ASIC-E4: Interplay of Beta-Amyloid, Synaptic Density and Neuroinflammation in Cognitively Normal Volunteers With Three Levels of Genetic Risk for Late-Onset Alzheimer's Disease – Study Protocol and Baseline Characteristics

Background: Detailed characterization of early pathophysiological changes in preclinical Alzheimer's disease (AD) is necessary to enable development of correctly targeted and timed disease-modifying treatments. ASIC-E4 study (“Beta-Amyloid, Synaptic loss, Inflammation and Cognition in healthy APOE ε4 carriers”) combines state-of-the-art neuroimaging and fluid-based biomarker measurements to study the early interplay of three key pathological features of AD, i.e., beta-amyloid (Aβ) deposition, neuroinflammation and synaptic dysfunction and loss in cognitively normal volunteers with three different levels of genetic (APOE-related) risk for late-onset AD. Objective: Here, our objective is to describe the study design, used protocols and baseline demographics of the ASIC-E4 study. Methods/Design: ASIC-E4 is a prospective observational multimodal imaging study performed in Turku PET Centre in collaboration with University of Gothenburg. Cognitively normal 60–75-year-old-individuals with known APOE ε4/ε4 genotype were recruited via local Auria Biobank (Turku, Finland). Recruitment of the project has been completed in July 2020 and 63 individuals were enrolled to three study groups (Group 1: APOE ε4/ε4, N = 19; Group 2: APOE ε4/ε3, N = 22; Group 3: APOE ε3/ε3, N = 22). At baseline, all participants will undergo positron emission tomography imaging with tracers targeted against Aβ deposition (11C-PIB), activated glia (11C-PK11195) and synaptic vesicle glycoprotein 2A (11C-UCB-J), two brain magnetic resonance imaging scans, and extensive cognitive testing. In addition, blood samples are collected for various laboratory measurements and blood biomarker analysis and cerebrospinal fluid samples are collected from a subset of participants based on additional voluntary informed consent. To evaluate the predictive value of the early neuroimaging findings, neuropsychological evaluation and blood biomarker measurements will be repeated after a 4-year follow-up period. Discussion: Results of the ASIC-E4 project will bridge the gap related to limited knowledge of the synaptic and inflammatory changes and their association with each other and Aβ in “at-risk” individuals. Thorough in vivo characterization of the biomarker profiles in this population will produce valuable information for diagnostic purposes and future drug development, where the field has already started to look beyond Aβ

Pancreatic metabolism, blood flow, and β-cell function in obese humans.

Context: Glucolipotoxicity is believed to induce pancreatic &beta;-cell dysfunction in obesity. Previously, it has not been possible to study pancreatic metabolism and blood flow in humans. Objective: The objective of the study was to investigate whether pancreatic metabolism and blood flow are altered in obesity using positron emission tomography (PET). In the preclinical part, the method was validated in animals. Design: This was a cross-sectional study. Setting: The study was conducted in a clinical research center. Participants: Human studies consisted of 52 morbidly obese and 25 healthy age-matched control subjects. Validation experiments were done with rodents and pigs. Interventions: PET and magnetic resonance imaging studies using a glucose analog ([18F]fluoro-2-deoxy-d-glucose), a palmitate analog [14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid], and radiowater ([15O]H2O) were performed. In animals, a comparison between ex vivo and in vivo data was performed. Main Outcome Measures: Pancreatic glucose/fatty acid (FA) uptake, fat accumulation, and blood flow parameters of &beta;-cell function were measured. Results: PET proved to be a feasible method to measure pancreatic metabolism. Compared with healthy participants, obese participants had elevated pancreatic FA uptake (P &lt; .0001), more fat accumulation (P = .0001), lowered glucose uptake both during fasting and euglycemic hyperinsulinemia, and blunted blood flow (P &lt; .01) in the pancreas. Blood flow, FA uptake, and fat accumulation were negatively associated with multiple markers of &beta;-cell function. Conclusions: Obesity leads to changes in pancreatic energy metabolism with a substrate shift from glucose to FAs. In morbidly obese humans, impaired pancreatic blood flow may contribute to &beta;-cell dysfunction and in the pathogenesis of type 2 diabetes. &nbsp;</div

Feasibility of MRI-guided transurethral ultrasound for lesion-targeted ablation of prostate cancer

Background: MRI-guided transurethral ultrasound ablation (TULSA) has been evaluated for organ-confined prostate cancer (PCa). The purpose of this study was to assess the safety and toxicity, accuracy and short-term evolution of cell-death after lesion-targeted TULSA.Methods: This prospective, registered, Phase-I treat-and-3-week-resect-study enrolled six patients with MRI-visible-biopsy-concordant PCa. Lesions were targeted using TULSA with radical intent, except near neurovascular bundles (NVB). Robot-assisted-laparoscopic-prostatectomy (RALP) was performed at 3 weeks. Post-TULSA assessments included MRI (1 and 3 weeks), adverse events and quality-of-life (QoL) to 3 weeks, followed by RALP and whole-mount-histology. Treatment accuracy and demarcation of thermal injury were assessed using MRI and histology.Results: Six patients (median age = 70 years, prostate volume = 60 ml, PSA = 8.9 ng/ml) with eight biopsy-confirmed MRI-lesions (PIRADS ≥3) were TULSA-treated without complications (median sonication and MRI-times of 17 and 117 min). Foley-catheter removal was uneventful at 2–3 days. Compared to baseline, no differences in QoL were noted at 3 weeks. During follow-up, MRI-derived non-perfused-volume covered ablated targets and increased 36% by 3 weeks, correlating with necrosis-area on histology. Mean histological demarcation between complete necrosis and outer-limit-of-thermal-injury was 1.7 ± 0.4 mm. Coagulation necrosis extended to capsule except near NVB, where 3 mm safety-margins were applied. RALPs were uncomplicated and histopathology showed no viable cancer within the ablated tumor-containing target.Conclusions: Lesion-targeted TULSA demonstrates accurate and safe ablation of PCa. A significant increase of post-TULSA non-perfused-volume was observed during 3 weeks follow-up concordant with necrosis on histology. TULSA achieved coagulation necrosis of all targeted tissues. A limitation of this treat-and-resect-study-design was conservative treatment near NVB in patients scheduled for RALP.</p

Prenatal maternal depressive symptoms are associated with smaller amygdalar volumes of four-year-old children

Prenatal maternal depressive symptoms are related to an increased offspring susceptibility to psychiatric disorders over the life course. Alterations in fetal brain development might partly mediate this association. The relation of prenatal depressive symptoms with child's amygdalar volumes is still underexplored, and this study aimed to address this gap. We explored the association of prenatal maternal depressive symptoms with amygdalar volumes in 28 4-year-old children (14 female). Amygdalar volumes were assessed using the volBrain pipeline and manual segmentation. Prenatal depressive symptoms were self-reported by mothers at gestational weeks 14, 24 and 34 (Edinburgh Postnatal Depression Scale). Sex differences were probed, and possible pre- and postnatal confounders, such as maternal general anxiety, were controlled for. We observed that elevated depressive symptoms of the early second trimester, after controlling for prenatal maternal general anxiety, were significantly related to smaller right amygdalar volumes in the whole sample. Higher depressive symptoms of the third trimester were associated with significantly smaller right amygdalar volumes in boys compared to girls. Altogether, our data suggest that offspring limbic brain development might be affected by maternal depressive symptoms in early pregnancy, and might also be more vulnerable to depressive symptoms in late pregnancy in boys compared to girls

Measurement of brown adipose tissue mass using a novel dual-echo magnetic resonance imaging approach: A validation study

ObjectiveThe aim of this study was to evaluate and validate magnetic resonance imaging (MRI) for the visualization and quantification of brown adipose tissue (BAT) in vivo in a rat model. We hypothesized that, based on differences in tissue water and lipid content, MRI could reliably differentiate between BAT and white adipose tissue (WAT) and could therefore be a possible alternative for 18 F-Fluorodeoxyglucose Positron Emission Tomography (18FDG-PET), the current gold standard for non-invasive BAT quantification.Materials/MethodsEleven rats were studied using both 18FDG-PET/CT and MRI (1.5 T). A dual echo (in-and-out-of-phase) sequence was used, both with and without spectral presaturation inversion recovery (SPIR) fat suppression (DUAL-SPIR) to visualize BAT, after which all BAT was surgically excised. The BAT volume measurements obtained via 18FDG-PET/CT and DUAL-SPIR MR were quantitatively compared with the histological findings. All study protocols were reviewed and approved by the local ethics committee.ResultsThe BAT mass measurements that were obtained using DUAL-SPIR MR subtraction images correlated better with the histological findings (P = 0.017, R = 0.89) than did the measurements obtained using 18FDG-PET/CT (P = 0.78, R = 0.15), regardless of the BAT metabolic activation state. Additionally, the basic feasibility of the DUAL-SPIR method was demonstrated in three human pilot subjects.ConclusionsThis study demonstrates the potential for MRI to reliably detect and quantify BAT in vivo. MRI can provide information beyond that provided by 18FDG-PET imaging, and its ability to detect BAT is independent of its metabolic activation state. Additionally, MRI is a low-cost alternative that does not require radiation

Reversibility of myocardial metabolism and remodelling in morbidly obese patients 6 months after bariatric surgery

AbstractAIMS: To study myocardial substrate uptake, structure and function, before and after bariatric surgery, to clarify the interaction between myocardial metabolism and cardiac remodelling in morbid obesity.METHODS: We studied 46 obese patients (age 44 ± 10 years, body mass index [BMI] 42 ± 4 kg/m2 ), including 18 with type 2 diabetes (T2D) before and 6 months after bariatric surgery and 25 healthy age-matched control group subjects. Myocardial fasting free fatty acid uptake (MFAU) and insulin-stimulated myocardial glucose uptake (MGU) were measured using positron-emission tomography. Myocardial structure and function, and myocardial triglyceride content (MTGC) and intrathoracic fat were measured using magnetic resonance imaging and magnetic resonance spectroscopy.RESULTS: The morbidly obese study participants, with or without T2D, had cardiac hypertrophy, impaired myocardial function and substrate metabolism compared with the control group. Surgery led to marked weight reduction and remission of T2D in most of the participants. Postoperatively, myocardial function and structure improved and myocardial substrate metabolism normalized. Intrathoracic fat, but not MTGC, was reduced. Before surgery, BMI and MFAU correlated with left ventricular hypertrophy, and BMI, age and intrathoracic fat mass were the main variables associated with cardiac function. The improvement in whole-body insulin sensitivity correlated positively with the increase in MGU and the decrease in MFAU.CONCLUSIONS: In the present study, obesity and age, rather than myocardial substrate uptake, were the causes of cardiac remodelling in morbidly obese patients with or without T2D. Cardiac remodelling and impaired myocardial substrate metabolism are reversible after surgically induced weight loss and amelioration of T2D.</div

The SGLT2 Inhibitor Dapagliflozin Reduces Liver Fat but Does Not Affect Tissue Insulin Sensitivity: A Randomized, Double-Blind, Placebo-Controlled Study With 8-Week Treatment in Type 2 Diabetes Patients

OBJECTIVE The aim of this study was to investigate tissue-specific effects of dapagliflozin on insulin sensitivity and liver and body fat in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS This randomized, double-blind, parallel group, placebo-controlled study recruited 32 patients with type 2 diabetes. Enrolled patients were to have HbA(1c) 6.5-10.5% (48-91 mmol/mol) and >= 3 months of stable treatment with metformin, dipeptidyl peptidase 4 inhibitor, or their combination. Patients were randomized 1:1 to receive 10 mg dapagliflozin or placebo daily for 8 weeks. Before and after the intervention, tissue insulin sensitivity was measured using [F-18]-fluorodeoxyglucose and positron emission tomography during hyperinsulinemic-euglycemic clamp. Liver proton density fat fraction (PDFF) and adipose tissue volumes were assessed using MRI, and blood biomarkers were analyzed. RESULTS After 8 weeks, glycemic control was improved by dapagliflozin (placebo-corrected change in HbA(1c) -0.39%, P < 0.01), but whole-body glucose uptake was not increased (P = 0.90). Tissue-specific insulin-stimulated glucose uptake did not change in skeletal muscle, liver, myocardium, or white and brown adipose tissue, and endogenous glucose production remained unaffected. However, there were significant placebo-corrected decreases in liver PDFF (-3.74%, P < 0.01), liver volume (-0.10 L, P < 0.05), visceral adipose tissue volume (-0.35 L, P < 0.01), interleukin-6 (-1.87 pg/mL, P < 0.05), and N-terminal prohormone of brain natriuretic peptide (-96 ng/L, P = 0.03). CONCLUSIONS In this study, 8 weeks of treatment with dapagliflozin reduced liver PDFF and the volume of visceral adipose tissue in obese patients with type 2 diabetes. Although glycemic control was improved, no effect on tissue-level insulin sensitivity was observed

Accuracy of echocardiographic area-length method in chronic myocardial infarction: comparison with cardiac CT in pigs

Background: We evaluated echocardiographic area-length methods to measure left ventricle (LV) volumes and ejection fraction (EF) in parasternal short axis views in comparison with cardiac computed tomography (CT) in pigs with chronic myocardial infarction (MI).Methods: Male farm pigs with surgical occlusion of the left anterior descending coronary artery (n = 9) or sham operation (n = 5) had transthoracic echocardiography and cardiac-CT 3 months after surgery. We measured length of the LV in parasternal long axis view, and both systolic and diastolic LV areas in parasternal short axis views at the level of mitral valve, papillary muscles and apex. Volumes and EF of the LV were calculated using Simpson's method of discs (tri-plane area) or Cylinder-hemiellipsoid method (single plane area).Results: The pigs with coronary occlusion had anterior MI scars and reduced EF (average EF 42 +/- 10%) by CT. Measurements of LV volumes and EF were reproducible by echocardiography. Compared with CT, end-diastolic volume (EDV) measured by echocardiography showed good correlation and agreement using either Simpson's method (r = 0.90; mean difference -2, 95% CI -47 to 43 mL) or Cylinder-hemiellipsoid method (r = 0.94; mean difference 3, 95% CI -44 to 49 mL). Furthermore, End-systolic volume (ESV) measured by echocardiography showed also good correlation and agreement using either Simpson's method (r = 0.94; mean difference 12 ml, 95% CI: -16 to 40) or Cylinder-hemiellipsoid method (r = 0.97; mean difference: 13 ml, 95% CI: -8 to 33). EF was underestimated using either Simpson's method (r = 0.78; mean difference -6, 95% CI -11 to 1%) or Cylinder-hemiellipsoid method (r = 0.74; mean difference -4, 95% CI-10 to 2%).Conclusion: Our results indicate that measurement of LV volumes may be accurate, but EF is underestimated using either three or single parasternal short axis planes by echocardiography in a large animal model of chronic MI

Folate receptor-targeted positron emission tomography of experimental autoimmune encephalomyelitis in rats

AbstractBACKGROUND: Folate receptor-β (FR-β) is a cell surface receptor that is significantly upregulated on activated macrophages during inflammation and provides a potential target for folate-based therapeutic and diagnostic agents. FR-β expression in central nervous system inflammation remains relatively unexplored. Therefore, we used focally induced acute and chronic phases of experimental autoimmune encephalomyelitis (EAE) to study patterns of FR-β expression and evaluated its potential as an in vivo imaging target. METHODS: Focal EAE was induced in rats using heat-killed Bacillus Calmette-Guérin followed by activation with complete Freund's adjuvant supplemented with Mycobacterium tuberculosis. The rats were assessed with magnetic resonance imaging and positron emission tomography/computed tomography (PET/CT) at acute (14 days) and chronic (90 days) phases of inflammation. The animals were finally sacrificed for ex vivo autoradiography of their brains. PET studies were performed using FR-β-targeting aluminum [18F]fluoride-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid conjugated folate ([18F]AlF-NOTA-folate, 18F-FOL) and 18 kDa translocator protein (TSPO)-targeting N-acetyl-N-(2-[11C]methoxybenzyl)-2-phenoxy-5-pyridinamine (11C-PBR28). Post-mortem immunohistochemistry was performed using anti-FR-β, anti-cluster of differentiation 68 (anti-CD68), anti-inducible nitric oxide synthase (anti-iNOS), and anti-mannose receptor C-type 1 (anti-MRC-1) antibodies. The specificity of 18F-FOL binding was verified using in vitro brain sections with folate glucosamine used as a blocking agent. RESULTS: Immunohistochemical evaluation of focal EAE lesions demonstrated anti-FR-β positive cells at the lesion border in both acute and chronic phases of inflammation. We found that anti-FR-β correlated with anti-CD68 and anti-MRC-1 immunohistochemistry; for MRC-1, the correlation was most prominent in the chronic phase of inflammation. Both 18F-FOL and 11C-PBR28 radiotracers bound to the EAE lesions. Autoradiography studies verified that this binding took place in areas of anti-FR-β positivity. A blocking assay using folate glucosamine further verified the tracer's specificity. In the chronic phase of EAE, the lesion-to-background ratio of 18F-FOL was significantly higher than that of 11C-PBR28 (P = 0.016). CONCLUSION: Our EAE results imply that FR-β may be a useful target for in vivo imaging of multiple sclerosis-related immunopathology. FR-β-targeted PET imaging with 18F-FOL may facilitate the monitoring of lesion development and complement the information obtained from TSPO imaging by bringing more specificity to the PET imaging armamentarium for neuroinflammation. </div

Vascular adhesion protein-1 is actively involved in the development of inflammatory lesions in rat models of multiple sclerosis

Background: Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible endothelial cell molecule and primary amine oxidase that mediates leukocyte entry to sites of inflammation. However, there is limited knowledge of the inflammation-related expression of VAP-1 in the central nervous system (CNS). Therefore, we investigated the expression of VAP-1 within the CNS vasculature in two focal rat models of experimental autoimmune encephalomyelitis (EAE) mimicking multiple sclerosis (MS).Methods: EAE was induced either with Bacillus Calmette-Guerin, resulting in a delayed-type hypersensitivity-like pathogenesis (fDTH-EAE), or with myelin oligodendrocyte glycoprotein (fMOG-EAE). A subgroup of fMOG-EAE rats were treated daily with a selective VAP-1 inhibitor (LJP1586; 5 mg/kg). On 3 and 14 days after lesion activation, rat brains were assessed using magnetic resonance imaging (MRI), and ex vivo autoradiography was conducted to evaluate the binding of Gallium-68-labelled VAP-1 ligand. Histology and immunohistochemistry (OX-42, VAP-1, intercellular adhesion protein-1 [ICAM-1], P-selectin) supported the ex vivo autoradiography.Results: EAE lesions showed MRI-detectable signal changes and binding of the VAP-1-targeting radiotracer in both rat models. Some of the VAP-1 positive vessels showed morphological features typical for high endothelial-like venules at sites of inflammation. Inhibition of VAP-1 activity with small molecule inhibitor, LJP1586, decreased lymphocyte density in the acute inflammatory phase of fMOG-EAE lesions (day 3, P = 0.026 vs. untreated), but not in the remission phase (day 14, P = 0.70 vs. untreated), and had no effect on the amount of OX-42-positive cells in either phase. LJP1586 treatment reduced VAP-1 and ICAM-1 expression in the acute inflammatory phase, whereas P-selectin remained not detectable at all studied stages of the disease.Conclusions: Our results revealed that VAP-1 is expressed and functionally active in vasculature within the induced focal EAE lesions during the acute phase of inflammation and remains expressed after the acute inflammation has subsided. The study indicates that VAP-1 is actively involved in the development of inflammatory CNS lesions. During this process, the endothelial cell lesion-related vasculature seem to undergo a structural transformation from regular flat-walled endothelium to HEV-like endothelium