Cerebrospinal fluid (CSF) phosphorylated tau231 (P‐tau231) is associated with neuropathological outcomes of Alzheimer's disease (AD). The invasive access of cerebrospinal fluid has greatly stimulated ...interest in the identification of blood‐based P‐tau231, and the recent advent of single‐molecule array assay for the quantification of plasma P‐tau231 may provide a turning point to evaluate the usefulness of P‐tau231 as an AD‐related biomarker. Yet, in the plasma P‐tau231 literature, findings with regard to its diagnostic utility have been inconsistent, and thus, we aimed to statistically investigate the potential of plasma P‐tau231 in the context of AD via meta‐analysis. Publications on plasma P‐tau231 were systematically retrieved from PubMed, EMBASE, the Cochrane library and Web of Science databases. A total of 10 studies covering 2007 participants were included, and we conducted random‐effect or fixed‐effect meta‐analysis, sensitivity analysis and publication bias analysis using the STATA SE 14.0 software. According to our quantitative integration, plasma P‐tau231 increased from cognitively unimpaired (CU) populations to mild cognitive impairment to AD and showed significant changes in pairwise comparisons of AD, mild cognitive impairment and CU. Plasma P‐tau231 level was significantly higher in CU controls with positive amyloid‐β (Aβ) status compared with Aβ‐negative CU group. Additionally, the excellent diagnostic accuracy of plasma P‐tau231 for asymptomatic Aβ pathology was verified by the pooled value of area under the receiver operating characteristic curves (standard mean difference 95% confidence interval: .75 .69, .81, P < 0.00001). Overall, the increased plasma P‐tau231 concentrations were found in relation to the early development and progression of AD.
The present meta‐analysis was conducted to evaluate the evidence for plasma P‐tau231 in relation to the early development and progression of AD, which indicated a clear stepwise increase in plasma P‐tau231 concentrations from CU controls to MCI to AD. Additionally, the significant difference of P‐tau231 levels was observed in CU individuals with binary Aβ status, with the pooled value of area under curves favouring potential efficacy of plasma P‐tau231 to detect asymptotic Aβ pathology.
Abstract
Background
Immune dysfunction in Alzheimer’s disease (AD) was previously thought to be limited to the central nervous system, but recent studies suggest that the peripheral immune system ...also plays a key role. This study compared and analyzed the changes in peripheral immune cells in patients with AD and mild cognitive impairment (MCI) and their correlation with cognition, and combined
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F‐FDG PET and
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F‐AV45 PET to investigate the role of peripheral immune cells in AD pathology and the possibility as biomarkers for early clinical diagnosis and disease assessment.
Methods
The 146 participants included 70 AD patients, 26 MCI patients, and 50 controls. 34 AD patients tested with
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F‐AV45 (
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F ‐Florbetapir) positron emission tomography (PET). 23 were Aβ‐positive (A+), and 11 were Aβ‐negative (A‐). All participants had a peripheral immune cell, cognitive evaluation, and detailed nervous system examination.
Results
(1) Significant differences in peripheral immune cells in AD compared with MCI and CG; (2) There was no significant correlation between NEU%, NLR, LY, and LY% and cognitive scale scores for patients in the AD and A+ groups, while there was a significant correlation with cognitive scale scores in the MCI and A‐ groups; and (3) Peripheral immune cells NEU%, NLR, LY, and LY% in A+ patients were correlated with FDG metabolism in several functional brain areas and Aβ load in some brain areas, but not with Aβ load in all functional brain areas in A‐ patients.
Conclusion
Differences in peripheral immune cells help to distinguish AD from MCI, with NLR having better diagnostic efficacy. peripheral immune cells may have a greater impact on early cognitive dysfunction; NEU%, NLR, LY, and LY% may be associated with Aβ deposition and could serve as potential biomarkers for early clinical diagnosis and disease assessment in AD.
The core microbiome, as a unique group of microorganisms, is an emerging research hotspot that provides a new opportunity to improve growth and production of a host. However, the subjectivity ...associated with the concept of “core microbiome” means there is currently no uniform definition method for the core microbiome. In this study, the strengths and limitations of four commonly used definition methods for the core microbiome were explored from composition to function based on the 16S rRNA gene dataset of Eucommia ulmoides bark from 25 different biogeographical regions in China. There were differences in the composition of the core microbiomes defined by the different methods. The four definition methods of phylogeny, membership, composition, and network connection contained 274, 10, 5, and 5 core OTUs (operational taxonomic units), respectively. In contrast, the core microbiomes defined by different methods displayed similarities in function. In addition, different definition methods showed varying preferences for abundant taxa, intermediate taxa, and rare taxa. Some core taxa defined by the definition method of phylogeny were significantly associated with pharmacologically active ingredients of E. ulmoides bark. The findings of this study suggest that although the core microbiomes defined by different methods have preferences in composition and function, the term refers to a group of microbes that are particularly notable and important for host-associated microbiomes. Therefore, we propose: (I) The definition method of the core microbiome should be selected according to the ecological problems faced; (II) A combination of multiple methods may comprehensively reveal the core microbiome at different levels of the host, and may also facilitate understanding of the ecological and evolutionary processes that govern host-microbe interactions.
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•The method of phylogeny showed preferences for rare taxa.•The methods of composition and network showed preferences for intermediate taxa.•A strong interaction between the core microbes of Eucommia ulmoides bark.•The core microbes defined by different methods displayed similarities in function.•Some core microorganisms were significantly related to the active ingredients.
Alzheimer’s disease (AD) is the most common type of dementia in the elderly and causes neurodegeneration, leading to memory loss, behavioral disorder, and psychiatric impairment. One potential ...mechanism contributing to the pathogenesis of AD may be the imbalance in gut microbiota, local and systemic inflammation, and dysregulation of the microbiota–gut–brain axis (MGBA). Most of the AD drugs approved for clinical use today are symptomatic treatments that do not improve AD pathologic changes. As a result, researchers are exploring novel therapeutic modalities. Treatments involving the MGBA include antibiotics, probiotics, transplantation of fecal microbiota, botanical products, and others. However, single-treatment modalities are not as effective as expected, and a combination therapy is gaining momentum. The purpose of this review is to summarize recent advances in MGBA-related pathological mechanisms and treatment modalities in AD and to propose a new concept of combination therapy. “MGBA-based multitherapy” is an emerging view of treatment in which classic symptomatic treatments and MGBA-based therapeutic modalities are used in combination. Donepezil and memantine are two commonly used drugs in AD treatment. On the basis of the single/combined use of these two drugs, two/more additional drugs and treatment modalities that target the MGBA are chosen based on the characteristics of the patient’s condition as an adjuvant treatment, as well as the maintenance of good lifestyle habits. “MGBA-based multitherapy” offers new insights for the treatment of cognitive impairment in AD patients and is expected to show good therapeutic results.
Background
Adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare autosomal dominant disorder caused by mutations in the colony‐stimulating factor 1 receptor ...(CSF1R) gene. As of 2022, more than 100 different CSF1R mutations were reported in patients with CSF1R‐related leukoencephalopathy.
Method
In this case report, we described ALSP in a previously healthy 46‐year‐old woman. The patient underwent detailed neurological examinations including cognitive assessment, brain magnetic resonance imaging (MRI) and whole‐exome sequencing.
Result
The patient manifested as memory impairment, poor interpersonal behavior and decreased verbal fluency. Brain MRI showed confluent white matter changes and atrophy of the corpus callosum. Whole‐exome sequencing identified a novel splice site mutation (C.1858 + 5G > A) in intron 13 of the CSF1R gene, which has not been reported worldwide.
Conclusion
ALSP has a wide range of clinical manifestations and genetic heterogeneity. It should be considered when diagnosing rapidly progressive dementia with or without motor impairment. We recommend biopsy or genetic testing in these patients to avoid misdiagnosis and delayed diagnosis. We will continue to monitor this family in the future to improve our understanding of ALSP, so as to correctly diagnose ALSP in clinic and provide clinical data for better research on the pathogenesis and treatment of this disease.
Background
Confusion between Alzheimer’s disease (AD) and semantic dementia (SD) in early diagnosis is common, and most previous studies have been based on clinical diagnoses without a pathological ...diagnosis by biomarkers.
Method
15 patients 18F‐AV 45 PET (+) with AD and 9 patients 18F‐AV 45 PET (‐) with SD enrolled. All patients underwent the following examinations: (1) Neuropsychological tests, including Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Activities of Daily Living (ADL), Boston Nomenclature Test (BNT), and Neuropsychiatric Scale table (NPI). (2) 3.0 head MRI examination, the imaging results were evaluated by MTA‐Scale, Koedam scale, and Kipps scale. (3) 18F‐FDG PET examination, PET images were quantitatively analyzed by Neuro Q software.
Result
ADL score increased in both groups, and the ADL score in the AD group was higher than that in the SD group (P = 0.035). BNT score decreased in both groups, but the BNT score in the SD group was lower than that in the AD group (P = 0.013). There were differences between the two groups in several psycho‐behavioral symptoms; delusions symptoms in the AD group were more prominent than those in the SD group (P = 0.009), and euphoria and disinhibition symptoms in the SD group were more pronounced than AD group (P = 0.015 and 0.015, respectively). The MRI atrophy rating scale showed that the left hippocampus, left frontal lobe, left anterior, and posterior temporal lobe atrophy in the SD group was more severe than that of the AD group (P = 0.018, 0.018, 0.022, and 0.044, respectively). Compared with the two groups of patients, the brain regions with significantly decreased metabolism in the AD group included the right inferior parietal lobule, right posterior cingulate gyrus, and left posterior cingulate gyrus (P = 0.037, 0.014, and 0.037, respectively); the brain regions with significantly decreased metabolism were left inferior frontal gyrus, left medial anterior temporal lobe, right medial anterior temporal lobe, left inferior lateral temporal lobe and left caudate nucleus (P = 0.017, 0.003, 0.037, 0.003, and 0.017, respectively).
Conclusion
Neuropsychology, brain structure, and brain metabolism aid in AD and SD differential diagnosis.
Abstract
Background
Confusion between Alzheimer’s disease (AD) and semantic dementia (SD) in early diagnosis is common, and most previous studies have been based on clinical diagnoses without a ...pathological diagnosis by biomarkers.
Method
15 patients
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F‐AV 45 PET (+) with AD and 9 patients
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F‐AV 45 PET (‐) with SD enrolled. All patients underwent the following examinations: (1) Neuropsychological tests, including Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Activities of Daily Living (ADL), Boston Nomenclature Test (BNT), and Neuropsychiatric Scale table (NPI). (2) 3.0 head MRI examination, the imaging results were evaluated by MTA‐Scale, Koedam scale, and Kipps scale. (3)
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F‐FDG PET examination, PET images were quantitatively analyzed by Neuro Q software.
Result
ADL score increased in both groups, and the ADL score in the AD group was higher than that in the SD group (P = 0.035). BNT score decreased in both groups, but the BNT score in the SD group was lower than that in the AD group (P = 0.013). There were differences between the two groups in several psycho‐behavioral symptoms; delusions symptoms in the AD group were more prominent than those in the SD group (P = 0.009), and euphoria and disinhibition symptoms in the SD group were more pronounced than AD group (P = 0.015 and 0.015, respectively). The MRI atrophy rating scale showed that the left hippocampus, left frontal lobe, left anterior, and posterior temporal lobe atrophy in the SD group was more severe than that of the AD group (P = 0.018, 0.018, 0.022, and 0.044, respectively). Compared with the two groups of patients, the brain regions with significantly decreased metabolism in the AD group included the right inferior parietal lobule, right posterior cingulate gyrus, and left posterior cingulate gyrus (P = 0.037, 0.014, and 0.037, respectively); the brain regions with significantly decreased metabolism were left inferior frontal gyrus, left medial anterior temporal lobe, right medial anterior temporal lobe, left inferior lateral temporal lobe and left caudate nucleus (P = 0.017, 0.003, 0.037, 0.003, and 0.017, respectively).
Conclusion
Neuropsychology, brain structure, and brain metabolism aid in AD and SD differential diagnosis.
Increasing evidence demonstrates that interleukin-10 (IL-10), known as an immunosuppressive cytokine, induces antitumor effects depending on CD8+ T cells. However, it remains elusive how ...immunosuppressive effects of IL-10 contribute to CD8+ T cell-mediated antitumor immunity. We generated Cetuximab-based IL-10 fusion protein (CmAb-(IL10)2) to prolong its half-life and allow tumor-targeted delivery of IL-10. Our results demonstrated potent antitumor effects of CmAb-(IL10)2 with reduced toxicity. Moreover, we revealed a mechanism of CmAb-(IL10)2 preventing dendritic cell (DC)-mediated CD8+ tumor-infiltrating lymphocyte apoptosis through regulating IFN-γ production. When combined with immune checkpoint blockade, CmAb-(IL10)2 significantly improves antitumor effects in mice with advanced tumors. Our findings reveal a DC-regulating role of IL-10 to potentiate CD8+ T cell-mediated antitumor immunity and provide a potential strategy to improve cancer immunotherapy.
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•CmAb-(IL10)2 prolongs the half-life of IL-10 and minimizes its toxicity•Tumor-targeted IL-10 induces superior antitumor effects over nontargeted IL-10•CmAb-(IL10)2 prevents tumor-specific CD8+ TILs apoptosis through IL-10R on DCs•CmAb-(IL10)2 overcomes resistance to immune checkpoint blockade
Qiao et al. generate a Cetuximab-based IL-10 fusion protein for EGFR-targeted delivery of IL-10 to tumors, in which IL-10 regulates IFN-γ production by dendritic cells and enhances CD8+ T cell-dependent antitumor responses. The fusion protein shows high efficacy alone and in combination with anti-PD-L1/CTLA-4.
The composition and yield of secondary metabolites of Eucommia ulmoides are important indices of the quality of medicinal materials, and their synthesis and accumulation are affected by both internal ...and external factors. However, the influential extent and mechanism of these factors on the pharmacologically active ingredients of E. ulmoides are still being elucidated. In this study, we selected 72 of E. ulmoides from 24 regions in China, and investigated the genetic diversity, pharmacologically active ingredients, soil physicochemical properties, and bark bacterial communities, along with the effects of genotypes and environmental factors on pharmacologically active ingredients. Results showed that genetic characteristics among the 24 regions there were no significant different, however, 12 different haplotypes were clearly revealed based on haplotype network analysis. The contents of pinoresinol diglucoside and geniposide acid were mainly affected by different climate and soil physiochemical factors, while aucubin was only sinificantly affected by soil organic matter. All of, the three pharmacologically active ingredients mentioned above were significantly correlated with the dominant genus Lactobacillus, Escherichia, Bacteroides and Faecalibacterium, suggesting that the active ingredients were affected by bark microorganisms. In conclusion, our analysis indicated that the accumulation of pharmacologically active ingredients of E. ulmoides were comprehensively affected genotype, environmental factors (biological and abiotic factors), and their interaction, with genotype had the greatest impact. These results provide important basic information for the future breeding, selection of cultivation conditions and assistance of microbial technology of E. ulmoides.
•Index ingredients were more sensitive to host evolution.•Microorganisms were important biological factors affecting active ingredients.•Active ingredients had different responses to environmental factors.•Genotypes have the greatest influence on the accumulation of active ingredients.
Plant seeds harbor numerous beneficial endophytes that can be vertically transmitted across generations, positively influencing plant growth. This study aimed to enhance our understanding of the ...functions of endophytes in Eucommia ulmoides seeds and investigate their potential mechanisms for promoting E. ulmoides seedling growth. Preliminary screening for seed endophytes that increase E. ulmoides seedling growth was conducted using microbe–seedling co-culture experiments. Subsequently, the two strains with the most pronounced growth-promoting effects were tested in pot experiments. The mechanism underlying their effects on E. ulmoides growth was elucidated through high-throughput sequencing analysis of rhizosphere soil. The bacterium Cytobacillus gottheilii B7 and the fungus Cladosporium halotolerans Z27 had the most significant growth-promoting effects on E. ulmoides seedlings. Inoculation of these strains into the soil led to substantial improvements in physiological indicators in E. ulmoides. Notably, strain B7 showed a superior effect compared to strain Z27. Although strain B7 inoculation reduced rhizosphere bacterial α-diversity, it strengthened the network interactions among rhizosphere microorganisms and selectively recruited specific rhizosphere microbial taxa, including Ilumatobacter, Algoriphagus and OLB13, while inhibiting the growth of Subulicystidium and Symmetrospora. Functional annotation suggested that strain B7 inoculation enhanced plant nitrite respiratory metabolism and inhibited plant pathogen. Similarly, strain Z27 inoculation recruited genera such as Flavihumibacter, Pseudoxanthomonas, and Myriococcum, while inhibiting Symmetrospora. These results provide scientific data for a comprehensive analysis of seed endophytes in the future and valuable resources for the development and application of microbial inoculants.
•Inoculation of endophytes promoted E. ulmoides growth and stress resistance.•Inoculation of endophytes changed the structure and function of E. ulmoides rhizosphere microbiota.•Inoculation of endophytes recruited beneficial microorganisms and inhibited plant pathogen in the rhizosphere.
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