Speech silence character as a diagnostic biomarker of early cognitive decline and its functional mechanism: a multicenter cross-sectional cohort study.

BACKGROUND: Language deficits frequently occur during the prodromal stages of Alzheimer's disease (AD). However, the characteristics of linguistic impairment and its underlying mechanism(s) remain to be explored for the early diagnosis of AD. METHODS: The percentage of silence duration (PSD) of 324 subjects was analyzed, including patients with AD, amnestic mild cognitive impairment (aMCI), and normal controls (NC) recruited from the China multi-center cohort, and the diagnostic efficiency was replicated from the Pitt center cohort. Furthermore, the specific language network involved in the fragmented speech was analyzed using task-based functional magnetic resonance. RESULTS: In the China cohort, PSD increased significantly in aMCI and AD patients. The area under the curve of the receiver operating characteristic curves is 0.74, 0.84, and 0.80 in the classification of NC/aMCI, NC/AD, and NC/aMCI+AD. In the Pitt center cohort, PSD was verified as a reliable diagnosis biomarker to differentiate mild AD patients from NC. Next, in response to fluency tasks, clusters in the bilateral inferior frontal gyrus, precentral gyrus, left inferior temporal gyrus, and inferior parietal lobule deactivated markedly in the aMCI/AD group (cluster-level P < 0.05, family-wise error (FWE) corrected). In the patient group (AD+aMCI), higher activation level of the right pars triangularis was associated with higher PSD in in both semantic and phonemic tasks. CONCLUSIONS: PSD is a reliable diagnostic biomarker for the early stage of AD and aMCI. At as early as aMCI phase, the brain response to fluency tasks was inhibited markedly, partly explaining why PSD was elevated simultaneously.

Diagnostic Performance of Dynamic Susceptibility Contrast-Enhanced Perfusion-Weighted Imaging in Differentiating Recurrence From Radiation Injury in Postoperative Glioma: A Meta-analysis.

PURPOSE: It is important to differentiate between radiation injury (RI) and tumor recurrence (TR) in patients with glioma after surgery and radiotherapy. Our objective was to evaluate the use of dynamic susceptibility contrast-enhanced perfusion-weighted imaging to distinguish between TR and RI in patients with glioma. METHODS: Relevant studies published until October 2021 were identified in the PubMed, Embase, and Cochrane Library databases. Stata v12.0 and RevMan 5.3 were used for meta-analysis. RESULTS: In total, the meta-analysis incorporated 13 retrospective studies that included 513 patients with 522 lesions. Among the 522 lesions, 329 lesions were TRs and 193 lesions were RIs. The pooled relative cerebral blood volume value was significantly greater in the TR group ( P < 0.00001) with significant heterogeneity ( I2 = 88%). The pooled sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR) were 83% (95 confidence interval [CI], 77%-88%), 85% (95 CI, 77%-91%), 5.60 (95 CI, 3.61-8.70), and 0.20 (95% CI, 0.14-0.27), respectively. The heterogeneity of sensitivity ( I2 = 33.18%), specificity ( I2 = 24.01%), PLR ( I2 = 0.00%), and NLR ( I2 = 6.68%) is not significant. The area under the receiver operating characteristic curve was 0.91 (95% CI, 0.88-0.93). The 3.0 T magnetic resonance imaging, high-grade glioma, and Europe/America patient subgroups showed PLR greater than 5 and NLR less than 0.2. There was no significant indication of publication bias in the analysis ( P = 0.496). CONCLUSIONS: It is concluded that dynamic susceptibility contrast-enhanced perfusion-weighted imaging is effective for the diagnostic differentiation between TR and RI in patients with glioma.

Computed tomography-guided cutting needle biopsy for lung nodules: A comparative study between low-dose and standard dose protocols.

ABSTRACT: We aim to compare the diagnostic accuracy, safety, and radiation exposure between low-dose and standard-dose computed tomography (CT)-guided cutting needle biopsy (CNB) for lung nodules.From January 2016 to August 2017, all consecutive patients admitted with lung nodule underwent low-dose or standard-dose CT-guided CNB procedure in our center. Diagnostic accuracy and radiation dose were compared.A total of 67 and 69 patients who underwent low-dose and standard-dose CT-guided CNB procedure were included in this study. Each patient underwent CT-guided CNB for 1 nodule. The technical success rates were 100% in both groups. The sensitivity, specificity, and overall diagnostic accuracy were 97.7%, 100%, and 98.5% for low-dose group and 91.5%, 100%, and 94.2% for standard-dose group. There was no significant difference in diagnostic accuracy (P = .380) between 2 groups. Pneumothorax was found in 8 and 15 patients in the low-dose and standard-dose groups, respectively (11.9% vs 21.7%, P = .127). Hemoptysis was found in 10 and 10 patients in the low-dose and standard-dose groups, respectively (14.9% vs 14.5%, P = .943). The mean dose-length product was 38.2 ±â€Š17.2 mGy-cm and 375.3 ±â€Š115.7 mGy-cm in the low-dose and standard-dose groups (P < .001). The mean dose-length product was 38.2 ±â€Š17.2 mGy-cm and 375.3 ±â€Š115.7 mGy-cm in the low-dose and standard-dose groups, respectively (P < .001). The mean effective dose was 0.5 ±â€Š0.2 mSv and 5.3 ±â€Š1.6 mSv in the low-dose and standard-dose groups, respectively (P < .001).Low-dose CT-guided CNB of lung nodules significantly decreased radiation dose compared with standard-dose CT. The low-dose protocol could provide similar diagnostic accuracy and safety as standard-dose CT-guided CNB for lung nodules.

Methylene Blue versus Coil-Based Computed Tomography-Guided Localization of Lung Nodules.

BACKGROUND: Preoperative computed tomography (CT)-guided localization has been shown to significantly improve lung nodule video-assisted thoracoscopic surgery (VATS)-based wedge resection technical success rates. However, at present, there was insufficient research regarding the optimal approaches to localization of these nodules prior to resection. We aimed to compare the relative clinical efficacy of preoperative CT-guided methylene blue and coil-based lung nodule localization. METHODS: In total, 91 patients with lung nodules were subjected to either CT-guided methylene blue (n = 34) or coil (n = 57) localization and VATS resection from January 2014 to December 2018. We compared baseline data, localization-associated complication rates, as well as the technical success of localization and resection between these two groups of patients. RESULTS: In total, 42 lung nodules in 34 patients underwent methylene blue localization, with associated localization and wedge resection technical success rates of 97.6 and 97.6%, respectively. A total of 71 lung nodules in 57 patients underwent coil localization, with associated localization and wedge resection technical success rates of 94.4 and 97.2%, respectively. There were no significant differences in technical success rates of localization or wedge resection between these groups (p = 0.416 and 1.000, respectively). The coil group sustained a longer duration between localization and VATS relative to the methylene blue group (13.2 vs. 2.5 hours, p = 0.003). CONCLUSION: Both methylene blue and coil localization can be safely and effectively implemented for conducting the diagnostic wedge resection of lung nodules. The coil-based approach is compatible with a longer period of time between localization and VATS procedures.

High Frequency Repetitive Transcranial Magnetic Stimulation Alleviates Cognitive Impairment and Modulates Hippocampal Synaptic Structural Plasticity in Aged Mice.

Normal aging is accompanied by hippocampus-dependent cognitive impairment, which is a risk factor of Alzheimer's disease. This study aims to investigate the effect of high frequency-repetitive transcranial magnetic stimulation (HF-rTMS) on hippocampus-dependent learning and memory in aged mice and explore its underlying mechanisms. Forty-five male Kunming mice (15 months old) were randomly divided into three groups: aged sham, 5 Hz rTMS, and 25 Hz rTMS. Two sessions of 5 Hz or 25 Hz rTMS comprising 1,000 pulses in 10 trains were delivered once a day for 14 consecutive days. The aged sham group was treated by the reverse side of the coil. In the adult sham group, 15 male Kunming mice (3 months old) were treated the same way as the aged sham group. A Morris water maze (MWM) was conducted following the stimulation, and synaptic ultrastructure was observed through a transmission electron microscope. HF-rTMS improved spatial learning and memory impairment in the aged mice, and 5 Hz was more significant than 25 Hz. Synaptic plasticity-associated gene profiles were modified by HF-rTMS, especially neurotrophin signaling pathways and cyclic adenosine monophosphate response element binding protein (CREB) cofactors. Compared to the aged sham group, synaptic plasticity-associated proteins, i.e., synaptophysin (SYN) and postsynaptic density (PSD)-95 were increased; brain-derived neurotrophic factor (BDNF) and phosphorylated CREB (pCREB) significantly increased after the 5 Hz HF-rTMS treatment. Collectively, our results suggest that HF-rTMS ameliorated cognitive deficits in naturally aged mice. The 5 Hz rTMS treatment significantly enhanced synaptic structural plasticity and activated the BDNF/CREB pathway in the hippocampus.

Prevalence and risk factors for depression and anxiety in Chinese patients with Parkinson disease.

BACKGROUND: Anxiety and depression are common in Parkinson disease and both are important determinants of quality of life in patients. Several risk factors are identified but few research have investigated general and Parkinson's disease (PD)-specific factors comprehensively. The aim of this work was to explore PD-specific and -non-specific risk factors for PD with depression or anxiety. METHODS: A cross-sectional survey was performed in 403 patients with PD. Multivariate logistic analysis was used to investigate the prevalence and risk factors for the depression and anxiety in PD. The data of patients included demographic information, medicine history, disease duration, age at onset (AAO), family history, anti-parkinsonism drug, modified Hoehn and Yahr staging (H-Y) stage, scales of motor and non-motor symptoms and substantia nigra (SN) echogenic areas. RESULTS: 403 PD patients were recruited in the study. Depression and anxiety were present in 11.17% and 25.81% respectively. Marital status, tumor, higher Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) II score, dyskinesia, higher Hamilton Anxiety Rating Scale (HARS) score and lower the Parkinson's disease sleep scale (PDSS) score were associated with depression in PD. female gender, higher rapid eye movement behavior disorder Questionnaire-Hong Kong (RBD-HK) score, higher Hamilton Deprssion Rating Scale (HAMD) score, higher the scale for outcomes in PD for autonomic symptoms (SCOPA-AUT)score and larger SN echogenic areas were associated with anxiety. Neither depression nor anxiety was related to any anti-parkinsonism drugs. CONCLUSIONS: The prevalence of depression and anxiety in the current PD patients was 11.17% and 25.81% respectively. Disease of tumor, currently having no partner, severer motor function, dyskinesia, poorer sleep quality and anxiety were risk factors for PD with depression. Female, depression, rapid eye movement behavior disorder (RBD), autonomic dysfunction and larger SN area were risk factors for PD with anxiety.

Chronic Stress Contributes to Cognitive Dysfunction and Hippocampal Metabolic Abnormalities in APP/PS1 Mice.

BACKGROUND/AIMS: Stress response is determined by the brain, and the brain is a sensitive target for stress. Our previous experiments have confirmed that once the stress response is beyond the tolerable limit of the brain, particularly that of the hippocampus, it will have deleterious effects on hippocampal structure and function; however, the metabolic mechanisms for this are not well understood. METHODS: Here, we used morris water maze, elisa and gas chromatography-time of flight/mass spectrometry to observe the changes in cognition, neuropathology and metabolomics in the hippocampus of APP/PS1 mice and wild-type (C57) mice caused by chronic unpredictable mild stress (CUMS), we also further explored the correlation between cognition and metabolomics. RESULTS: We found that 4 weeks of CUMS aggravated cognitive impairment and increased amyloid-ß deposition in APP/PS1 mice, but did not affect C57 mice. Under non-stress conditions, compared with C57 mice, there were 8 different metabolites in APP/PS1 mice. However, following CUMS, 3 different metabolites were changed compared with untreated C57 mice. Compared to APP/PS1 mice, there were 7 different metabolites in APP/PS1+CUMS mice. Among these alterations, 3-hydroxybutyric acid, valine, serine, beta-alanine and o-phosphorylethanolamine, which are involved in sphingolipid metabolism, synthesis and degradation of ketone bodies, and amino acid metabolism. CONCLUSION: The results indicate that APP/PS1 mice are more vulnerable to stress than C57 mice, and the metabolic mechanisms of stress-related cognitive impairment in APP/PS1 mice are related to multiple pathways and networks, including sphingolipid metabolism, synthesis and degradation of ketone bodies, and amino acid metabolism.

Age-related alterations of neuronal excitability and voltage-dependent Ca2+ current in a spontaneous mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common age-dependent neurodegenerative disorder, characterized by a progressive dysfunction of central neurons, and senescence-accelerated mouse prone 8 (SAMP8), a spontaneous AD mouse model, appears to be an excellent model to investigate the process of AD. Previous studies have indicated that neuronal excitability is impaired in transgenic AD mice. In this study, the cognition of SAMP8 mice was tested using the passive avoidance task and Morris water maze; whole-cell current-clamp recordings were used to evaluate the neuronal excitability, including the resting membrane potential, the number of action potentials, and after-hyperpolarization; and the voltage-dependent Ca2+ current in hippocampal slices was measured using whole-cell voltage-clamp recordings. We found that compared to the young mice, the performance in the learning and memory behavior tasks was impaired in aged mice, and the hippocampal CA1 pyramidal neurons of the aged mice showed a significantly depolarized resting membrane potential, increased numbers of action potentials after injection of depolarizing current, and increased after-hyperpolarization after the action potentials. Consistent with the above changes, the voltage-dependent Ca2+ current was larger in aged mice than in young mice. These data suggested that the aged SAMP8 neurons were hyperexcitable, and the alterations in the voltage-dependent Ca2+ current of aged neurons occurred in parallel to the elevation in excitability.

Cholesterol, 24-Hydroxycholesterol, and 27-Hydroxycholesterol as Surrogate Biomarkers in Cerebrospinal Fluid in Mild Cognitive Impairment and Alzheimer's Disease: A Meta-Analysis.

Abnormal cholesterol metabolism is an established feature of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) is the fluid surrounding the central nervous system, and the protein and lipid content alterations in the CSF could be biomarkers for degenerative changes in the brain. The laboratory diagnosis of AD is limited to the analysis of three biomarkers in CSF: Aß42, total tau, and phospho-tau. The purpose of this analysis is to systematically analyze the available data describing the biomarkers of cholesterol and its metabolites in the CSF of subjects with AD. MEDLINE, EMBASE, and the Cochrane Central database were systematically queried to collect studies that have evaluated the markers of cholesterol and its metabolites in the CSF of subjects with mild cognitive impairment (MCI) or AD and age-matched controls. Analysis of the published data shows that the levels of cholesterol are increased in MCI subjects; 24-hydroxycholesterol and 27-hydroxycholesterol are elevated in AD and MCI subjects compared to controls. There is a significant dysfunction of cholesterol metabolism in the CSF of AD subjects. This analysis indicates that in addition to the available biomarkers in the CSF, such as Aß42, total tau, and phospho-tau, 24-hydroxycholesterol, 27-hydroxycholesterol, and cholesterol appear to be sensitive biomarkers for the evaluation of MCI and AD.

[A high content screening method for detection of anaphylactoid reaction of injection formulations].

Anaphylactoid reaction (AR) is the most common adverse reaction of injection formulations, however, there are obvious drawbacks in available methods for AR detection. A novel in vitro detection method for AR was established based on fluorescent labeling and high content screen (HCS) system in present study. With the use of RBL-2H3 cells degranulation model, positive cell count was determined with specific cellular membrane fluorescent dye FM4-64 labeling vesicle recycle, and total cells count was determined with specific nucleus fluorescent dye Hochest 3334, and then the ratio of cells degranulation after drug stimulation was calculated. In order to verify the reliability of this HCS method, positive drug Compound 48/80 was first used to confirm the consistence of HCS method with the traditional ß-hexosaminidase release test and the Evans blue staining ears test in mice. The results showed high consistence between HCS method and traditional testing methods, and the HCS method showed higher sensitivity than the other two tests. Then 30 samples of Danhong injection (DHI) with clinical allergy symptoms further were used to confirm the reliability of this HCS method. The HCS results showed high consistence with the clinical report, and the HCS method had the advantage in reducing the interference by drug color. Therefore, this HCS method is reliable, sensitive, simple and high-throughput method in detection of AR, applicable for the AR evaluation of injection formulations, and can provide guidance for safety of clinical application in clinical practice.

Chronic high-frequency repetitive transcranial magnetic stimulation improves age-related cognitive impairment in parallel with alterations in neuronal excitability and the voltage-dependent Ca2+ current in female mice.

Chronic high-frequency repetitive transcranial magnetic stimulation (rTMS) is a noninvasive method to increase the excitability of neurons, and it induces long-term effects that can improve symptoms related to neurodegenerative diseases, including cognitive ability. The present study was undertaken to identify the mechanism by which rTMS improves cognitive impairments in mice. The novel object recognition test in vivo was used to evaluate the cognitive function of the mice. Whole-cell patch-clamp recordings were used to evaluate the neuronal excitability, including the resting membrane potential, the number of action potentials induced by depolarized current, after-hyperpolarization, and the voltage-dependent Ca(2+) current in hippocampal slices. We found that the aged mice showed impairments in cognitive function, and high-frequency (25Hz) rTMS for 14 consecutive-days ameliorated the impairments. Whole-cell patch-clamp recordings showed that, compared to matured mice, the hippocampal CA1 pyramidal neurons of aged mice showed significantly hyperpolarized resting membrane potential, significantly decreased numbers of action potentials after injection of depolarizing current, and significantly increased after-hyperpolarization after an action potential. The exposure to high-frequency rTMS significantly improved the above deficits in the neuronal excitability in the aged rTMS mice. Consistent with the above changes, the exposure to high-frequency rTMS also significantly decreased the voltage-dependent Ca(2+) current of the neurons compared with the aged sham mice. These data suggested that the rTMS could improve the age-related cognitive impairment in parallel with regulating the neuronal excitability and modifying the voltage-dependent Ca(2+) channels.

Understanding strategy of nitrate and urea assimilation in a Chinese strain of Aureococcus anophagefferens through RNA-seq analysis.

Aureococcus anophagefferens is a harmful alga that dominates plankton communities during brown tides in North America, Africa, and Asia. Here, RNA-seq technology was used to profile the transcriptome of a Chinese strain of A. anophagefferens that was grown on urea, nitrate, and a mixture of urea and nitrate, and that was under N-replete, limited and recovery conditions to understand the molecular mechanisms that underlie nitrate and urea utilization. The number of differentially expressed genes between urea-grown and mixture N-grown cells were much less than those between urea-grown and nitrate-grown cells. Compared with nitrate-grown cells, mixture N-grown cells contained much lower levels of transcripts encoding proteins that are involved in nitrate transport and assimilation. Together with profiles of nutrient changes in media, these results suggest that A. anophagefferens primarily feeds on urea instead of nitrate when urea and nitrate co-exist. Furthermore, we noted that transcripts upregulated by nitrate and N-limitation included those encoding proteins involved in amino acid and nucleotide transport, degradation of amides and cyanates, and nitrate assimilation pathway. The data suggest that A. anophagefferens possesses an ability to utilize a variety of dissolved organic nitrogen. Moreover, transcripts for synthesis of proteins, glutamate-derived amino acids, spermines and sterols were upregulated by urea. Transcripts encoding key enzymes that are involved in the ornithine-urea and TCA cycles were differentially regulated by urea and nitrogen concentration, which suggests that the OUC may be linked to the TCA cycle and involved in reallocation of intracellular carbon and nitrogen. These genes regulated by urea may be crucial for the rapid proliferation of A. anophagefferens when urea is provided as the N source.