Expression of regional brain amyloid-ß deposition with [18F]Flutemetamol in Centiloid scale -a multi-site study.

PURPOSE: The Centiloid project helps calibrate the quantitative amyloid-ß (Aß) load into a unified Centiloid (CL) scale that allows data comparison across multi-site. How the smaller regional amyloid converted into CL has not been attempted. We first aimed to express regional Aß deposition in CL using [18F]Flutemetamol and evaluate regional Aß deposition in CL with that in standardized uptake value ratio (SUVr). Second, we aimed to determine the presence or absence of focal Aß deposition by measuring regional CL in equivocal cases showing negative global CL. METHODS: Following the Centiloid project pipeline, Level-1 replication, Level-2 calibration, and quality control were completed to generate corresponding Centiloid conversion equations to convert SUVr into Centiloid at regional levels. In equivocal cases, the regional CL was compared with visual inspection to evaluate regional Aß positivity. RESULTS: 14 out of 16 regional conversions from [18F]Flutemetamol SUVr to Centiloid successfully passed the quality control, showing good reliability and relative variance, especially precuneus/posterior cingulate and prefrontal regions with good stability for Centiloid scaling. The absence of focal Aß deposition could be detected by measuring regional CL, showing a high agreement rate with visual inspection. The regional Aß positivity in the bilateral anterior cingulate cortex was most prevalent in equivocal cases. CONCLUSION: The expression of regional brain Aß deposition in CL with [18F]Flutemetamol has been attempted in this study. Equivocal cases had focal Aß deposition that can be detected by measuring regional CL.

[Mechanism of Ganke Granules intervening acute lung injury based on network pharmacology and experimental verification].

This study aims to explore the potential mechanism of action in the intervention of acute lung injury(ALI) based on the blood entry components of Ganke Granules in rats and in conjunction with network pharmacology, molecular docking, and animal experimental validation. The blood entry components of Ganke Granules in rats were imported into the SwissTargetPrediction platform to predict drug targets, and ALI-related targets were collected from the disease database. Intersections were taken, and protein-protein interaction(PPI) networks were constructed to screen the core targets, followed by Gene Ontology(GO) functional and Kyoto encyclopedia of genes and gnomes(KEGG) pathway enrichment analyses. A "blood entry components-target-pathway-disease" network was constructed, and the core components for disease intervention based on their topological parameters were screened. Molecular docking was used to predict the binding ability of the core components to key targets. The key targets of Ganke Granules in the intervention of ALI were verified by the lipopolysaccharide(LPS)-induced ALI mouse model. Through PPI topological parameter analysis, the top six key targets of STAT3, SRC, HSP90AA1, MAPK3, HRAS, and MAPK1 related to ALI were obtained. GO functional analysis showed that it was mainly related to ERK1 and ERK2 cascade, inflammatory response, and response to LPS. KEGG analysis showed that the main enrichment pathways were MAPK, neutrophil extracellular trap(NET) formation, and so on. Six core components(schizantherin B, schisandrin, besigomsin, harpagoside, isotectorigenin, and trachelanthamine) were filtered out by the "blood entry components-target-pathway-disease" network based on the analysis of topological parameters. Molecular docking results showed that the six core components and Tectoridin with the highest content in the granules had a high affinity with the key targets of MAPK3, SRC, MAPK1, and STAT3. In vivo experiment results showed that compared with the model group, Ganke Granules could effectively alleviate LPS-induced histopathological injury in the lungs of mice and reduce the percentage of inflammatory infiltration. The total protein content, nitric oxide(NO) level, myeloperoxidase(MPO) content, tumor necrosis factor-α(TNF-α), gamma interferon(IFN-γ), interleukin-1ß(IL-1ß), interleukin-6(IL-6), vascular endothelial growth factor(VEGF), and chemokine(C-X-C motif) ligand 1(CXCL1) chemokines in bronchoalveolar lavage fluid(BALF) were decreased, and the expression levels of lymphocyte antigen 6G(Ly6G), citrullinated histones 3(Cit-H3), and phosphorylated proteins SRC, ERK1/2, and STAT3 in lung tissue were significantly down-regulated. In conclusion, Ganke Granules could effectively inhibit the inflammatory response of ALI induced by LPS, protect lung tissue, regulate the release of inflammatory factors, and inhibit neutrophil infiltration and NET formation, and the mechanism of action may be related to inhibiting the activation of SRC/ERK1/2/STAT3 signaling pathway.

Disrupted Structural White Matter Network in Alzheimer's Disease Continuum, Vascular Dementia, and Mixed Dementia: A Diffusion Tensor Imaging Study.

BACKGROUND: Dementia presents a significant burden to patients and healthcare systems worldwide. Early and accurate diagnosis, as well as differential diagnosis of various types of dementia, are crucial for timely intervention and management. However, there is currently a lack of clinical tools for accurately distinguishing between these types. OBJECTIVE: This study aimed to investigate the differences in the structural white matter (WM) network among different types of cognitive impairment/dementia using diffusion tensor imaging, and to explore the clinical relevance of the structural network. METHODS: A total of 21 normal control, 13 subjective cognitive decline (SCD), 40 mild cognitive impairment (MCI), 22 Alzheimer's disease (AD), 13 mixed dementia (MixD), and 17 vascular dementia (VaD) participants were recruited. Graph theory was utilized to construct the brain network. RESULTS: Our findings revealed a monotonic trend of disruption in the brain WM network (VaD > MixD > AD > MCI > SCD) in terms of decreased global efficiency, local efficiency, and average clustering coefficient, as well as increased characteristic path length. These network measurements were significantly associated with the clinical cognition index in each disease group separately. CONCLUSION: These findings suggest that structural WM network measurements can be utilized to differentiate between different types of cognitive impairment/dementia, and these measurements can provide valuable cognition-related information.

Circulating tumor cells as potential prognostic biomarkers for early-stage pancreatic cancer: A systematic review and meta-analysis.

BACKGROUND: Pancreatic cancer is difficult to be diagnosed early clinically, while often leads to poor prognosis. If optimal personalized treatment plan can be provided to pancreatic cancer patient at an earlier stage, this can greatly improve overall survival (OS). Circulating tumor cells (CTCs) are a collective term for various types of tumor cells present in the peripheral blood (PB), which are formed by detachment during the development of solid tumor lesions. Most CTCs undergo apoptosis or are phagocytosed after entering the PB, whereas a few can escape and anchor at distal sites to develop metastasis, increasing the risk of death for patients with malignant tumors. AIM: To investigate the significance of CTCs in predicting the prognosis of early pancreatic cancer patients. METHODS: The PubMed, EMBASE, Web of Science, Cochrane Library, China National Knowledge Infrastructure, China Biology Medicine, and ChinaInfo databases were searched for articles published through December 2022. Studies were considered qualified if they included patients with early pancreatic cancer, analyzed the prognostic value of CTCs, and were full papers reported in English or Chinese. Researches were selected and assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol and the Newcastle-Ottawa Scale criteria. We used a funnel plot to assess publication bias. RESULTS: From 1595 publications, we identified eight eligible studies that collectively enrolled 355 patients with pancreatic cancer. Among these original studies, two were carried out in China; three in the United States; and one each in Italy, Spain, and Norway. All eight studies analyzed the relevance between CTCs and the prognosis of patients with early-stage pancreatic cancer after surgery. A meta-analysis showed that the patients that were positive pre-treatment or post-treatment for CTCs were associated with decreased OS [hazard ratio (HR) = 1.93, 95% confidence interval (CI): 1.197-3.126, P = 0.007] and decreased relapse-free/disease-free/progression-free survival (HR = 1.27, 95%CI: 1.137-1.419, P < 0.001) in early-stage pancreatic cancer. Additionally, the results suggest no statistically noticeable publication bias for overall, disease-free, progression-free, and recurrence-free survival. CONCLUSION: This pooled meta-analysis shows that CTCs, as biomarkers, can afford reliable prognostic information for patients with early-stage pancreatic cancer and help develop individualized treatment plans.

Incremental diagnostic value of 18F-Fluetemetamol PET in differential diagnoses of Alzheimer's Disease-related neurodegenerative diseases from an unselected memory clinic cohort.

To evaluate the incremental diagnostic value of 18F-Flutemetamol PET following MRI measurements on an unselected prospective cohort collected from a memory clinic. A total of 84 participants was included in this study. A stepwise study design was performed including initial analysis (based on clinical assessments), interim analysis (revision of initial analysis post-MRI) and final analysis (revision of interim analysis post-18F-Flutemetamol PET). At each time of evaluation, every participant was categorized into SCD, MCI or dementia syndromal group and further into AD-related, non-AD related or non-specific type etiological subgroup. Post 18F-Flutemetamol PET, the significant changes were seen in the syndromal MCI group (57%, p < 0.001) involving the following etiological subgroups: AD-related MCI (57%, p < 0.01) and non-specific MCI (100%, p < 0.0001); and syndromal dementia group (61%, p < 0.0001) consisting of non-specific dementia subgroup (100%, p < 0.0001). In the binary regression model, amyloid status significantly influenced the diagnostic results of interim analysis (p < 0.01). 18F-Flutemetamol PET can have incremental value following MRI measurements, particularly reflected in the change of diagnosis of individuals with unclear etiology and AD-related-suspected patients due to the role in complementing AD-related pathological information.

The fractional amplitude of low-frequency fluctuations signals related to amyloid uptake in high-risk populations-A pilot fMRI study.

Background: Patients with type 2 diabetes mellitus (T2DM) and subjective cognitive decline (SCD) have a higher risk to develop Alzheimer's Disease (AD). Resting-state-functional magnetic resonance imaging (rs-fMRI) was used to document neurological involvement in the two groups from the aspect of brain dysfunction. Accumulation of amyloid-ß (Aß) starts decades ago before the onset of clinical symptoms and may already have been associated with brain function in high-risk populations. However, this study aims to compare the patterns of fractional amplitude of low-frequency fluctuations (fALFF) maps between cognitively normal high-risk groups (SCD and T2DM) and healthy elderly and evaluate the association between regional amyloid deposition and local fALFF signals in certain cortical regions. Materials and methods: A total of 18 T2DM, 11 SCD, and 18 healthy elderlies were included in this study. The differences in the fALFF maps were compared between HC and high-risk groups. Regional amyloid deposition and local fALFF signals were obtained and further correlated in two high-risk groups. Results: Compared to HC, the altered fALFF signals of regions were shown in SCD such as the left posterior cerebellum, left putamen, and cingulate gyrus. The T2DM group illustrated altered neural activity in the superior temporal gyrus, supplementary motor area, and precentral gyrus. The correlation between fALFF signals and amyloid deposition was negative in the left anterior cingulate cortex for both groups. In the T2DM group, a positive correlation was shown in the right occipital lobe and left mesial temporal lobe. Conclusion: The altered fALFF signals were demonstrated in high-risk groups compared to HC. Very early amyloid deposition in SCD and T2DM groups was observed to affect the neural activity mainly involved in the default mode network (DMN).

Heterogeneity of Amyloid Binding in Cognitively Impaired Patients Consecutively Recruited from a Memory Clinic: Evaluating the Utility of Quantitative 18F-Flutemetamol PET-CT in Discrimination of Mild Cognitive Impairment from Alzheimer's Disease and Other Dementias.

BACKGROUND: With the more widespread use of 18F-radioligand-based amyloid-ß (Aß) PET-CT imaging, we evaluated Aß binding and the utility of neocortical 18F-Flutemetamol standardized uptake value ratio (SUVR) as a biomarker. OBJECTIVE: 18F-Flutemetamol SUVR was used to differentiate 1) mild cognitive impairment (MCI) from Alzheimer's disease (AD), and 2) MCI from other non-AD dementias (OD). METHODS: 109 patients consecutively recruited from a University memory clinic underwent clinical evaluation, neuropsychological test, MRI and 18F-Flutemetamol PET-CT. The diagnosis was made by consensus of a panel consisting of 1 neuroradiologist and 2 geriatricians. The final cohort included 13 subjective cognitive decline (SCD), 22 AD, 39 MCI, and 35 OD. Quantitative analysis of 16 region-of-interests made by Cortex ID software (GE Healthcare). RESULTS: The global mean 18F-Flutemetamol SUVR in SCD, MCI, AD, and OD were 0.50 (SD-0.08), 0.53 (SD-0.16), 0.76 (SD-0.10), and 0.56 (SD-0.16), respectively, with SUVR in SCD and MCI and OD being significantly lower than AD. Aß binding in SCD, MCI, and OD was heterogeneous, being 23%, 38.5%, and 42.9% respectively, as compared to 100% amyloid positivity in AD. Using global SUVR, ROC analysis showed AUC of 0.868 and 0.588 in differentiating MCI from AD and MCI from OD respectively. CONCLUSION: 18F-Flutemetamol SUVR differentiated MCI from AD with high efficacy (high negative predictive value), but much lower efficacy from OD. The major benefit of the test was to differentiate cognitively impaired patients (either SCD, MCI, or OD) without AD-related-amyloid-pathology from AD in the clinical setting, which was under-emphasized in the current guidelines proposed by Amyloid Imaging Task Force.