BackgroundIdiopathic multicentric Castleman disease (iMCD) is a lymphoproliferative disorder characterized by dysregulated systemic immunity. Multiple cytokines had been found involved in the disease pathogenesis. Hence, involvement of multiple systems in iMCD complicates diagnosis and efficacy assessments. Although guidelines recommend anti-interleukin-6 (IL-6) agents as the primary treatment, options for second-line therapy remain indeterminate.Case presentationA 65-year-old woman presented with progressive polyneuropathy and nephrotic-range proteinuria ten days after COVID-19 vaccination. Evaluation revealed multicentric lymphadenopathy, elevated IL-6, and plasmacytic-variant CD histopathology (HHV-8 negative). Concurrent Sjögren’s syndrome and anti-PLA2R-negative membranous nephropathy were confirmed. After exclusion of POEMS syndrome, iMCD-NOS with intermediate severity was diagnosed. Initial rituximab-cyclophosphamide-dexamethasone therapy resulted in paradoxical neurological worsening despite declining VEGF levels. Anti-IL-6 therapy was inaccessible due to economic constraints. Single-agent rituximab was initiated and continued for nine cycles over 24 months, achieving clinical remission by January 2024 with near-normalization of inflammatory markers, resolution of proteinuria, and neurological recovery.ConclusionsThis case demonstrates that rituximab monotherapy can achieve clinical remission in iMCD-NOS with concurrent autoimmune manifestations when anti-IL-6 therapy is unavailable. The delayed response pattern—with biomarker improvement preceding clinical recovery—highlights the importance of serial VEGF monitoring and persistence with B-cell–directed therapy before concluding treatment failure.

Laminin gamma 2 (LAMC2) is upregulated in various tumors and is strongly associated with tumorigenesis, aggressiveness, metastasis, and a poor prognosis. This study evaluated the feasibility of 89Zr-labeled F(ab')2 fragments of an anti-LAMC2 monoclonal antibody (αLAMC2) for the noninvasive PET/CT imaging of LAMC2-positive nonsmall cell lung cancer (NSCLC) xenografts. LAMC2 expression in NSCLC cell lines was assessed with immunofluorescence staining and Western blotting, and NCIH292 (LAMC2-high) and A549 (LAMC2-low) cells were selected for further analyses. The F(ab')2 fragment of αLAMC2 was radiolabeled with 89Zr and evaluated in vitro for radiochemical purity, stability, cellular uptake, and internalization. PET/CT imaging and biodistribution analyses were conducted in NSCLC xenograft models to determine probe uptake and tumor targeting, with 89Zr-DFO-IgG-F(ab')2 used as a nontargeted control. The radiochemical purity of the 89Zr-DFO-αLAMC2-F(ab')2 probe started at 99.55 ± 0.37% and decreased to 98.00 ± 0.99% in PBS and 96.68 ± 1.66% in 5% FBS by day 5. Compared with A549 cells, NCIH292 cells exhibited substantial probe internalization and uptake at 24 h and 37 °C. Probe uptake was consistently higher in NCIH292 cells than in A549 cells, with NCIH292 exhibiting greater uptake than the control 89Zr-DFO-IgG-F(ab')2 at all time points, whereas A549 showed higher uptake than the control only at 24 h. PET imaging revealed significantly greater uptake in LAMC2-high xenografts (NCIH292) than in LAMC2-low xenografts (A549). Biodistribution studies corroborated these findings, showing high accumulation in NCIH292 xenografts (30.66 ± 3.72%ID/g at 72 h) versus low uptake in A549 xenografts (19.06 ± 3.03%ID/g at 72 h). The control probe 89Zr-DFO-IgG-F(ab')2 exhibited consistently low uptake in both PET imaging and biodistribution analyses. Immuno-PET with 89Zr-DFO-αLAMC2-F(ab')2 enabled the robust and specific visualization of LAMC2-expressing xenografts, supporting its potential as a noninvasive molecular imaging probe for the in vivo detection and quantification of LAMC2-positive tumors.

Type 2 diabetes mellitus (T2DM) is associated with a greater risk of Alzheimer's disease (AD). Synaptic impairment and protein aggregates have been reported in the brains of T2DM rodent models. Here, we assessed the changes in synaptic vesicle 2A (SV2A), amyloid-β, and tau that are featured pathologies in AD in T2DM rats in vivo. Positron emission tomography (PET) using [ 18 F]SynVesT-1 (SV2A), [ 18 F]flumazenil (GABA A receptor), [ 18 F]florbetapir (amyloid-β), [ 18 F]APN-1607 (tau), was carried out in 12-month-old diabetic Zucker diabetic fatty (ZDF) and Sprague‒Dawley (SD) rats. Immunofluorescence staining as well as proteomic profiling and pathway analysis were performed on the brain tissues of ZDF and SD rats. Reduced cortical [ 18 F]SynVesT-1 uptake were observed in 12-month-old ZDF rats compared to SD rats. No difference was observed in the [ 18 F]florbetapir and [ 18 F]APN-1607 uptake in the brains of 12-month-old ZDF and SD rats. Immunofluorescence staining revealed Thioflavin S-negative, phospho-tau-positive inclusions in the cortex and hypothalamus of ZDF rats, without amyloid-beta deposits. Proteomic analysis further demonstrated downregulated synaptic-related proteins pathways in the hippocampus of ZDF rats compared to SD rats. These findings provide in vivo evidence for synaptic impairment in the brains of aged T2DM ZDF rats.

As the brain’s resident immune cells, microglia perform crucial functions such as phagocytosis, neuronal network maintenance, and injury restoration by adopting various phenotypes. Dynamic imaging of these phenotypes is essential for accessing brain diseases and therapeutic responses. Although numerous probes are available for imaging pro-inflammatory microglia, no PET tracers have been developed specifically to visualize anti-inflammatory microglia. In this study, we present an 18F-labeled PET tracer (QTFT) that targets the P2Y12, a receptor highly expressed on anti-inflammatory microglia. [18F]QTFT exhibited high binding affinity to the P2Y12 (14.43 nmol/L) and superior blood-brain barrier permeability compared to other candidates. Micro-PET imaging in IL-4-induced neuroinflammation models showed higher [18F]QTFT uptake in lesions compared to the contralateral normal brain tissues. Importantly, this specific uptake could be blocked by QTFT or a P2Y12 antagonist. Furthermore, [18F]QTFT visualized brain lesions in mouse models of epilepsy, glioma, and aging by targeting the aberrantly expressed P2Y12 in anti-inflammatory microglia. In a pilot clinical study, [18F]QTFT successfully located epileptic foci, showing enhanced radioactive signals in a patient with epilepsy. Collectively, these studies suggest that [18F]QTFT could serve as a valuable diagnostic tool for imaging various brain disorders by targeting P2Y12 overexpressed in anti-inflammatory microglia.

Metabotropic glutamate receptor 5 (mGluR5) modulates excitatory glutamatergic synaptic transmission and plays an important role in learning and memory, and in the pathphysiology of Alzheimer’s disease (AD). Here, we aimed to assess the alterations of mGluR5 in the hippocampus of AD patients and mouse model, and the association with amyloid pathology. Immunofluorescence staining was performed on postmortem brain tissue from 35 AD patients and 36 control patients, as well as on the brain tissue slices from 15 months-old 3×Tg and arcAβ mouse models of AD amyloidosis. Autoradiography was performed on brain tissue slices from arcAβ mice using mGluR5 tracer [ 18 F]PSS232. Proteomic profiling and pathway analysis were performed on hippocampal tissue from six 15 months-old 3xTg mice and six age-matched wildtype mice. Reduced levels of mGluR5 were observed in the hippocampus of AD patients compared to non-demented control. Ex vivo autoradiography revealed a reduced level of [ 18 F]PSS232 in the hippocampus and striatum of arcAβ mice compared to nontransgenic littermate mice. Reduced mGluR5 immunoreactivity was observed near 6E10-positive Aβ plaques in the hippocampus. In contrast, upregulated levels of Shank3, Grin2a, Grin2b, and Grm5; and upregulation of glutamatergic pathway (GO and KEGG pathway enrichment analyses) were detected in hippocampal tissue from 3xTg mice compared to wildtype mice. This study revealed a reduction in the level of mGluR5 in the hippocampus of AD patients, and a strain-dependent alteration of mGluR5 in mouse models of AD.

RATIONALE AND OBJECTIVES:Systemic amyloidosis is underdiagnosed in light-chain amyloidosis (AL), as is plasma cell dyscrasias (PCD). Early detection and accurate evaluation of organ involvement in systemic amyloidosis remain critical challenges. We aimed to assess the utility of [18F]florbetapir (FBP) and [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) for the early detection and evaluation of organ involvement in systemic amyloidosis. MATERIALS AND METHODS:We included 66 participants and performed biochemical assays in serum and urine and whole-body PET/computed tomography using [18F]FBP and [18F]FDG, followed by visual, maximum standardized uptake value (SUVmax), and target-to-background ratio (TBR) analyses. The clinical evaluation of organ involvement was based on the histological analysis of tissue biopsies obtained from suspected organs in AL and PCD cases. RESULTS:[18F]FBP SUVmax and TBR analyses revealed comparable uptake in AL patients and significantly greater uptake than in PCD patients. Distinct regional distributions of [18F]FBP and [18F]FDG were observed between the PCD and AL groups. The [18F]FBP SUVmax and visual analysis provided comparable measures of organ involvement and demonstrated high sensitivity, outperforming [18F]FDG in detecting organ amyloidosis in both PCD and AL patients. More organ involvement was detected by [18F]FBP PET (SUVmax or visual) than by biopsies based evaluation. CONCLUSION:[18F]FBP PET, through both visual and SUVmax analysis, is more sensitive than [18F]FDG PET and biopsy-based analysis for detecting organ amyloidosis in PCD and AL patients. It serves as a valuable noninvasive method for the early and accurate detection of systemic amyloidosis, with the potential to improve diagnostic precision and facilitate timely intervention in systemic amyloidosis patients.

Reactive astrocytes play an important role in the development of Alzheimer’s disease (AD). Here, we aimed to investigate the temporospatial relationships among monoamine oxidase-B, tau and amyloid-β (Aβ), translocator protein, and glucose metabolism by using multitracer imaging in AD transgenic mouse models. Positron emission tomography (PET) imaging with [18F]SMBT-1 (monoamine oxidase-B), [18F]florbetapir (Aβ), [18F]PM-PBB3 (tau), [18F]fluorodeoxyglucose (FDG), and [18F]DPA-714 (translocator protein) was carried out in 5- and 10-month-old APP/PS1, 11-month-old 3×Tg mice, and aged-matched wild-type mice. The brain regional referenced standard uptake value (SUVR) was computed with the cerebellum as the reference region. Immunofluorescence staining was performed on mouse brain tissue slices. [18F]SMBT-1 and [18F]florbetapir SUVRs were greater in the cortex and hippocampus of 10-month-old APP/PS1 mice than in those of 5-month-old APP/PS1 mice and wild-type mice. No significant difference in the regional [18F]FDG or [18F]DPA-714 SUVRs was observed in the brains of 5- or 10-month-old APP/PS1 mice or wild-type mice. No significant difference in the SUVRs of any tracer was observed between 11-month-old 3×Tg mice and age-matched wild-type mice. A positive correlation between the SUVRs of [18F]florbetapir and [18F]DPA-714 in the cortex and hippocampus was observed among the transgenic mice. Immunostaining validated the distribution of MAO-B and limited Aβ and tau pathology in 11-month-old 3×Tg mice; and Aβ deposits in brain tissue from 10-month-old APP/PS1 mice. In summary, these findings provide in vivo evidence that an increase in astrocyte [18F]SMBT-1 accompanies Aβ accumulation in APP/PS1 models of AD amyloidosis.

PURPOSE:Type 2 diabetes mellitus (T2DM) is associated with a greater risk of Alzheimer's disease. Synaptic impairment and protein aggregates have been reported in the brains of T2DM models. Here, we assessed whether neurodegenerative changes in synaptic vesicle 2 A (SV2A), γ-aminobutyric acid type A (GABAA) receptor, amyloid-β, tau and receptor for advanced glycosylation end product (RAGE) can be detected in vivo in T2DM rats. METHODS:Positron emission tomography (PET) using [18F]SDM-8 (SV2A), [18F]flumazenil (GABAA receptor), [18F]florbetapir (amyloid-β), [18F]PM-PBB3 (tau), and [18F]FPS-ZM1 (RAGE) was carried out in 12-month-old diabetic Zucker diabetic fatty (ZDF) and SpragueDawley (SD) rats. Immunofluorescence staining, Thioflavin S staining, proteomic profiling and pathway analysis were performed on the brain tissues of ZDF and SD rats. RESULTS:Reduced cortical [18F]SDM-8 uptake and cortical and hippocampal [18F]flumazenil uptake were observed in 12-month-old ZDF rats compared to SD rats. The regional uptake of [18F]florbetapir and [18F]PM-PBB3 was comparable in the brains of 12-month-old ZDF and SD rats. Immunofluorescence staining revealed Thioflavin S-negative, phospho-tau-positive inclusions in the cortex and hypothalamus in the brains of ZDF rats and the absence of amyloid-beta deposits. The level of GABAA receptors was lower in the cortex of ZDF rats than SD rats. Proteomic analysis further demonstrated that, compared with SD rats, synaptic-related proteins and pathways were downregulated in the hippocampus of ZDF rats. CONCLUSION:These findings provide in vivo evidence for regional reductions in SV2A and GABAA receptor levels in the brains of aged T2DM ZDF rats.

Background Metabotropic glutamate receptor 5 (mGluR5) modulates excitatory glutamatergic synaptic transmission and plays an important role in learning and memory formation and in neurodegeneration and amyloid deposition in Alzheimer’s disease (AD). Conflicting results on the cerebral mGluR5 levels in AD have been reported based on in vivo and postmortem studies. Here, we aimed to assess alterations in hippocampal mGluR5 expression in AD, and the associations between mGluR5 expression and pathologies. Methods Immunofluorescence staining for mGluR5 was performed on postmortem brain tissue from 34 AD patients and 31 nondemented controls (NCs) and from aged 3×Tg and arcAβ model mice of AD. Autoradiography was performed on brain tissue slices from arcAβ mice using mGluR5 tracer [18F]PSS232. Analysis of different cellular source of GRM5 RNA in human and mouse brains was performed. Proteomic profiling and pathway analysis were performed on hippocampal tissue from aged 3×Tg mice and wild-type mice. Results No differences in hippocampal mGluR5 expression or entorhinal cortical GRM5 RNA levels were detected between the AD and NC groups. Hippocampal mGluR5 levels increased with Braak stage and decreased with amyloid level in the NC group. No correlations were detected between the levels of mGluR5 and amyloid, tau, or Iba1/P2X7R in the hippocampus of AD patients and NC cases. Ex vivo autoradiography revealed comparable cerebral levels of [18F]PSS232 in arcAβ mice compared to nontransgenic mice. GO and KEGG pathway enrichment analyses revealed that the Shank3, Grm5 and glutamatergic pathways were upregulated in hippocampal tissue from aged 3×Tg mice compared to wild-type mice. Conclusion This study revealed no difference in hippocampal mGluR5 levels between AD patients and NCs and revealed the divergent influence of amyloid and tau pathologies on hippocampal mGluR5 levels in NCs. Species differences were observed in the GRM5 RNA level as well as at the cellular location. ![Figure][1] ### Competing Interest Statement CH and RMN are employees and shareholders of Neurimmune AG. The authors declare no conflicts of interest. [1]: pending:yes

Neuroinflammation plays an important role in Alzheimer’s disease and primary tauopathies. The aim of the current study was to map [18F]GSK1482160 for imaging of purinergic P2X7R in Alzheimer’s disease and primary tauopathy mouse models. MicroPET was performed using [18F]GSK1482160 in widely used mouse models of Alzheimer’s disease (APP/PS1, 5×FAD and 3×Tg), 4-repeat tauopathy (rTg4510) mice and age-matched wild-type mice. Increased uptake of [18F]GSK1482160 was observed in the cortex and basal forebrain of 7-month-old rTg4510 mice compared to age-matched wild-type mice and compared to 3-month-old rTg4510 mice. Nonparametric Spearman’s rank analysis revealed a positive correlation between tau [18F]APN-1607 uptake and [18F]GSK1482160 in the hippocampus of rTg4510 mice. No significant differences in the uptake of [18F]GSK1482160 were observed between wild-type mice and APP/PS1 mice (5, 10 months), 5×FAD mice (3, 7 months) or 3×Tg mice (10 months). Immunofluorescence staining further indicated the distribution of P2X7Rs in the brains of 7-month-old rTg4510 mice with accumulation of tau inclusion compared to wild-type mice. These findings provide in vivo imaging evidence for increased P2X7R in the brains of tauopathy model mice.### Competing Interest StatementThe authors have declared no competing interest.

Neuroinflammation plays an important role in Alzheimer's disease and primary tauopathies. The aim of the current study was to map [18F]GSK1482160 for imaging of purinergic P2X7R in Alzheimer's disease and primary tauopathy mouse models. Small animal PET was performed using [18F]GSK1482160 in widely used mouse models of Alzheimer's disease (APP/PS1, 5×FAD, and 3×Tg), 4-repeat tauopathy (rTg4510) mice, and age-matched wild-type mice. Increased uptake of [18F]GSK1482160 was observed in the brains of 7-month-old rTg4510 mice compared to wild-type mice and compared to 3-month-old rTg4510 mice. A positive correlation between hippocampal tau [18F]APN-1607 and [18F]GSK1482160 uptake was found in rTg4510 mice. No significant differences in the uptake of [18F]GSK1482160 was observed for APP/PS1 mice, 5×FAD mice, or 3×Tg mice. Immunofluorescence staining further indicated the distribution of P2X7Rs in the brains of 7-month-old rTg4510 mice with accumulation of tau inclusion. These findings provide in vivo imaging evidence for an increased level of P2X7R in the brains of tauopathy mice.

Background: Reactive astrocytes play important roles in the development of Alzheimer’s disease (AD) and primary tauopathies. Here, we aim to investigate the relationship between reactive astrocytes, tau and amyloid beta, microgliosis and glucose metabolism by using multitracer imaging in widely used tauopathy and familial AD mouse models. Results: Positron emission tomography (PET) imaging using [ 18 F]SMBT-1 (monoamine oxidase-B), [ 18 F]florbetapir (amyloid-beta), [ 18 F]PM-PBB3 (tau), [ 18 F]DPA-714 (translocator protein) and [ 18 F]fluorodeoxyglucose (FDG) was carried out in 3- and 7-month-old rTg4510 tau mice, 5×FAD familial AD mice and aged-matched wild-type mice. We found increased regional [ 18 F]SMBT-1, [ 18 F]DPA-714 uptake, and hypoglucose metabolism in the brains of 7-month-old rTg4510 mice with tau accumulation as well as in 7-month-old 5×FAD mice with higher amyloid-beta and tau accumulation compared to age-matched wild-type mice. Conclusion: In summary, these findings provide in-vivo evidence for reactive astrocytes, microglial activation, and cerebral hypoglucose metabolism in animal models of tauopathy and familial AD.

Background LncRNAs regulate tumorigenesis and development in a variety of cancers. We substantiate for the first time that LINC00606 is considerably expressed in glioblastoma (GBM) patient specimens and is linked with adverse prognosis. This suggests that LINC00606 may have the potential to regulate glioma genesis and progression, and that the biological functions and molecular mechanisms of LINC00606 in GBM remain largely unknown.Methods The expression of LINC00606 and ATP11B in glioma and normal brain tissues was evaluated by qPCR, and the biological functions of the LINC00606/miR-486-3p/TCF12/ATP11B axis in GBM were verified through a series of in vitro and in vivo experiments. The molecular mechanism of LINC00606 was elucidated by immunoblotting, FISH, RNA pulldown, CHIP-qPCR, and a dual-luciferase reporter assay.Results We demonstrated that LINC00606 promotes glioma cell proliferation, clonal expansion and migration, while reducing apoptosis levels. Mechanistically, on the one hand, LINC00606 can sponge miR-486-3p; the target gene TCF12 of miR-486-3p affects the transcriptional initiation of LINC00606, PTEN and KLLN. On the other hand, it can also regulate the PI3K/AKT signaling pathway to mediate glioma cell proliferation, migration and apoptosis by binding to ATP11B protein.Conclusions Overall, the LINC00606/miR-486-3p/TCF12/ATP11B axis is involved in the regulation of GBM progression and plays a role in tumor regulation at transcriptional and post-transcriptional levels primarily through LINC00606 sponging miR-486-3p and targeted binding to ATP11B. Therefore, our research on the regulatory network LINC00606 could be a novel therapeutic strategy for the treatment of GBM.Graphical Abstract LINC00606 is highly expressed in GBM patients with carcinogenic function and correlated with poor prognosis. LINC00606 regulates glioblastoma progression by sponging miR-486-3p and interacting with ATP11B.

Purpose Reactive astrocytes play an important role in the development of Alzheimer’s disease (AD). Here, we aim to investigate the temporospatial relationship between reactive astrocytes, tau and amyloid-β, glucose metabolism, and microgliosis by using multitracer imaging in AD transgenic mouse models. Methods Positron emission tomography (PET) imaging with [18F]SMBT-1 (monoamine oxidase-B), [18F]florbetapir (Aβ), [18F]PM-PBB3 (tau), [18F]FDG, and [18F]DPA-714 (translocator protein) was carried out in 5- and 10-month-old APP/PS1, 11-month-old 3×Tg mice, and aged-matched wild-type mice. The brain regional referenced standard uptake value (SUVR) was computed with the cerebellum as the reference region. Immunofluorescence staining was performed in mouse brain tissue slices. Results [18F]SMBT-1 and [18F]florbetapir SUVRs were higher in the cortex and hippocampus of 10-month-old APP/PS1 mice than in 5-month-old APP/PS1 mice and wild-type mice. Reduced [18F]FDG SUVR was observed in the thalamus and midbrain of 5-month-old APP/PS1 mice compared to wild-type mice. No significant difference in brain regional [18F]DPA-714 SUVR was observed in 5- and 10-month-old APP/PS1 mice compared to wild- type mice. No significant difference in the SUVRs of any tracers was observed in 11-month-old 3×Tg mice compared to age-matched wild-type mice. A positive correlation between the SUVRs of [18F]SMBT-1 and [18F]DPA-714 in the cortex was observed. Immunostaining validated the distribution of MAO-B and TSPO, amyloid and tau inclusions in brain tissue from 10-month-old APP/PS1 mice and limited changes in 11-month- old 3×Tg mice. Conclusion The findings provide in vivo evidence for reactive astrocytes along with amyloid plaque and tau deposition preceding microgliosis in animal models of AD pathologies.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant solid tumor that lacks early diagnostic methods. Recently, targeted immunotherapy and radiotherapy have been integrated with radionuclide-antibody conjugate drugs, which can be used for targeted diagnosis and dynamic imaging of tumors. CEACAM6 is overexpressed in pancreatic tumors and is a potential theranostic target for PDAC. We aimed to develop a novel targeted carrier for theranostics of PDAC and other solid tumors. Based on camelid heavy-chain-only antibodies, we developed a CEACAM6-targeting recombinant antibody NY004, and evaluated it as a novel antibody-carrier for imaging and therapy of cancer in tumor models. We labeled NY004 with theranostic nuclides and applied this self-developed antibody platform in diagnostic imaging and antitumor assessment in PDAC models. Through microPET, IHC, and biodistribution assays, targeting and biodistribution of [89Zr]-NY004 in solid tumors including PDAC was examined, and the investigated tumors were all CEACAM6-positive malignancies. We found that NY004 was suitable for use as a drug carrier for radioimmunotheranostics. Our study showed that NY004 was characterized by high targeted uptake and a long retention time in PANC-1 tumors (up to 6 days post-injection), with good specificity and high imaging efficiency. Therapeutic evaluation of the radionuclide-labeled antibody drug [177Lu]-NY004 in PDAC tumor-bearing model revealed that NY004 had high and prolonged uptake in tumors, relatively low non-target organ uptake, and good anti-tumor efficacy. As a drug platform for radiotheranostics, CEACAM6-specific antibody NY004 met the requirements of easy-labeling, targeting specificity, and effective persistence in pancreatic adenocarcinoma tissues. • [89Zr]-NY004 has good specificity and high imaging efficiency, and is characterized by high tumor-targeting uptake and a long tumor retention time as a PET molecular imaging tracer. • Therapeutic radionuclide-conjugated antibody drug [177Lu]-NY004 has high uptake and prolonged uptake duration in tumors, low non-target organ uptake, and significant tumor-inhibiting efficacy in PDAC model. • The self-developed antibody structure NY004 is a promising drug platform for radioimmunotheranostics of CEACAM6-positive tumors including pancreatic ductal adenocarcinoma.

The microtubule-associated protein tau (MAPT) plays an important role in Alzheimer's disease and primary tauopathy diseases. The abnormal accumulation of tau contributes to the development of neurotoxicity, inflammation, neurodegeneration, and cognitive deficits in tauopathy diseases. Tau synergically interacts with amyloid-beta in Alzheimer's disease leading to detrimental consequence. Thus, tau has been an important target for therapeutics development for Alzheimer's disease and primary tauopathy diseases. Tauopathy animal models recapitulating the tauopathy such as transgenic, knock-in mouse and rat models have been developed and greatly facilitated the understanding of disease mechanisms. The advance in PET and imaging tracers have enabled non-invasive detection of the accumulation and spread of tau, the associated microglia activation, metabolic, and neurotransmitter receptor alterations in disease animal models. In vivo microPET studies on mouse or rat models of tauopathy have provided significant insights into the phenotypes and time course of pathophysiology of these models and allowed the monitoring of treatment targeting at tau. In this study, we discuss the utilities of PET and recently developed tracers for evaluating the pathophysiology in tauopathy animal models. We point out the outstanding challenges and propose future outlook in visualizing tau-related pathophysiological changes in brain of tauopathy disease animal models.

Existing diagnostic methods are limited to observing appearance and demeanor, even though genetic factors play important roles in the pathology of schizophrenia. Indeed, no molecular-level test exists to assist diagnosis, which has limited treatment strategies. To address this serious shortcoming, we used a bioinformatics approach to identify 61 genes that are differentially expressed in schizophrenia patients compared with healthy controls. In particular, competing endogenous RNA network revealed the important role of the gene RASD2, which is regulated by miR-4763-3p. Indeed, analysis of blood samples confirmed that RASD2 is downregulated in schizophrenia patients. Moreover, positron emission tomography data collected for 44 human samples identified the prefrontal and temporal lobes as potential key brain regions in schizophrenia patients. Mechanistic studies indicated that miR-4763-3p inhibits RASD2 by base-pairing with the 3' untranslated region of RASD2 mRNA. Importantly, RASD2 has been shown to interact with β-arrestin2, which contributes to the regulation of the DRD2-dependent CREB response element-binding protein pathway in the dopamine system. Finally, results obtained with a mouse model of schizophrenia revealed that inhibition of miR-4763-3p function alleviated anxiety symptoms and improved memory. The dopamine transporters in the striatal regions were significantly reduced in schizophrenia model mice as compared with wild-type mice, suggesting that inhibition of miR-4763-3p can lessen the symptoms of schizophrenia. Our findings demonstrate that miR-4763-3p may target RASD2 mRNA and thus may serve as a potential biomarker and therapeutic target for schizophrenia, providing a theoretical foundation for further studies of the molecular basis of this disease.

Background Non-invasive diagnosis of IDH1 mutation for gliomas has great clinical significance, and PET has natural advantage to detect metabolism, as IDH mutated gliomas share lower glucose consumption. Methods Clinical data of patients with gliomas and 18 F-FDG PET were retrospectively reviewed. Receiver operating characteristic curve (ROC) analysis was conducted, and standard uptake value (SUV) was estimated in combination with grades or IDH1 mutation. The glucose consumption was investigated with U251 cells expressing wild-type or mutated IDH1 by glucose assay. Quantification of glucose was determined by HPLC in clinical tissues. Meanwhile, bioinformatics and western blot were applied to analyze the expression level of metabolic enzymes (e.g. HK1, PKM2, PC) in gliomas. Results Seventy-one glioma cases were enrolled, including 30 carrying IDH1 mutation. The sensitivity and specificity dependent on SUV max (3.85) predicting IDH1 mutation reached 73.2 and 86.7%, respectively. The sensitivity and specificity of differentiating grades by SUVmax (3.1) were 92.3 and 64.4%, respectively. Glucose consumption of U251 IDH1 mutant cells (0.209 ± 0.0472 mg/ml) was obviously lower than IDH1wild-type cells (0.978 ± 0.0773 mg/ml, P = 0.0001 ) and astrocyte controls (0.335 ± 0.0592 mg/ml, P = 0.0451 ). Meanwhile, the glucose quantity in IDH1mutant glioma samples were significantly lower than those in IDH1 wild-type tissues (1.033 ± 1.19608 vs 6.361 ± 4.3909 mg/g, P = 0.0051 ). Silico analysis and western blot confirmed that HK1 and PKM2 in IDH1 wild-type gliomas were significantly higher than in IDH1 mutant group, while PC was significantly higher in IDH1 mutant gliomas. Conclusion SUV max on PET can predict IDH1 mutation with adequate sensitivity and specificity, as is supported by reduced glucose consumption in IDH1 mutant gliomas.

The uneven distribution of sample points is a common problem in medical datasets. How to improve the classification accuracy with these datasets remains to be solved. Based on the density-based spatial clustering of applications with noise (DBSCAN) algorithm, a weight learning approach is proposed to utilize the density information of datasets for the accurate prediction of cardiovascular diseases (CVDs). The approach selects important features by the random forest (RF) algorithm, divides the sample points into three types and weights them using different values by weight learning based on the density. Thus, the constructed machine learning models that combine the original features and weight feature can learn density information, more effectively identify decision boundaries, and achieve better performance. Compared with conventional machine learning models, the cross-validation approach showed that the performance of machine learning models with weight learning could achieve improved accuracy by 3 percentage points with the Stroke dataset and more than 10 percentage points with the University of California, Irvine (UCI) dataset.