Personalized drug screening in patient-derived organoids of biliary tract cancer and its clinical application.

Patients with biliary tract cancer (BTC) show different responses to chemotherapy, and there is no effective way to predict chemotherapeutic response. We have generated 61 BTC patient-derived organoids (PDOs) from 82 tumors (74.4%) that show similar histological and genetic characteristics to the corresponding primary BTC tissues. BTC tumor tissues with enhanced stemness- and proliferation-related gene expression by RNA sequencing can more easily form organoids. As expected, BTC PDOs show different responses to the chemotherapies of gemcitabine, cisplatin, 5-fluoruracil, oxaliplatin, etc. The drug screening results in PDOs are further validated in PDO-based xenografts and confirmed in 92.3% (12/13) of BTC patients with actual clinical response. Moreover, we have identified gene expression signatures of BTC PDOs with different drug responses and established gene expression panels to predict chemotherapy response in BTC patients. In conclusion, BTC PDO is a promising precision medicine tool for anti-cancer therapy in BTC patients.

Low-temperature molten salt synthesis and catalytic mechanism of CoS2/NC as an advanced bifunctional electrocatalyst.

The development of productive and sustainable bifunctional electrocatalysts for the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) plays an important role in the commercial evolution of metal-air batteries. In this paper, a low-temperature molten salt template method was adopted to synthesize the composite of CoS2 and nitrogen-doped carbon (CoS2/NC) without the protection of inert gas. The structural characterization studies show that the specific surface area (SSA) and crystal growth kinetics are increased and effectively improved, respectively, by the composite of CoS2 and NC. The as-synthesized CoS2/NC composite demonstrates outstanding bifunctional catalytic activity in alkaline electrolytes and exhibits a half-wave potential (E1/2) of 0.854 V (vs. RHE) and an overpotential of only 220 mV for the OER at a current density of 10 mA cm-2 (η10). Simultaneously, CoS2/NC also exhibits excellent electrochemical stability. Additionally, density functional theory (DFT) calculations have manifested that the synergistic effect of CoS2 and NC results in a remarkable enhancement in the bifunctional catalytic performance of the composite materials. This study offers a new pathway and theoretical guidance for the fabrication of efficient bifunctional electrocatalysts.

Interferon-γ secreted by recruited Th1 cells in peritoneal cavity inhibits the formation of malignant ascites.

Type 1 T helper (Th1) cells generate an efficient antitumor immune response in multiple malignancies. The functions of Th1 cells in malignant ascites (MA) have not been elucidated. The distribution of helper T cells in peritoneal fluid and peripheral blood was determined in patients and animal models with malignant ascites. The effects of Th1-derived interferon-γ (IFN-γ) on the formation of malignant ascites were investigated. The mechanism underlying the recruitment of Th1 cells into peritoneal cavity was explored. In patients with malignant ascites and animal models of malignant ascites, the percentage of Th1 cells increased in peritoneal fluid compared with peripheral blood. Next, our experiment demonstrated that Th1 cells inhibited the growth of tumor cells by secreting IFN-γ in vitro. In murine models of malignant ascites, increased peritoneal fluid and shorter survival time were observed in IFN-γ-/- mice compared with wild-type (WT) mice. Then, the levels of C-X-C motif chemokine ligand (CXCL) 9/10 and the ratio of CXCR3+ Th1 cells indicated the involvement of CXCL9, 10/CXCR3 axis in the recruitment of Th1 cells into peritoneal cavity. As expected, in murine models of malignant ascites, the gradient between ascitic Th1 ratio and blood Th1 ratio decreased in CXCR3-/- mice compared with WT mice. IFN-γ secreted by recruited Th1 cells in peritoneal cavity inhibits the formation of malignant ascites. Hence, manipulation of Th1 cells or IFN-γ will provide a therapeutic candidate against malignant ascites.

Eliminating METTL1-mediated accumulation of PMN-MDSCs prevents hepatocellular carcinoma recurrence after radiofrequency ablation.

BACKGROUND AND AIMS: Radiofrequency ablation (RFA) is an important curative therapy in hepatocellular carcinoma (HCC), but recurrence rate remains as high as all the other HCC therapeutic modalities. Methyltransferase 1 (METTL1), an enzyme for m 7 G tRNA modification, was reported to promote HCC development. Here, we assessed the role of METTL1 in shaping the immunosuppressive tumor microenvironment after insufficient RFA (iRFA). APPROACH AND RESULTS: By immunohistochemistry and multiplex immunofluorescence (mIF) staining, we showed that METTL1 expression was enhanced in post-RFA recurrent HCC, accompanied by increased CD11b + CD15 + polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSCs) and decreased CD8 + T cells. Mechanistically, heat-mediated METTL1 upregulation enhanced TGF-ß2 translation to form the immunosuppressive environment by induction of myeloid-derived suppressor cell. Liver-specific overexpression or knockdown of Mettl1 significantly affected the accumulation of PMN-MDSCs and subsequently affected CD8 + T cell infiltration. Complete RFA successfully eliminated the tumor, whereas iRFA-treated mice exhibited enhanced tumor growth and metastasis with increased PMN-MDSC accumulation and decreased CD8 + T cells compared to sham surgery. Interrupting METTL1-TGF-ß2-PMN-MDSC axis by anti-Ly6G antibody, or knockdown of hepatoma-intrinsic Mettl1 or Tgfb2 , or TGF-ß signaling blockade significantly mitigated tumor progression induced by iRFA and restored CD8 + T cell population. CONCLUSIONS: Our study sheds light on the pivotal role of METTL1 in modulating an immunosuppressive microenvironment and demonstrated that interrupting METTL1-TGF-ß2-PMN-MDSC axis could be a therapeutic strategy to restore antitumor immunity and prevent HCC recurrence after RFA treatment, meriting further clinical studies.

Targeting N7-methylguanosine tRNA modification blocks hepatocellular carcinoma metastasis after insufficient radiofrequency ablation.

Radiofrequency heat ablation is an ideal radical treatment for hepatocellular carcinoma (HCC). However, insufficient radiofrequency ablation (IRFA) could lead to high recurrence of HCC. N7-methylguanosine (m7G) on tRNAs, an evolutionally conservative modification in mammals and yeast, modulates heat stress responses and tumor progression, while its function in HCC recurrence after IRFA remains unknown. Here, we found that IRFA significantly upregulates the level of m7G tRNA modification and its methyltransferase complex components METTL1/WDR4 in multiple systems including HCC patient-derived xenograft (PDX) mouse, patients' HCC tissues, sublethal-heat-treated models of HCC cell lines, and organoids. Functionally, gain-/loss-of-function assays showed that METTL1-mediated m7G tRNA modification promotes HCC metastasis under sublethal heat exposure both in vitro and in vivo. Mechanistically, we found that METTL1 and m7G tRNA modification enhance the translation of SLUG/SNAIL in a codon frequency-dependent manner under sublethal heat stress. Overexpression of SLUG/SNAIL rescued the malignant potency of METTL1 knockdown HCC cells after sublethal heat exposure. Our study uncovers the key functions of m7G tRNA modification in heat stress responses and HCC recurrence after IRFA, providing molecular basis for targeting METTL1-m7G-SLUG/SNAIL axis to prevent HCC metastasis after radiofrequency heat ablation treatment.

Overexpression of LtuHB6 from Liriodendron tulipifera causes lobed-leaf formation in Arabidopsis thaliana.

Liriodendron tulipifera L. is an ornamental tree species with extraordinarily lobed leaves. However, the mechanisms underlying lobed leaf formation in plants remain unclear. The transcription factor, ARABIDOPSIS THALIANA HOMEBOX 6 (HB6), plays a role in regulating leaf margin development. HB6 is involved in cell division and differentiation of developmental organs and negatively regulates abscisic acid (ABA) signal transmission under external abiotic stress; it is unclear whether HB6 performs a pivotal role in leaf morphogenesis in L. tulipifera. In this study, full-length LtuHB6 from L. tulipifera was heterologously expressed in tobacco and Arabidopsis thaliana; its expression pattern was analyzed to determine its potential role in leaf development. In addition, LtuHB6 is localized in the nucleus and cell membrane of tobacco leaves. The expression of LtuHB6 was highest in mature leaves compared to the other stages of leaf development (bud growth, young leaves, and leaf senescence). Transgenic A. thaliana plants overexpressing LtuHB6 exhibited an abnormal phenotype with lobed leaves. Moreover, LtuHB6 overexpression significantly affected the expression of seven genes related to leaf serration in the initial stage of leaf primordia and altered the expression levels of hormonal genes. Our findings indicate that LtuHB6 is an essential regulatory factor in L. tulipifera lobed-leaf formation and is involved in regulating and responding to hormones. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-022-01254-9.

METTL1 promotes hepatocarcinogenesis via m7 G tRNA modification-dependent translation control.

BACKGROUND: N7 -methylguanosine (m7 G) modification is one of the most common transfer RNA (tRNA) modifications in humans. The precise function and molecular mechanism of m7 G tRNA modification in hepatocellular carcinoma (HCC) remain poorly understood. METHODS: The prognostic value and expression level of m7 G tRNA methyltransferase complex components methyltransferase-like protein-1 (METTL1) and WD repeat domain 4 (WDR4) in HCC were evaluated using clinical samples and TCGA data. The biological functions and mechanisms of m7 G tRNA modification in HCC progression were studied in vitro and in vivo using cell culture, xenograft model, knockin and knockout mouse models. The m7 G reduction and cleavage sequencing (TRAC-seq), polysome profiling and polyribosome-associated mRNA sequencing methods were used to study the levels of m7 G tRNA modification, tRNA expression and mRNA translation efficiency. RESULTS: The levels of METTL1 and WDR4 are elevated in HCC and associated with advanced tumour stages and poor patient survival. Functionally, silencing METTL1 or WDR4 inhibits HCC cell proliferation, migration and invasion, while forced expression of wild-type METTL1 but not its catalytic dead mutant promotes HCC progression. Knockdown of METTL1 reduces m7 G tRNA modification and decreases m7 G-modified tRNA expression in HCC cells. Mechanistically, METTL1-mediated tRNA m7 G modification promotes the translation of target mRNAs with higher frequencies of m7 G-related codons. Furthermore, in vivo studies with Mettl1 knockin and conditional knockout mice reveal the essential physiological function of Mettl1 in hepatocarcinogenesis using hydrodynamics transfection HCC model. CONCLUSIONS: Our work reveals new insights into the role of the misregulated tRNA modifications in liver cancer and provides molecular basis for HCC diagnosis and treatment.

An Optimization Approach for Transcranial Direct Current Stimulation Using Nondominated Sorting Genetic Algorithm II.

Transcranial direct current stimulation (tDCS) delivers weak current into the brain to modulate neural activities. Many methods have been proposed to determine electrode positions and stimulation intensities. Due to the trade-off between intensity and focality, it is actually a multi-objective optimization problem that has a set of optimal solutions. However, traditional methods can produce only one solution at each time, and many parameters need to be determined by experience. In this study, we proposed the nondominated sorting genetic algorithm II (NSGA-II) to solve the current optimization problem of multi-electrode tDCS. We also compared the representative solutions with LCMV solutions. The result shows that a group of solutions close to the optimal front can be obtained just in only one run without any prior knowledge.

Quantitative burst suppression on serial intermittent EEG in refractory status epilepticus.

OBJECTIVES: In refractory status epilepticus (RSE), the optimal degree of suppression (EEG burst suppression or merely suppressing seizures) remains unknown. Many centers lacking continuous EEG must default to serial intermittent recordings where uncertainty from lack of data may prompt more aggressive suppression. In this study, we sought to determine whether the quantitative burst suppression ratio (QBSR) from serial intermittent EEG recording is associated with RSE patient outcome. METHODS: We screened the EEG database to identify non-anoxic adult RSE patients for EEG and chart review. QBSR was calculated per 10-second EEG epoch as the percentage of time during which EEG amplitude was <3 µV. Patients who survived 1-3 months after discharge from ICU and hospital comprised the favorable group. Further to initial unadjusted univariate analysis of all pooled QBSR, we conducted multivariate analyses to account for individual patient confounders ("per-capita analysis"), uneven number of EEG recordings ("per-session analysis"), and uneven number of epochs ("per-epoch analysis"). We analyzed gender, anesthetic number, and adjusted status epilepticus severity score (aSTESS) as confounders. RESULTS: In 135,765 QBSR values over 160 EEG recordings (median 2.17 h every ≥24 h) from 17 patients on Propofol, Midazolam, and/or Ketamine, QBSR was deeper in the favorable group (p < 0.001) on initial unadjusted analysis. However, on adjusted multivariate analysis, there was consistently no association between QBSR and outcome. Higher aSTESS consistently associated with unfavorable outcome on per-capita (p = 0.033), per-session (p = 0.048) and per-epoch (p < 0.001) analyses. Greater maximal number of non-barbiturate anesthetic associated with favorable outcome on per-epoch analysis (p < 0.001). CONCLUSIONS: There was no association between depth of EEG suppression using non-barbiturate anesthetic and RSE patient outcome based on QBSR from serial intermittent EEG. A per-epoch association between non-barbiturate anesthetic and favorable outcome suggests an effect from non-suppressive time-varying EEG content. SIGNIFICANCE: Targeting and following deeper burst suppression through non-barbiturate anesthetics on serial intermittent EEG monitoring of RSE is of limited utility.

N7-Methylguanosine tRNA modification enhances oncogenic mRNA translation and promotes intrahepatic cholangiocarcinoma progression.

Cancer cells selectively promote translation of specific oncogenic transcripts to facilitate cancer survival and progression, but the underlying mechanisms are poorly understood. Here, we find that N7-methylguanosine (m7G) tRNA modification and its methyltransferase complex components, METTL1 and WDR4, are significantly upregulated in intrahepatic cholangiocarcinoma (ICC) and associated with poor prognosis. We further reveal the critical role of METTL1/WDR4 in promoting ICC cell survival and progression using loss- and gain-of-function assays in vitro and in vivo. Mechanistically, m7G tRNA modification selectively regulates the translation of oncogenic transcripts, including cell-cycle and epidermal growth factor receptor (EGFR) pathway genes, in m7G-tRNA-decoded codon-frequency-dependent mechanisms. Moreover, using overexpression and knockout mouse models, we demonstrate the crucial oncogenic function of Mettl1-mediated m7G tRNA modification in promoting ICC tumorigenesis and progression in vivo. Our study uncovers the important physiological function and mechanism of METTL1-mediated m7G tRNA modification in the regulation of oncogenic mRNA translation and cancer progression.

Genome-wide identification of MIKC-type genes related to stamen and gynoecium development in Liriodendron.

The organogenesis and development of reproductive organs, i.e., stamen and gynoecium, are important floral characteristics that are closely related to pollinators and reproductive fitness. As a genus from Magnoliaceae, Liriodendron has only two relict species: L. chinense and L. tulipifera. Despite the similar flower shapes of these species, their natural seed-setting rates differ significantly, implying interspecies difference in floral organogenesis and development. MADS-box genes, which participate in floral organogenesis and development, remain unexplored in Liriodendron. Here, to explore the interspecies difference in floral organogenesis and development and identify MADS-box genes in Liriodendron, we examined the stamen and gynoecium primordia of the two Liriodendron species by scanning electron microscopy combined with paraffin sectioning, and then collected two types of primordia for RNA-seq. A total of 12 libraries were constructed and 42,268 genes were identified, including 35,269 reference genes and 6,999 new genes. Monoterpenoid biosynthesis was enriched in L. tulipifera. Genome-wide analysis of 32 MADS-box genes was conducted, including phylogenetic trees, exon/intron structures, and conserved motif distributions. Twenty-six genes were anchored on 17 scaffolds, and six new genes had no location information. The expression profiles of MIKC-type genes via RT-qPCR acrossing six stamen and gynoecium developmental stages indicates that the PI-like, AG/STK-like, SEP-like, and SVP-like genes may contribute to the species-specific differentiation of the organogenesis and development of reproductive organs in Liriodendron. Our findings laid the groundwork for the future exploration of the mechanism underlying on the interspecific differences in reproductive organ development and fitness in Liriodendron.

Insufficient Radiofrequency Ablation Promotes Hepatocellular Carcinoma Metastasis Through N6-Methyladenosine mRNA Methylation-Dependent Mechanism.

BACKGROUND AND AIMS: The dynamic N6-methyladenosine (m6 A) mRNA modification is essential for acute stress response and cancer progression. Sublethal heat stress from insufficient radiofrequency ablation (IRFA) has been confirmed to promote HCC progression; however, whether m6 A machinery is involved in IRFA-induced HCC recurrence remains open for study. APPROACH AND RESULTS: Using an IRFA HCC orthotopic mouse model, we detected a higher level of m6 A reader YTH N6-methyladenosine RNA binding protein 1-3 (YTHDF1) in the sublethal-heat-exposed transitional zone close to the ablation center than that in the farther area. In addition, we validated the increased m6 A modification and elevated YTHDF1 protein level in sublethal-heat-treated HCC cell lines, HCC patient-derived xenograft (PDX) mouse model, and patients' HCC tissues. Functionally, gain-of-function/loss-of-function assays showed that YTHDF1 promotes HCC cell viability and metastasis. Knockdown of YTHDF1 drastically restrains the tumor metastasis evoked by sublethal heat treatment in tail vein injection lung metastasis and orthotopic HCC mouse models. Mechanistically, we found that sublethal heat treatment increases epidermal factor growth receptor (EGFR) m6 A modification in the vicinity of the 5' untranslated region and promotes its binding with YTHDF1, which enhances the translation of EGFR mRNA. The sublethal-heat-induced up-regulation of EGFR level was further confirmed in the IRFA HCC PDX mouse model and patients' tissues. Combination of YTHDF1 silencing and EGFR inhibition suppressed the malignancies of HCC cells synergically. CONCLUSIONS: The m6 A-YTHDF1-EGFR axis promotes HCC progression after IRFA, supporting the rationale for targeting m6 A machinery combined with EGFR inhibitors to suppress HCC metastasis after RFA.

Prognostic factors for pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome: a multicenter study in China.

BACKGROUND: In China, one of the major causes of hepatic sinusoidal obstruction syndrome (HSOS) is the intake of herbals containing pyrrolizidine alkaloid (PA). However, prognostic factors for PA-induced HSOS are poorly understood. The aim of this study was to identify the independent prognostic factors for PA-induced HSOS using a multi-center study. METHODS: A total of 117 PA-induced HSOS patients were enrolled for data collection in three university hospitals from November 2003 to September 2018. Univariate and multivariate Cox proportional hazards analysis were used to determine prognostic factors for PA-induced HSOS. RESULTS: The median age of the PA-induced HSOS patients was 61 years (range, 21-88 years), and 64% of them were male. The survival rates at 1, 3, and 36 months were 89.71%, 72.60%, and 69.19%, respectively. Significant differences in prothrombin time (PT), international normalized ratio, total bilirubin, severity grading [new criteria for severity grading of hematopoietic stem cell transplantation (HSCT)-related HSOS in adults] were found between patients who survived and those who died. Univariate and multivariate survival analysis using Cox's regression model demonstrated low serum albumin (<35 g/L), elevated serum urea (>8.2 mmol/L) and severe or very severe HSOS (European Society for Blood and Marrow Transplantation 2016 criteria) were independent prognostic factors of survival. CONCLUSIONS: Serum albumin, serum urea, and severity grading were independent prognostic factors for patients with PA-induced HSOS, and can contribute to identifying potentially high-risk patients for early effective intervention. TRIAL REGISTRATION: ChiCTR-DRD-17010709 (www.chictr.org.cn).

[Clinical Status and Research Progress of Tuberculous Peritonitis].

Tuberculous peritonitis(TBP)is currently one of the common manifestations of extrapulmonary tuberculosis.Due to the atypical clinical features,diverse types of diseases to be distinguished,and limited detection methods,TBP is difficult to be diagnosed and the fatality caused by delayed diagnosis increases significantly.We studied the current research status of TBP and found that T cells spot test,abdominal CT,and laparoscopic biopsy were of high diagnostic value for TBP.However,the application of ascites Xpert-MTB/RIF-ultra assay,ascites ADA,and whole-body positron emission tomography/computed tomography remained to be studied.Serum CA125 helps to judge the efficacy of anti-tuberculosis treatment.

Myofibroblast induces hepatocyte-to-ductal metaplasia via laminin-ɑvß6 integrin in liver fibrosis.

Hepatocytes undergo the metaplasia into ductal biliary epithelial cells (BECs) in response to chronic injury, and subsequently contribute to liver regeneration. The mechanism underlying hepatocyte-to-ductal metaplasia has not been explored until now. In mouse models of liver fibrosis, a florid BEC response was observed in fibrotic liver, and the depletion of myofibroblasts attenuated BEC expansion remarkably. Then, in hepatocyte fate-tracing mouse model, we demonstrated the conversion of mature hepatocytes into ductal BECs in fibrotic liver, and the depletion of myofibroblasts diminished the hepatocyte-to-ductal metaplasia. Finally, the mechanism underlying the metaplasia was investigated. Myofibroblasts secreted laminin-rich extracellular matrix, and then laminin induced hepatocyte-to-ductal metaplasia through ɑvß6 integrin. Therefore, our results demonstrated myofibroblasts induce the conversion of mature hepatocytes into ductal BECs through laminin-ɑvß6 integrin, which reveals that the strategy improve regeneration in fibrotic liver through the modification of specific microenvironment.

Ascitic fluid total protein, a useful marker in non-portal hypertensive ascites.

BACKGROUND AND AIMS: Diagnostic performance of ascitic fluid total protein (AFTP) concentration remained unsettled. Our aim was to determine diagnostic value of AFTP in differential diagnosis of causes of ascites. METHODS: Seven hundred four consecutive patients with new-onset ascites were prospectively enrolled in this study. RESULTS: In the training cohort, diagnostic performance of quantitative AFTP assay was superior to that of Rivalta test in differential diagnosis of ascites. At the predetermined cut-off value of 25 g/L, quantitative AFTP assay was more useful in the differentiation of non-portal hypertensive ascites from portal hypertensive ascites compared with the exudate-transudate classification, area under curve of receiver operating characteristic curve was 0.958. Quantitative AFTP assay was superior to serum-ascites albumin gradient in the detection of non-portal hypertensive ascites, especially malignant ascites and tuberculous peritonitis. In mixed ascites, AFTP was useful in identifying peritoneal lesions. CONCLUSIONS: Ascitic fluid total protein is a useful marker in non-portal hypertensive ascites; thus, it should be determined in diagnostic work-up of the patients with ascites.

Ascitic cholesterol is superior to serum-ascites albumin gradient in the detection of non-portal hypertensive ascites and the diagnosis of mixed ascites.

BACKGROUND: The diagnostic value of ascitic cholesterol in the differential diagnosis of ascites is controversial. AIM: To investigate the diagnostic performance of ascitic cholesterol in the differential diagnosis of ascites. METHODS: Consecutive patients with new-onset ascites were enrolled prospectively. The pertinent data were collected from 629 patients with all forms of ascites. RESULTS: In the training cohort, determination of the ascitic cholesterol level was a highly effective method of distinguishing non-portal hypertension (NPH) from portal hypertension (PH). At the pre-determined cut-off value of 45 mg/dL, the sensitivity of ascitic cholesterol was superior to the serum-ascites albumin gradient (SAAG) in identifying NPH-related ascites; the area under the receiver operating characteristic curve was 0.945. In the patients misdiagnosed based on SAAG classification, the diagnostic accuracy of ascitic cholesterol was 69%. The ascitic cholesterol level showed excellent performance in identifying peritoneal lesions in patients with mixed ascites. CONCLUSION: Ascitic cholesterol is an excellent measure for detecting NPH ascites and for identifying peritoneal lesions in mixed ascites. Thus, this simple and cost-effective measure should be determined in patients with new-onset ascites (www.chictr.org.cn; ChiCTR-DCD-15006907).

T1, diffusion tensor, and quantitative magnetization transfer imaging of the hippocampus in an Alzheimer's disease mouse model.

Alzheimer's disease (AD) pathology causes microstructural changes in the brain. These changes, if quantified with magnetic resonance imaging (MRI), could be studied for use as an early biomarker for AD. The aim of our study was to determine if T1 relaxation, diffusion tensor imaging (DTI), and quantitative magnetization transfer imaging (qMTI) metrics could reveal changes within the hippocampus and surrounding white matter structures in ex vivo transgenic mouse brains overexpressing human amyloid precursor protein with the Swedish mutation. Delineation of hippocampal cell layers using DTI color maps allows more detailed analysis of T1-weighted imaging, DTI, and qMTI metrics, compared with segmentation of gross anatomy based on relaxation images, and with analysis of DTI or qMTI metrics alone. These alterations are observed in the absence of robust intracellular Aß accumulation or plaque deposition as revealed by histology. This work demonstrates that multiparametric quantitative MRI methods are useful for characterizing changes within the hippocampal substructures and surrounding white matter tracts of mouse models of AD.

The role of neuroinflammation and amyloid in cognitive impairment in an APP/PS1 transgenic mouse model of Alzheimer's disease.

AIMS: Both amyloid deposition and neuroinflammation appear in the early course of Alzheimer's disease (AD). However, the progression of neuroinflammation and its relationship with amyloid deposition and behavioral changes have not been fully elucidated. A better understanding the role of neuroinflammation in AD might extend our current knowledge to therapeutic intervention possibilities. METHODS: This study systematically characterized changes in behavioral abnormalities in APP/PS1 transgenic mice. Brain pathology measures were performed in post-mortem brain tissues of mice from 2 to 22 months. RESULTS: APP/PS1 mice exhibited significant memory deficits from 5 months old, which were aggravated at the later stage of life. However, the degree of memory impairments reached a plateau at 12 months. An early appearance of amyloid plaques was at 3 months with a linear increase throughout the disease course. CD11b-positive microglia and glial fibrillary acidic protein-(GFAP) positive astrocytes were first detected at 3 months with a close association with amyloid plaques. Yet, the rate of changes in glial activation slowed down from 12 months despite the steady increase in Aß. CONCLUSION: These findings provided evidence that neuroinflammation might be involved in the development and progression of cognitive deficits in APP/PS1 mice, suggesting novel intervention and prevention strategies for AD.