Noncanonical regulation of HOIL-1 on cancer stemness and sorafenib resistance identifies pixantrone as a novel therapeutic agent for HCC.

BACKGROUND AND AIMS: Cancer stem cells (CSCs) contribute to therapy resistance in HCC. Linear ubiquitin chain assembly complex (LUBAC) has been reported to accelerate the progression of cancers, yet its role in the sorafenib response of HCC is poorly defined. Herein, we investigated the impact of LUBAC on sorafenib resistance and the CSC properties of HCC, and explored the potential targeted drugs. APPROACH AND RESULTS: We found that HOIL-1, but not the other components of LUBAC, played a contributing role in LUBAC-mediated HCC sorafenib resistance, independent of its ubiquitin ligase activity. Both in vitro and in vivo assays revealed that the upregulated HOIL-1 expression enhanced the CSC properties of HCC. Mechanistically, HOIL-1 promoted sorafenib resistance and the CSC properties of HCC through Notch1 signaling. Mass spectrometry, co-immunoprecipitation, western blot, and immunofluorescence were used to determine that the A64/Q65 residues of HOIL-1 bound with the K78 residue of Numb, resulting in impaired Numb-mediated Notch1 lysosomal degradation. Notably, pixantrone was screened out by Autodock Vina, which was validated to disrupt HOIL-1/Numb interaction to inhibit Notch1 signaling and CSC properties by targeting the Q65 residue of HOIL-1. Moreover, pixantrone exerted synergistic effects with sorafenib for the treatment of HCC in different HCC mouse models. CONCLUSIONS: HOIL-1 is critical in promoting sorafenib resistance and CSC properties of HCC through Notch1 signaling. Pixantrone targeting HOIL-1 restrains the sorafenib resistance and provides a potential therapeutic intervention for HCC.

Clinical features of progressive supranuclear palsy.

Background: Progressive supranuclear palsy (PSP) is a clinically heterogenous atypical parkinsonian syndrome. Therefore, early recognition and correct diagnosis of PSP is challenging but essential. This study aims to characterize the clinical manifestations, magnetic resonance imaging (MRI), and longitudinal MRI changes of PSP in China. Method: Clinical and MRI presentations were compared among 150 cases with PSP. Then the longitudinal MRI changes among 20 patients with PSP were further explored. Additionally, a series of midbrain-based MRI parameters was compared between PSP-P and PD. Results: Throughout the course of the disease, there were differences in the symptoms of the fall and hand tremor between the PSP-RS and PSP-P. There were significant differences in the six midbrain-based MRI parameters between the PSP-RS and the PSP-P, including hummingbird sign, midbrain diameter, midbrain to pons ratio (MTPR), midbrain area, midbrain area to pons area ratio (Ma/Pa), and midbrain tegmental length (MBTegm). Longitudinal MRI studies revealed that the annual rel.ΔMTPR and rel.Δ (Ma/Pa) for PSP were 5.55 and 6.52%, respectively; additionally, PSP-RS presented a higher decline rate than PSP-P. Moreover, MTPR ≤0.56, midbrain diameter ≤ 0.92, midbrain area ≤ 1.00, and third ventricle width ≤ 0.75 could identify PSP-P from PD. Conclusion: PSP-P differs from PSP-RS regarding clinical manifestations, MRI, and longitudinal MRI changes. MRI parameters could be potential imaging markers to identify PSP-P from PD.

Highly sensitive and broadband meta-mechanoreceptor via mechanical frequency-division multiplexing.

Bio-mechanoreceptors capable of micro-motion sensing have inspired mechanics-guided designs of micro-motion sensors in various fields. However, it remains a major challenge for mechanics-guided designs to simultaneously achieve high sensitivity and broadband sensing due to the nature of resonance effect. By mimicking rat vibrissae, here we report a metamaterial mechanoreceptor (MMR) comprised of piezoelectric resonators with distributed zero effective masses featuring a broad range of local resonances, leading to near-infinite sensitivity for micro-motion sensing within a broad bandwidth. We developed a mechanical frequency-division multiplexing mechanism for MMR, in which the measured micro-motion signal is mechanically modulated in non-overlapping frequency bands and reconstructed by a computational multi-channel demodulation approach. The maximum sensitivity of MMR is improved by two orders of magnitude compared to conventional mechanics-guided mechanoreceptors, and its bandwidth with high sensitivity is extendable towards both low-frequency and high-frequency ranges in 0-12 kHz through tuning the local resonance of each individual sensing cell. The MMR is a promising candidate for highly sensitive and broadband micro-motion sensing that was previously inaccessible for mechanics-guided mechanoreceptors, opening pathways towards spatio-temporal sensing, remote-vibration monitoring and smart-driving assistance.

Characteristics of autonomic dysfunction in neuronal intranuclear inclusion disease.

Background: This study aimed to investigate the features of autonomic dysfunction (AutD) in a large cohort of patients with neuronal intranuclear inclusion disease (NIID). Methods: A total of 122 patients with NIID and 122 controls were enrolled. All participants completed the Scales for Outcomes in Parkinson's Disease-Autonomic Questionnaire (SCOPA-AUT) and genetic screening for GGC expanded repeats within the NOTCH2NLC gene. All patients underwent neuropsychological and clinical assessments. SCOPA-AUT was performed to compare AutD between patients and controls. The associations between AutD and disease-related characteristics of NIID were studied. Results: 94.26% of patients had AutD. Compared with controls, patients had more severe AutD in total SCOPA-AUT, gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillomotor and sexual domains (all p < 0.05). The area under the curve (AUC) value for the total SCOPA-AUT (AUC = 0.846, sensitivity = 69.7%, specificity = 85.2%, cutoff value = 4.5) was high in differentiating AtuD of patients with NIID from controls. The total SCOPA-AUT was significantly and positively associated with age (r = 0.185, p = 0.041), disease duration (r = 0.207, p = 0.022), Neuropsychiatric Inventory (NPI) (r = 0.446, p < 0.01), and Activities of Daily Living (ADL) (r = 0.390, p < 0.01). Patients with onset-of-AutD had higher SCOPA-AUT scores than patients without onset-of-AutD (p < 0.001), especially in the urinary system (p < 0.001) and male sexual dysfunction (p < 0.05). Conclusion: SCOPA-AUT can be used as a diagnostic and quantitative tool for autonomic dysfunction in NIID. The high prevalence of AutD in patients suggests that NIID diagnosis should be considered in patients with AutD, especially in those with unexplained AutD alone. AutD in patients is related to age, disease duration, impairment of daily living ability, and psychiatric symptoms.

Mendelian randomization analyses of smoking and Alzheimer's disease in Chinese and Japanese populations.

Background: Previous epidemiological studies have reported controversial results on the relationship between smoking and Alzheimer's disease (AD). Therefore, we sought to assess the association using Mendelian randomization (MR) analysis. Methods: We used single nucleotide polymorphisms (SNPs) associated with smoking quantity (cigarettes per day, CPD) from genome-wide association studies (GWAS) of Japanese population as instrumental variables, then we performed two-sample MR analysis to investigate the association between smoking and AD in a Chinese cohort (1,000 AD cases and 500 controls) and a Japanese cohort (3,962 AD cases and 4,074 controls), respectively. Results: Genetically higher smoking quantity showed no statistical causal association with AD risk (the inverse variance weighted (IVW) estimate in the Chinese cohort: odds ratio (OR) = 0.510, 95% confidence interval (CI) = 0.149-1.744, p = 0.284; IVW estimate in the Japanese cohort: OR = 1.170, 95% confidence interval CI = 0.790-1.734, p = 0.434). Conclusion: This MR study, for the first time in Chinese and Japanese populations, found no significant association between smoking and AD.

Brain-derived extracellular vesicles promote bone-fat imbalance in Alzheimer's disease.

Inadequate osteogenesis and excessive adipogenesis of bone marrow mesenchymal stem cells (BMSCs) are key factors in the pathogenesis of osteoporosis. Patients with Alzheimer's disease (AD) have a higher incidence of osteoporosis than healthy adults, but the underlying mechanism is not clear. Here, we show that brain-derived extracellular vesicles (EVs) from adult AD or wild-type mice can cross the blood-brain barrier to reach the distal bone tissue, while only AD brain-derived EVs (AD-B-EVs) significantly promote the shift of the BMSC differentiation fate from osteogenesis to adipogenesis and induce a bone-fat imbalance. MiR-483-5p is highly enriched in AD-B-EVs, brain tissues from AD mice, and plasma-derived EVs from AD patients. This miRNA mediates the anti-osteogenic, pro-adipogenic, and pro-osteoporotic effects of AD-B-EVs by inhibiting Igf2. This study identifies the role of B-EVs as a promoter of osteoporosis in AD by transferring miR-483-5p.

African swine fever virus I73R is a critical virulence-related gene: A potential target for attenuation.

African swine fever virus (ASFV) is a large, double-stranded DNA virus that causes a fatal disease in pigs, posing a threat to the global pig industry. Whereas some ASFV proteins have been found to play important roles in ASFV-host interaction, the functional roles of many proteins are still largely unknown. In this study, we identified I73R, an early viral gene in the replication cycle of ASFV, as a key virulence factor. Our findings demonstrate that pI73R suppresses the host innate immune response by broadly inhibiting the synthesis of host proteins, including antiviral proteins. Crystallization and structural characterization results suggest that pI73R is a nucleic-acid-binding protein containing a Zα domain. It localizes in the nucleus and inhibits host protein synthesis by suppressing the nuclear export of cellular messenger RNA (mRNAs). While pI73R promotes viral replication, the deletion of the gene showed that it is a nonessential gene for virus replication. In vivo safety and immunogenicity evaluation results demonstrate that the deletion mutant ASFV-GZΔI73R is completely nonpathogenic and provides effective protection to pigs against wild-type ASFV. These results reveal I73R as a virulence-related gene critical for ASFV pathogenesis and suggest that it is a potential target for virus attenuation. Accordingly, the deletion mutant ASFV-GZΔI73R can be a potent live-attenuated vaccine candidate.

Neural biomarker diagnosis and prediction to mild cognitive impairment and Alzheimer's disease using EEG technology.

BACKGROUND: Electroencephalogram (EEG) has emerged as a non-invasive tool to detect the aberrant neuronal activity related to different stages of Alzheimer's disease (AD). However, the effectiveness of EEG in the precise diagnosis and assessment of AD and its preclinical stage, amnestic mild cognitive impairment (MCI), has yet to be fully elucidated. In this study, we aimed to identify key EEG biomarkers that are effective in distinguishing patients at the early stage of AD and monitoring the progression of AD. METHODS: A total of 890 participants, including 189 patients with MCI, 330 patients with AD, 125 patients with other dementias (frontotemporal dementia, dementia with Lewy bodies, and vascular cognitive impairment), and 246 healthy controls (HC) were enrolled. Biomarkers were extracted from resting-state EEG recordings for a three-level classification of HC, MCI, and AD. The optimal EEG biomarkers were then identified based on the classification performance. Random forest regression was used to train a series of models by combining participants' EEG biomarkers, demographic information (i.e., sex, age), CSF biomarkers, and APOE phenotype for assessing the disease progression and individual's cognitive function. RESULTS: The identified EEG biomarkers achieved over 70% accuracy in the three-level classification of HC, MCI, and AD. Among all six groups, the most prominent effects of AD-linked neurodegeneration on EEG metrics were localized at parieto-occipital regions. In the cross-validation predictive analyses, the optimal EEG features were more effective than the CSF + APOE biomarkers in predicting the age of onset and disease course, whereas the combination of EEG + CSF + APOE measures achieved the best performance for all targets of prediction. CONCLUSIONS: Our study indicates that EEG can be used as a useful screening tool for the diagnosis and disease progression evaluation of MCI and AD.

GSN gene frameshift mutations in Alzheimer's disease.

BACKGROUND: The pathogenic missense mutations of the gelsolin (GSN) gene lead to familial amyloidosis of the Finnish type (FAF); however, our previous study identified GSN frameshift mutations existed in patients with Alzheimer's disease (AD). The GSN genotype-phenotype heterogeneity and the role of GSN frameshift mutations in patients with AD are unclear. METHOD: In total, 1192 patients with AD and 1403 controls were screened through whole genome sequencing, and 884 patients with AD were enrolled for validation. Effects of GSN mutations were evaluated in vitro. GSN, Aß42, Aß40 and Aß42/40 were detected in both plasma and cerebrospinal fluid (CSF). RESULTS: Six patients with AD with GSN P3fs and K346fs mutations (0.50%, 6/1192) were identified, who were diagnosed with AD but not FAF. In addition, 13 patients with AD with GSN frameshift mutations were found in the validation cohort (1.47%, 13/884). Further in vitro experiments showed that both K346fs and P3fs mutations led to the GSN loss of function in inhibiting Aß-induced toxicity. Moreover, a higher level of plasma (p=0.001) and CSF (p=0.005) GSN was observed in AD cases than controls, and a positive correlation was found between the CSF GSN and CSF Aß42 (r=0.289, p=0.009). Besides, the GSN level was initially increasing and then decreasing with the disease course and cognitive decline. CONCLUSIONS: GSN frameshift mutations may be associated with AD. An increase in plasma GSN is probably a compensatory reaction in AD, which is a potential biomarker for early AD.

The associations of APP, PSEN1, and PSEN2 genes with Alzheimer's disease: A large case-control study in Chinese population.

AIM: The associations of non-pathogenic variants of APP, PSEN1, and PSEN2 with Alzheimer's disease (AD) remain unclear. This study is aimed at determining the role of these variants in AD. METHODS: Our study recruited 1154 AD patients and 2403 controls. APP, PSEN1, PSEN2, and APOE were sequenced using a targeted panel. Variants were classified into common or rare variants with the minor allele frequencies (MAF) cutoff of 0.01. Common variant (MAF≥0.01)-based association test was performed by PLINK 1.9, and gene-based (MAF <0.01) association analysis was conducted using Sequence Kernel Association Test-Optimal (SKAT-O test). Additionally, using PLINK 1.9, we performed AD endophenotypes association studies. RESULTS: A common variant, PSEN2 rs11405, was suggestively associated with AD risk (p = 1.08 × 10-2 ). The gene-based association analysis revealed that the APP gene exhibited a significant association with AD (p = 1.43 × 10-2 ). In the AD endophenotypes association studies, APP rs459543 was nominally correlated with CSF Aß42 level (p = 7.91 × 10-3 ). CONCLUSION: Our study indicated that non-pathogenic variants in PSEN2 and APP may be involved in AD pathogenesis in the Chinese population.

Age of onset correlates with clinical characteristics and prognostic outcomes in neuromyelitis optica spectrum disorder.

Objective: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease preferentially affects the optic nerve and the spinal cord. The first attack usually occurs in the third or fourth decade, though patients with disease onset in the fifties or later are not uncommon. This study aimed to investigate the clinical characteristics and prognosis in patients with different age of onset and to explore the correlations between age of onset and clinical characteristics and prognostic outcomes. Method: We retrospectively reviewed the medical records of 298 NMOSD patients diagnosed according to the 2015 updated version of diagnostic criteria. Patients were divided into early-onset NMOSD (EO-NMOSD) (<50 years at disease onset) and late-onset NMOSD (LO-NMOSD) (≥50 years at disease onset) based on the age of disease onset. LO-NMOSD patients were divided into two subgroups: relative-late-onset NMOSD (RLO-NMOSD) (50~70 years at disease onset) and very-late-onset NMOSD (≥70 years at disease onset). Clinical characteristics, laboratory findings, neuroimaging features, and prognostic outcomes were investigated. Results: Compared to EO-NMOSD patients, patients with LO-NMOSD showed more frequent transverse myelitis (TM) (58.20% vs. 36.00%, p = 0.007) while less frequent optic neuritis (ON) (23.10% vs. 34.80%, p = 0.031) and brainstem/cerebral attacks (7.50% vs. 18.30%, p = 0.006) as the first attack. Patients with LO-NMOSD showed less frequent relapses, higher Expanded Disability Status Scale (EDSS) score at the last follow-up, fewer NMOSD-typical brain lesions, and longer segments of spinal cord lesions. Patients with older onset age showed a higher proportion of increased protein levels in cerebrospinal fluid during the acute phase of attacks. Age at disease onset positively correlated with length of spinal cord lesions at first attack and at last follow-up, negatively correlated with ARR-1 (ARR excluding the first attack, calculated from disease onset to final follow-up), irrespective of AQP4-IgG serostatus. Patients with older age at disease onset progressed to severe motor disability sooner, and age of onset positively correlated with EDSS score at the last follow-up, irrespective of AQP4-IgG serostatus. Conclusion: Age of disease onset affects clinical characteristics and prognosis outcomes of patients with NMOSD.

Consistency analysis and conversion model establishment of mini-mental state examination and montreal cognitive assessment in Chinese patients with Alzheimer's disease.

Background: The Chinese version of the Mini-Mental State Examination (MMSE-C) and the Beijing version of the Montreal Cognitive Assessment (MoCA-BJ) are the most commonly used scales to screen for Alzheimer's disease (AD) among Chinese patients; however, their consistency varies according to populations and languages. Equivalent conversion of MMSE-C and MoCA-BJ scores is important for meta-analysis. Materials and methods: MMSE-C and MoCA-BJ scoring were performed on the enrolled patients with AD (n = 332). Consistency analysis of MMSE-C and MoCA-BJ scores of patients in the conversion groups was performed. The circle-arc method was used to convert the MMSE-C scores of the conversion groups into MoCA-BJ scores, and the conversion formula was generated. The MMSE-C data of the verification group was converted to MoCA-BJ according to the formula, and the consistency analysis of the original MoCA-BJ of the verification group and the converted MoCA-BJ was performed to verify the conversion model. Results: The results of the consistency analysis of MMSE-C and MoCA-BJ in group A showed that the correlation coefficients of the total group, high education years subgroup, medium education years subgroup, and low education years subgroup were 0.905 (P < 0.001), 0.874 (P < 0.001), 0.949 (P < 0.001), and 0.874 (P < 0.001), respectively, with high consistency and statistical significance. After applying the circle-arc method for equivalent conversion, the consistency analysis results of the original and the converted MoCA-BJ of the patients in group B of the total group, high education years subgroup, medium education years subgroup, and low education years subgroup were 0.891 (P < 0.001), 0.894 (P < 0.001), 0.781 (P < 0.001), 0.909 (P < 0.001), respectively, with high consistency and statistical significance. Conclusion: We established and validated a model of MMSE-C and MoCA-BJ score conversion for Chinese patients with AD using the circle-arc method. This model could be useful for multi-centers clinical trials and meta-analysis.

Clinical characteristics and genotype-phenotype correlation analysis of familial Alzheimer's disease patients with pathogenic/likely pathogenic amyloid protein precursor mutations.

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with aging, environmental, and genetic factors. Amyloid protein precursor (APP) is a known pathogenic gene for familial Alzheimer's disease (FAD), and now more than 70 APP mutations have been reported, but the genotype-phenotype correlation remains unclear. In this study, we collected clinical data from patients carrying APP mutations defined as pathogenic/likely pathogenic according to the American college of medical genetics and genomics (ACMG) guidelines. Then, we reanalyzed the clinical characteristics and identified genotype-phenotype correlations in APP mutations. Our results indicated that the clinical phenotypes of APP mutations are generally consistent with typical AD despite the fact that they show more non-demented symptoms and neurological symptoms. We also performed genotype-phenotype analysis according to the difference in APP processing caused by the mutations, and we found that there were indeed differences in onset age, behavioral and psychological disorders of dementia (BPSD) and myoclonus.

Macular Microvascular Density as a Diagnostic Biomarker for Alzheimer's Disease.

BACKGROUND: Some previous studies showed abnormal pathological and vascular changes in the retina of patients with Alzheimer's disease (AD). However, whether retinal microvascular density is a diagnostic indicator for AD remains unclear. OBJECTIVE: This study evaluated the macular vessel density (m-VD) in the superficial capillary plexus and fovea avascular zone (FAZ) area in AD, explored their correlations with clinical parameters, and finally confirmed an optimal machine learning model for AD diagnosis. METHODS: 77 patients with AD and 145 healthy controls (HCs) were enrolled. The m-VD and the FAZ area were measured using optical coherence tomography angiography (OCTA) in all participants. Additionally, AD underwent neuropsychological assessment, brain magnetic resonance imaging scan, cerebrospinal fluid (CSF) biomarker detection, and APOE ɛ4 genotyping. Finally, the performance of machine learning algorithms based on the OCTA measurements was evaluated by Python programming language. RESULTS: The m-VD was noticeably decreased in AD compared with HCs. Moreover, m-VD in the fovea, superior inner, inferior inner, nasal inner subfields, and the whole inner ring declined significantly in mild AD, while it was more serious in moderate/severe AD. However, no significant difference in the FAZ was noted between AD and HCs. Furthermore, we found that m-VD exhibited a significant correlation with cognitive function, medial temporal atrophy and Fazekas scores, and APOE ɛ4 genotypes. No significant correlations were observed between m-VD and CSF biomarkers. Furthermore, results revealed the Adaptive boosting algorithm exhibited the best diagnostic performance for AD. CONCLUSION: Macular vascular density could serve as a diagnostic biomarker for AD.

Machine learning based on Optical Coherence Tomography images as a diagnostic tool for Alzheimer's disease.

AIMS: We mainly evaluate retinal alterations in Alzheimer's disease (AD) patients, investigate the associations between retinal changes with AD biomarkers, and explore an optimal machine learning (ML) model for AD diagnosis based on retinal thickness. METHODS: A total of 159 AD patients and 299 healthy controls were enrolled. The retinal parameters of each participant were measured using optical coherence tomography (OCT). Additionally, cognitive impairment severity, brain atrophy, and cerebrospinal fluid (CSF) biomarkers were measured in AD patients. RESULTS: AD patients demonstrated a significant decrease in the average, superior, and inferior quadrant peripapillary retinal nerve fiber layer, macular retinal nerve fiber layer, ganglion cell layer (GCL), inner plexiform layer (IPL) thicknesses, as well as total macular volume (TMV) (all p < 0.05). Moreover, TMV was positively associated with Mini-Mental State Examination and Montreal Cognitive Assessment scores, IPL thickness was correlated negatively with the medial temporal lobe atrophy score, and the GCL thickness was positively correlated with CSF Aß42 /Aß40 and negatively associated with p-tau level. Based on the significantly decreased OCT variables between both groups, the XGBoost algorithm exhibited the best diagnostic performance for AD, whose four references, including accuracy, area under the curve, f1 score, and recall, ranged from 0.69 to 0.74. Moreover, the macular retinal thickness exhibited an absolute superiority for AD diagnosis compared with other enrolled variables in all ML models. CONCLUSION: We identified the retinal alterations in AD patients and found that macular thickness and volume were associated with AD severity and biomarkers. Furthermore, we confirmed that OCT combined with ML could serve as a potential diagnostic tool for AD.

Protection Evaluation of a Five-Gene-Deleted African Swine Fever Virus Vaccine Candidate Against Homologous Challenge.

African swine fever virus (ASFV) represents a serious threat to the global swine industry, and there are no safe or commercially available vaccines. Previous studies have demonstrated that inactivated vaccines do not provide sufficient protection against ASFV and that attenuated vaccines are effective, but raise safety concerns. Here, we first constructed a deletion mutant in which EP153R and EP402R gene clusters were knocked out. Based on the deletion mutant, a further deletion from the MGF_360-12L, MGF_360-13L to MGF_360-14L genes was obtained. The five-genes knockout virus was designated as ASFV-ΔECM3. To investigate the efficacy and safety of the ASFV-ΔECM3 virus as a vaccine candidate, the evaluation of the virus was subsequently carried out in pigs. The results showed that the ASFV-ΔECM3 virus could induce homologous protection against the parental isolate, and no significant clinical signs or viremia were observed. These results show that the contiguous deletion mutant, ASFV-ΔECM3 encompassing the EP153R/EP402R and MGF_360-12L/13L/14L genes, could be a potential live-attenuated vaccine candidate for the prevention of ASFV infection.

Associations of multiple visual rating scales based on structural magnetic resonance imaging with disease severity and cerebrospinal fluid biomarkers in patients with Alzheimer's disease.

The relationships between multiple visual rating scales based on structural magnetic resonance imaging (sMRI) with disease severity and cerebrospinal fluid (CSF) biomarkers in patients with Alzheimer's disease (AD) were ambiguous. In this study, a total of 438 patients with clinically diagnosed AD were recruited. All participants underwent brain sMRI scan, and medial temporal lobe atrophy (MTA), posterior atrophy (PA), global cerebral atrophy-frontal sub-scale (GCA-F), and Fazekas rating scores were visually evaluated. Meanwhile, disease severity was assessed by neuropsychological tests such as the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Clinical Dementia Rating (CDR). Among them, 95 patients were tested for CSF core biomarkers, including Aß1-42, Aß1-40, Aß1-42/Aß1-40, p-tau, and t-tau. As a result, the GCA-F and Fazekas scales showed positively significant correlations with onset age (r = 0.181, p < 0.001; r = 0.411, p < 0.001, respectively). Patients with late-onset AD (LOAD) showed higher GCA-F and Fazekas scores (p < 0.001, p < 0.001). With regard to the disease duration, the MTA and GCA-F were positively correlated (r = 0.137, p < 0.05; r = 0.106, p < 0.05, respectively). In terms of disease severity, a positively significant association emerged between disease severity and the MTA, PA GCA-F, and Fazekas scores (p < 0.001, p < 0.001, p < 0.001, p < 0.05, respectively). Moreover, after adjusting for age, gender, and APOE alleles, the MTA scale contributed to moderate to severe AD in statistical significance independently by multivariate logistic regression analysis (p < 0.05). The model combining visual rating scales, age, gender, and APOE alleles showed the best performance for the prediction of moderate to severe AD significantly (AUC = 0.712, sensitivity = 51.5%, specificity = 84.6%). In addition, we observed that the MTA and Fazekas scores were associated with a lower concentration of Aß1-42 (p < 0.031, p < 0.022, respectively). In summary, we systematically analyzed the benefits of multiple visual rating scales in predicting the clinical status of AD. The visual rating scales combined with age, gender, and APOE alleles showed best performance in predicting the severity of AD. MRI biomarkers in combination with CSF biomarkers can be used in clinical practice.

CYLD variants identified in Alzheimer's disease and frontotemporal dementia patients.

OBJECTIVES: CYLD was a novel causative gene for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis. Given the clinical and pathological overlap of FTD and Alzheimer's disease (AD), it is necessary to screen CYLD in AD patients and FTD patients in the Chinese population. METHODS: In our study, using a targeted sequencing panel, we sequenced the CYLD gene in a large cohort of 2485 participants in the Chinese population, including 1008 AD patients, 105 FTD patients, and 1372 controls. RESULTS: In the present study, the average onset age of AD and FTD patients was 66.84 ± 30.42 years old and 60 ± 10.00 years old, respectively. Our study reported three novel CYLD variants: p.Phe288Leu (patient No. 1, AD), p.Tyr485Phe (patients No. 6-9, all AD) and p.Thr951Ala (patient No. 10, AD), plus a previously reported variant: p.Arg397Ser (patient No. 2-5, AD and No. 11, FTD). These variants were absent in our in-house controls and predicted to be deleterious according to the MutationTaster. The variant carriers were composed of 10 AD patients and one FTD patient, and the average onset age was 61.2 ± 10.9 years. The frequency of CYLD variants in AD was similar to that in FTD, which was 0.99% (10/1008) and 0.95% (1/105), respectively. INTERPRETATION: Our finding extended the genotype and phenotype of the CYLD gene and demonstrated that CYLD rare damaging variants may be implicated in AD and FTD pathogenesis.

Genetics of progressive supranuclear palsy in a Chinese population.

BACKGROUND: Genetics plays an important role in progressive supranuclear palsy (PSP) and remains poorly understood. A detailed literature search identified 19 PSP-associated genes: MAPT, LRRK2, LRP10, DCTN1, GRN, NPC1, PARK, TARDBP, TBK1, BSN, GBA, STX6, EIF2AK3, MOBP, DUSP10, SLCO1A2, RUNX2, CXCR4, and APOE. To date, genetic studies on PSP have focused on Caucasian population. The gaps in PSP genetic study on East Asian populations need to be filled. METHODS: Exon and flanking regions of the PSP-associated genes were sequenced in 104 patients with PSP and 488 healthy controls. Common variant-based association analysis and gene-based association tests of rare variants were performed using PLINK 1.9 and the sequence kernel association test-optimal, respectively. Additionally, the association of APOE and MAPT genotypes with PSP was evaluated. The above association analyses were repeated among probable PSP patients. Finally, PLINK 1.9 was used to test variants associated with the onset age of PSP. RESULTS: A rare non-pathogenic variant of MAPT (c.425C > T,p.A142V) was detected in a PSP patient. No common variants were significantly associated with PSP. In both the rare-variant and the rare-damaging-variant groups, the combined effect for GBA reached statistical significance (p = 1.43 × 10-3, p = 4.98 × 10-4). The result between APOE, MAPT genotypes and PSP risk were inconsistent across all PSP group and probably PSP group. CONCLUSIONS: The pathogenic variant in MAPT were uncommon in PSP patients. Moreover, GBA gene was likely to increase the risk of PSP, and GBA-associated diseases were beyond α-synucleinopathies. The association between APOE, MAPT and PSP is still unclear among the non-Caucasian population.

Dynamic mass isolation method utilized in self-moving precision positioning stage for improved speed performance.

The method of dynamic mass isolation is utilized in a self-moving precision positioning stage actuated by a piezostack to increase its moving speed. Two prototypes, namely, the referenced stage and the modified stage, have been fabricated. The only difference between the two stages is the flexure hinge manufactured in the modified stage to achieve an efficient dynamic mass isolation method. The step response has been investigated. The modified stage with dynamic mass isolation presents the average displacement of 6.6 µm with the applied step voltage being 55 V. By contrast, the referenced stage without dynamic mass isolation presents the average displacement of 1.6 µm. As a type of quasi-static piezoactuator/motors, the modified stage moves approximately four times faster than the referenced stage under the same driving frequency. By utilizing the dynamic mass isolation method, the modified stage still features the advantages of the referenced stage, such as cost-effective controllers, heavy-load capability, and motion of nanoscale. The concept and technique presented in this study can be applied to precision positioning stages for improved speed performance.