INTRODUCTION
Alzheimer's disease (AD), the leading cause of dementia worldwide, represents a human and financial impact for which few effective drugs exist to treat the disease. Advances in molecular ...imaging have enabled assessment of cerebral glycolytic metabolism, and network modeling of brain region have linked to alterations in metabolic activity to AD stage.
METHODS
We performed 18F‐FDG positron emission tomography (PET) imaging in 4‐, 6‐, and 12‐month‐old 5XFAD and littermate controls (WT) of both sexes and analyzed region data via brain metabolic covariance analysis.
RESULTS
The 5XFAD model mice showed age‐related changes in glucose uptake relative to WT mice. Analysis of community structure of covariance networks was different across age and sex, with a disruption of metabolic coupling in the 5XFAD model.
DISCUSSION
The current study replicates clinical AD findings and indicates that metabolic network covariance modeling provides a translational tool to assess disease progression in AD models.
Acquired and intrinsic resistance to receptor tyrosine kinase inhibitors (RTKi) represents a major hurdle in improving the management of clear cell renal cell carcinoma (ccRCC). Recent reports ...suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways. The histone methyl transferase EZH2 is frequently altered in many cancers, including ccRCC. To evaluate its role in ccRCC resistance to RTKi, we established and characterized a spontaneously metastatic, patient-derived xenograft model that is intrinsically resistant to the RTKi sunitinib, but not to the VEGF therapeutic antibody bevacizumab. Sunitinib maintained its antiangiogenic and antimetastatic activity but lost its direct antitumor effects due to kinome reprogramming, which resulted in suppression of proapoptotic and cell-cycle-regulatory target genes. Modulating EZH2 expression or activity suppressed phosphorylation of certain RTKs, restoring the antitumor effects of sunitinib in models of acquired or intrinsically resistant ccRCC. Overall, our results highlight EZH2 as a rational target for therapeutic intervention in sunitinib-resistant ccRCC as well as a predictive marker for RTKi response in this disease.
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The 5xFAD mouse is a popular model of familial Alzheimer's disease (AD) that is characterized by early beta-amyloid (Aβ) deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse ...has not been comprehensively phenotyped for vascular and metabolic perturbations over its lifespan.
Male and female 5xFAD and wild type (WT) littermates underwent
F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at 4, 6, and 12 months of age to assess regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent "vessel painting" which labels all cerebral vessels and were analyzed for vascular characteristics such as vessel density, junction density, vessel length, network complexity, number of collaterals, and vessel diameter.
With increasing age, vessels on the cortical surface in both 5xFAD and WT mice showed increased vessel length, vessel and junction densities. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but collateral diameters were significantly increased only in 5xFAD mice. MCA total vessel length and junction density were decreased in 5xFAD mice compared to WT at 4 months. Analysis of
F-FDG cortical uptake revealed significant differences between WT and 5xFAD mice spanning 4-12 months. Broadly, 5xFAD males had significantly increased
F-FDG uptake at 12 months compared to WT mice. In most cortical regions, female 5xFAD mice had reduced
F-FDG uptake compared to WT across their lifespan.
While the 5xFAD mouse exhibits AD-like cognitive deficits as early as 4 months of age that are associated with increasing Aβ deposition, we only found significant differences in cortical vascular features in males, not in females. Interestingly, 5xFAD male and female mice exhibited opposite effects in
F-FDG uptake. The MCA supplies blood to large portions of the somatosensory cortex and portions of motor and visual cortex and increased vessel length alongside decreased collaterals which coincided with higher metabolic rates in 5xFAD mice. Thus, a potential mismatch between metabolic demand and vascular delivery of nutrients in the face of increasing Aβ deposition could contribute to the progressive cognitive deficits seen in the 5xFAD mouse model.
Renal sympathetic denervation (RD) is a promising method of neuromodulation for the management of cardiac arrhythmia.
We tested the hypothesis that RD is antiarrhythmic in ambulatory dogs because it ...reduces the stellate ganglion nerve activity (SGNA) by remodeling the stellate ganglion (SG) and brain stem.
We implanted a radiotransmitter to record SGNA and electrocardiogram in 9 ambulatory dogs for 2 weeks, followed by a second surgery for RD and 2 months SGNA recording. Cell death was probed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay.
Integrated SGNA at baseline and 1 and 2 months after RD were 14.0 ± 4.0, 9.3 ± 2.8, and 9.6 ± 2.0 μV, respectively (P = .042). The SG from RD but not normal control dogs (n = 5) showed confluent damage. An average of 41% ± 10% and 40% ± 16% of ganglion cells in the left and right SG, respectively, were TUNEL positive in RD dogs compared with 0% in controls dogs (P = .005 for both). The left and right SG from RD dogs had more tyrosine hydroxylase-negative ganglion cells than did the left SG of control dogs (P = .028 and P = .047, respectively). Extensive TUNEL-positive neurons and glial cells were also noted in the medulla, associated with strongly positive glial fibrillary acidic protein staining. The distribution was heterogeneous, with more cell death in the medial than lateral aspects of the medulla.
Bilateral RD caused significant central and peripheral sympathetic nerve remodeling and reduced SGNA in ambulatory dogs. These findings may in part explain the antiarrhythmic effects of RD.
To evaluate whether technetium-99 (
Tc)-labeled macroaggregated albumin (MAA) can predict subsequent yttrium-90 (
Y) distribution and imaging response in patients with hepatocellular carcinoma (HCC).
...Retrospective review was performed of records of 83 patients with HCC who underwent
Y glass microsphere radioembolization with
Tc-MAA single photon emission computed tomography (SPECT) and
Y positron emission tomography (PET)/CT between January 2013 and December 2014. Images were fused to segment the whole liver normal tissue (WLNT) and the largest tumors. Fused images were reviewed and analyzed for comparison of absorbed dose (AD) to tumors and WLNT as calculated from
Tc-MAA SPECT and from
Y PET/CT, subjective imaging comparison of
Tc-MAA SPECT and
Y PET for tumors and WLNT, and correlation of tumoral AD with response on follow-up CT.
Final analysis included 73 and 63 patients for WLNT and tumor
Tc-MAA/
Y correlation, respectively, and 62 patients for AD vs response.
Tc-MAA/
Y limit of agreement for each reviewer was viewed as clinically acceptable only for WLNT (-15 to 15 Gy). AD interreviewer variability was clinically acceptable for WLNT but was too broad for tumor. Mean tumor AD for objective response (78%) was 313 Gy vs 234 Gy for nonresponders. No threshold was found between tumor AD and response (P > .1). Catheter mismatch between
Tc-MAA and
Y had a direct impact on AD mismatch between the 2 image sets.
Tc-MAA was found to be a poor surrogate to quantitatively predict subsequent
Y AD to hepatocellular tumors.
Tc-MAA distribution correlated with
Y distribution in the normal hepatic parenchyma.
Subcritical epileptiform activity is associated with impaired cognitive function and is commonly seen in patients with Alzheimer's disease (AD). The anti-convulsant, levetiracetam (LEV), is currently ...being evaluated in clinical trials for its ability to reduce epileptiform activity and improve cognitive function in AD. The purpose of the current study was to apply pharmacokinetics (PK), network analysis of medical imaging, gene transcriptomics, and PK/PD modeling to a cohort of amyloidogenic mice to establish how LEV restores or drives alterations in the brain networks of mice in a dose-dependent basis using the rigorous preclinical pipeline of the MODEL-AD Preclinical Testing Core.
Chronic LEV was administered to 5XFAD mice of both sexes for 3 months based on allometrically scaled clinical dose levels from PK models. Data collection and analysis consisted of a multi-modal approach utilizing
F-FDG PET/MRI imaging and analysis, transcriptomic analyses, and PK/PD modeling.
Pharmacokinetics of LEV showed a sex and dose dependence in C
, CL/F, and AUC
, with simulations used to estimate dose regimens. Chronic dosing at 10, 30, and 56 mg/kg, showed
F-FDG specific regional differences in brain uptake, and in whole brain covariance measures such as clustering coefficient, degree, network density, and connection strength (i.e., positive and negative). In addition, transcriptomic analysis via nanoString showed dose-dependent changes in gene expression in pathways consistent
F-FDG uptake and network changes, and PK/PD modeling showed a concentration dependence for key genes, but not for network covariance modeling.
This study represents the first report detailing the relationships of metabolic covariance and transcriptomic network changes resulting from LEV administration in 5XFAD mice. Overall, our results highlight non-linear kinetics based on dose and sex, where gene expression analysis demonstrated LEV dose- and concentration-dependent changes, along with cerebral metabolism, and/or cerebral homeostatic mechanisms relevant to human AD, which aligned closely with network covariance analysis of
F-FDG images. Collectively, this study show cases the value of a multimodal connectomic, transcriptomic, and pharmacokinetic approach to further investigate dose dependent relationships in preclinical studies, with translational value toward informing clinical study design.
Vascular contributions to cognitive impairment and dementia (VCID) particularly Alzheimer’s disease and related dementias (ADRDs) are increasing; however, mechanisms driving cerebrovascular decline ...are poorly understood. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate and methionine cycles. Variants in MTHFR, notably 677 C > T, are associated with dementias, but no mouse model existed to identify mechanisms by which MTHFR677C > T increases risk. Therefore, MODEL-AD created a novel knock-in (KI) strain carrying the Mthfr677C > T allele on the C57BL/6J background (Mthfr677C > T) to characterize morphology and function perturbed by the variant. Consistent with human clinical data, Mthfr677C > T mice have reduced enzyme activity in the liver and elevated plasma homocysteine levels. MTHFR enzyme activity is also reduced in the Mthfr677C > T brain. Mice showed reduced tissue perfusion in numerous brain regions by PET/CT as well as significantly reduced vascular density, pericyte number and increased GFAP-expressing astrocytes in frontal cortex. Electron microscopy revealed cerebrovascular damage including endothelial and pericyte apoptosis, reduced luminal size, and increased astrocyte and microglial presence in the microenvironment. Collectively, these data support a mechanism by which variations in MTHFR perturb cerebrovascular health laying the foundation to incorporate our new Mthfr677C > T mouse model in studies examining genetic susceptibility for cerebrovascular dysfunction in ADRDs.
Our understanding of the pathophysiological basis of chronic thromboembolic pulmonary hypertension (CTEPH) will be accelerated by an animal model that replicates the phenotype of human CTEPH. ...Sprague-Dawley rats were administered a combination of a single dose each of plastic microspheres and vascular endothelial growth factor receptor antagonist in polystyrene microspheres (PE) + tyrosine kinase inhibitor SU5416 (SU) group. Shams received volume-matched saline; PE and SU groups received only microspheres or SU5416, respectively. PE + SU rats exhibited sustained pulmonary hypertension (62 ± 13 and 53 ± 14 mmHg at 3 and 6 weeks, respectively) with reduction of the ventriculoarterial coupling in vivo coincident with a large decrement in peak rate of oxygen consumption during aerobic exercise, respectively. PE + SU produced right ventricular hypokinesis, dilation, and hypertrophy observed on echocardiography, and 40% reduction in right ventricular contractile function in isolated perfused hearts. High-resolution computed tomographic pulmonary angiography and Ki-67 immunohistochemistry revealed abundant lung neovascularization and cellular proliferation in PE that was distinctly absent in the PE + SU group. We present a novel rodent model to reproduce much of the known phenotype of CTEPH, including the pivotal pathophysiological role of impaired vascular endothelial growth factor–dependent vascular remodeling. This model may reveal a better pathophysiological understanding of how PE transitions to CTEPH in human treatments.
Purpose
To determine the diagnostic performance of parenchymal MRI features differentiating CP from controls.
Methods
This prospective study performed abdominal MRI scans at seven institutions, using ...1.5 T Siemens and GE scanners, in 50 control and 51 definite CP participants, from February 2019 to May 2021. MRI parameters included the T1-weighted signal intensity ratio of the pancreas (T1 score), arterial-to-venous enhancement ratio (AVR) during venous and delayed phases, pancreas volume, and diameter. We evaluated the diagnostic performance of these parameters individually and two semi-quantitative MRI scores derived using logistic regression: SQ-MRI Model A (T1 score, AVR venous, and tail diameter) and Model B (T1 score, AVR venous, and volume).
Results
When compared to controls, CP participants showed a significantly lower mean T1 score (1.11 vs. 1.29), AVR venous (0.86 vs. 1.45), AVR delayed (1.07 vs. 1.57), volume (54.97 vs. 80.00 ml), and diameter of the head (2.05 vs. 2.39 cm), body (2.25 vs. 2.58 cm), and tail (1.98 vs. 2.51 cm) (
p
< 0.05 for all). AUCs for these individual MR parameters ranged from 0.66 to 0.79, while AUCs for the SQ-MRI scores were 0.82 and 0.81 for Model A (T1 score, AVR venous, and tail diameter) and Model B (T1 score, AVR venous, and volume), respectively. After propensity-matching adjustments for covariates, AUCs for Models A and B of the SQ-MRI scores increased to 0.92 and 0.93, respectively.
Conclusion
Semi-quantitative parameters of the pancreatic parenchyma, including T1 score, enhancement ratio, pancreas volume, diameter and multi-parametric models combining these parameters are helpful in diagnosis of CP. Longitudinal analyses including more extensive population are warranted to develop new diagnostic criteria for CP.
Graphical abstract
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