinical trials. © 2023 International Parkinson and Movement Disorder Society.

Multi-omics Analysis Reveals Key Gut Microbiota and Metabolites Closely Associated with Huntington's Disease.

Dysbiosis of the gut microbiota is closely associated with neurodegenerative diseases, including Huntington's disease (HD). Gut microbiome-derived metabolites are key factors in host-microbiome interactions. This study aimed to investigate the crucial gut microbiome and metabolites in HD and their correlations. Fecal and serum samples from 11 to 26 patients with HD, respectively, and 16 and 23 healthy controls, respectively, were collected. The fecal samples were used for shotgun metagenomics while the serum samples for metabolomics analysis. Integrated analysis of the metagenomics and metabolomics data was also conducted. Firmicutes, Bacteroidota, Proteobacteria, Uroviricota, Actinobacteria, and Verrucomicrobia were the dominant phyla. At the genus level, the presence of Bacteroides, Faecalibacterium, Parabacteroides, Alistipes, Dialister, and Christensenella was higher in HD patients, while the abundance of Lachnospira, Roseburia, Clostridium, Ruminococcus, Blautia, Butyricicoccus, Agathobaculum, Phocaeicola, Coprococcus, and Fusicatenibacter decreased. A total of 244 differential metabolites were identified and found to be enriched in the glycerophospholipid, nucleotide, biotin, galactose, and alpha-linolenic acid metabolic pathways. The AUC value from the integrated analysis (1) was higher than that from the analysis of the gut microbiota (0.8632). No significant differences were found in the ACE, Simpson, Shannon, Sobs, and Chao indexes between HD patients and controls. Our study determined crucial functional gut microbiota and potential biomarkers associated with HD pathogenesis, providing new insights into the role of the gut microbiota-brain axis in HD occurrence and development.

The Chinese Version of UHDRS in Huntington's Disease: Reliability and Validity Assessment.

BACKGROUND: The Unified Huntington's Disease Rating Scale (UHDRS) is a universal scale assessing disease severity of Huntington's disease (HD). However, the English version cannot be widely used in China, and the reliability and validity of the Chinese UHDRS have not yet been confirmed. OBJECTIVE: To test the reliability and validity of Chinse UHDRS in patients with HD. METHODS: Between August 2013 and August 2021, 159 HD patients, 40 premanifest HD, and 64 healthy controls were consecutively recruited from two medical centers in China and assessed by Chinese UHDRS. Internal consistency and interrater reliability of the scale were examined. Intercorrelation was performed to analyze the convergent and divergent validity of the scale. A receiver operating characteristic analysis was conducted to explore the optimal cutoff point of each cognitive test. RESULTS: High internal consistency was found in Chinese UHDRS, and its Cronbach's alpha values of the motor, cognitive, behavioral and functional subscales were 0.954, 0.826, 0.804, and 0.954, respectively. The interrater reliability of the total motor score was 0.960. The convergent and divergent validity revealed that motor, cognitive and functional subscales strongly related to each other except for Problem Behavior Assessment. Furthermore, we not only provided the normal level of each cognitive test in controls, but also gave the optimal cutoff points of cognitive tests between controls and HD patients. CONCLUSION: We demonstrate for the first time that the translated version of UHDRS is reliable for assessing HD patients in China. This can promote the universal use of UHDRS in clinical practice.

Comparative study of two Chinese versions of Montreal Cognitive Assessment for Screening of Mild Cognitive Impairment.

Our aim was to compare the utility and accuracy of the Chinese Version of Montreal Cognitive Assessment Basic (MoCA-BC) and the Montreal Cognitive Assessment-Beijing Version (MoCA-BJ) in the identification of mild cognitive impairment (MCI) under different education levels. A sample of individuals with MCI (n = 295), Alzheimer's disease (AD; n = 254), and normal controls (NC; n = 259) at 2 Memory Clinics and communities was administered the MoCA-BC, MoCA-BJ, Mini-Mental State Examination (MMSE), and other neuropsychological tests. The discriminant validity of the MoCA-BC and MoCA-BJ as diagnostic instruments was ascertained. The overall discriminant validity for detection of MCI from NC (receiver operating characteristic area under the curve [95% confidence interval]) was that the MoCA-BC (0.95 [0.93, 0.97]) had better sensitivity and accuracy than MoCA-BJ (0.87 [0.84, 0.90]). In addition, we provide an easy to use table that enables the conversion of MoCA-BC to the MoCA-BJ scores or to MMSE scores. The MoCA-BC and MoCA-BJ provided good diagnostic accuracy when compared to MMSE. The MoCA-BC, which was proved to be an appropriate tool when screening for MCI among elderly subjects, can now be compared directly with the MoCA-BJ.

miR-30b protects nigrostriatal dopaminergic neurons from MPP(+)-induced neurotoxicity via SNCA.

OBJECTIVE: To explore the function of miR-30b in pathogenesis of Parkinson's disease (PD) and its underlying molecular mechanism. MATERIALS AND METHODS: We used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPP(+)) as a tool for constructing the PD cell model, using miR-30b mimics or inhibitors to manipulate miR-30b level for an experimental model of acquisition. The cell viability of SH-SY5Y was detected by CCK, and luciferase was used to screen the binding of target genes. The protein levels of SNCA were measured by Western blot. Then, we investigate the changes in pro- and anti-apoptotic markers with or without miR-30b treatment. RESULTS: There was a significant low expression of MiR-30b in MPP(+)-induced cells. SH-SY5Y cell viability was rescued by MiR-30b overexpression. Luciferase experiments showed that MiR-30b may bind to the 3'-UTR side of SNCA and inhibited its expression. By Western blot, the SNCA level was markedly decreased by miR-30b. miR-30b attenuated the upregulation of Bax and the depletion of Bcl-2 induced by MPP(+).