A single-domain antibody for the detection of pathological Tau protein in the early stages of oligomerization.

BACKGROUND: Soluble oligomeric forms of Tau protein have emerged as crucial players in the propagation of Tau pathology in Alzheimer's disease (AD). Our objective is to introduce a single-domain antibody (sdAb) named 2C5 as a novel radiotracer for the efficient detection and longitudinal monitoring of oligomeric Tau species in the human brain. METHODS: The development and production of 2C5 involved llama immunization with the largest human Tau isoform oligomers of different maturation states. Subsequently, 2C5 underwent comprehensive in vitro characterization for affinity and specificity via Enzyme-Linked Immunosorbent Assay and immunohistochemistry on human brain slices. Technetium-99m was employed to radiolabel 2C5, followed by its administration to healthy mice for biodistribution analysis. RESULTS: 2C5 exhibited robust binding affinity towards Tau oligomers (Kd = 6.280 nM ± 0.557) and to Tau fibers (Kd = 5.024 nM ± 0.453), with relatively weaker binding observed for native Tau protein (Kd = 1791 nM ± 8.714) and amyloid peptide (Kd > 10,000 nM). Remarkably, this SdAb facilitated immuno-histological labeling of pathological forms of Tau in neurons and neuritic plaques, yielding a high-contrast outcome in AD patients, closely mirroring the performance of reference antibodies AT8 and T22. Furthermore, 2C5 SdAb was successfully radiolabeled with 99mTc, preserving stability for up to 6 h post-radiolabeling (radiochemical purity > 93%). However, following intravenous injection into healthy mice, the predominant uptake occurred in kidneys, amounting to 115.32 ± 3.67, 97.70 ± 43.14 and 168.20 ± 34.52% of injected dose per gram (% ID/g) at 5, 10 and 45 min respectively. Conversely, brain uptake remained minimal at all measured time points, registering at 0.17 ± 0.03, 0.12 ± 0.07 and 0.02 ± 0.01% ID/g at 5, 10 and 45 min post-injection respectively. CONCLUSION: 2C5 demonstrates excellent affinity and specificity for pathological Tau oligomers, particularly in their early stages of oligomerization. However, the current limitation of insufficient blood-brain barrier penetration necessitates further modifications before considering its application in nuclear medicine imaging for humans.

Recent Pre-Clinical Advancements in Nuclear Medicine: Pioneering the Path to a Limitless Future.

The theranostic approach in oncology holds significant importance in personalized medicine and stands as an exciting field of molecular medicine. Significant achievements have been made in this field in recent decades, particularly in treating neuroendocrine tumors using 177-Lu-radiolabeled somatostatin analogs and, more recently, in addressing prostate cancer through prostate-specific-membrane-antigen targeted radionuclide therapy. The promising clinical results obtained in these indications paved the way for the further development of this approach. With the continuous discovery of new molecular players in tumorigenesis, the development of novel radiopharmaceuticals, and the potential combination of theranostics agents with immunotherapy, nuclear medicine is poised for significant advancements. The strategy of theranostics in oncology can be categorized into (1) repurposing nuclear medicine agents for other indications, (2) improving existing radiopharmaceuticals, and (3) developing new theranostics agents for tumor-specific antigens. In this review, we provide an overview of theranostic development and shed light on its potential integration into combined treatment strategies.

Regional CZT myocardial perfusion reserve for the detection of territories with simultaneously impaired CFR and IMR in patients without obstructive coronary artery disease: a pilot study.

OBJECTIVES: To assess the diagnostic performances of CZT myocardial perfusion reserve (MPR) for the detection of territories with simultaneous impaired coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) in patients without obstructive coronary artery disease. METHODS: Patients were prospectively included before being referred for coronary angiography. All patients underwent CZT MPR before invasive coronary angiography (ICA) and coronary physiology assessment. Rest and dipyridamole-induced stress myocardial blood flow (MBF) and MPR were quantified using 99mTc-SestaMIBI and a CZT camera. Fractional flow reserve (FFR), Thermodilution CFR, and IMR were assessed during ICA. RESULTS: Between December 2016 and July 2019, 36 patients were included. 25/36 patients presented no obstructive coronary artery disease. A complete functional assessment was performed in 32 arteries. No territory presented a significant ischemia on CZT myocardial perfusion imaging. A moderate yet significant correlation was observed between regional CZT MPR and CFR (r = 0.4, P = .03). Sensitivity, specificity, positive and negative predictive value, and accuracy of regional CZT MPR versus the composite invasive criterion (impaired CFR and IMR) were 87 [47% to 99%], 92% [73% to 99%], 78% [47% to 93%], 96% [78% to 99%], and 91% [75% to 98%], respectively. All territories with a regional CZT MPR ≤ 1.8 showed a CFR < 2. Regional CZT MPR values were significantly higher in arteries with CFR ≥ 2 and IMR < 25 (negative composite criterion, n = 14) than in those with CFR < 2 and IMR ≥ 25 (2.6 [2.1 to 3.6] versus 1.6 [1.2 to 1.8]), P < .01). CONCLUSION: Regional CZT MPR presented excellent diagnostic performances for the detection of territories with simultaneously impaired CFR and IMR reflecting a very high cardiovascular risk in patients without obstructive coronary artery disease.

Early onset of sleep/wake disturbances in a progressive macaque model of Parkinson's disease.

Parkinsonian patients often experience sleep/wake disturbances, which may appear at an early stage of the disease; however, these disturbances have not been fully described. To better understand the evolution of these disturbances with respect to disease progression, we aimed to characterize these clinical signs in a progressive nonhuman primate model of Parkinson's disease. Three adult macaques (Macaca fascicularis) were equipped with a polysomnographic telemetry system allowing the characterization of sleep/wake behavior via long-term neurophysiological recordings and underwent a modified multiple sleep latency test. Experiments were first performed in a healthy state and then during the progressive induction of a parkinsonian syndrome by intramuscular injections of low doses of MPTP. We observed an early onset of significant sleep/wake disturbances (i.e., before the appearance of motor symptoms). These disturbances resulted in (i) a disorganization of nighttime sleep with reduced deep sleep quality and (ii) an excessive daytime sleepiness characterized by sleep episodes occurring more rapidly in the morning and spreading through the middle of the day. The present study suggests that nighttime and daytime sleep/wake disturbances may appear early in the disease and should be considered in the development of biomarkers in further studies.

Non-invasive Multimodality Imaging of Coronary Vulnerable Patient.

Atherosclerotic plaque rupture or erosion remain the primary mechanism responsible for myocardial infarction and the major challenge of cardiovascular researchers is to develop non-invasive methods of accurate risk prediction to identify vulnerable plaques before the event occurs. Multimodal imaging, by CT-TEP or CT-SPECT, provides both morphological and activity information about the plaque and cumulates the advantages of anatomic and molecular imaging to identify vulnerability features among coronary plaques. However, the rate of acute coronary syndromes remains low and the mechanisms leading to adverse events are clearly more complex than initially assumed. Indeed, recent studies suggest that the detection of a state of vulnerability in a patient is more important than the detection of individual sites of vulnerability as a target of focal treatment. Despite this evolution of concepts, multimodal imaging offers a strong potential to assess patient's vulnerability. Here we review the current state of multimodal imaging to identify vulnerable patients, and then focus on emerging imaging techniques and precision medicine.

Noninvasive assessment of coronary microvascular dysfunction using SPECT myocardial perfusion imaging and myocardial perfusion entropy quantification in a rodent model of type 2 diabetes.

PURPOSE: Coronary microvascular dysfunction (CMVD) plays a major role in the occurrence of cardiovascular events (CVE). We recently suggested the clinical potential of myocardial perfusion entropy (MPE) quantification from SPECT myocardial perfusion images (MPI) for the prognosis of CVE occurrence. We hypothesized that the quantification of MPE from SPECT MPI would allow the assessment of CMVD-related MPE variations in a preclinical model of type 2 diabetes (T2D) including treatment with the anti-diabetic incretin liraglutide (LIR). METHODS: Optimal conditions for the preclinical quantification of MPE using 201Tl SPECT MPI were determined in rats with a T2D-like condition induced by a high-fat diet and streptozotocin injection (feasibility study, n = 43). Using such conditions, echocardiography and post-mortem LV capillary density evaluation were then used in order to assess the effect of LIR and the ability of MPE to assess CMVD (therapeutic study, n = 39). RESULTS: The feasibility study identified dobutamine stress and acute NO synthase and cyclooxygenase inhibition as optimal conditions for the quantification of MPE, with significant increases in MPE being observed in T2D animals (P < 0.01 vs controls). In the therapeutic study, T2D rats were hyperglycemic (5.5 ± 0.5 vs 1.1 ± 0.3 g/L for controls, P < 0.001) and had a significantly lower left ventricular ejection fraction (LVEF) (65 ± 4% vs 74 ± 9%, P < 0.01) and LV capillary density (2400 ± 300 vs 2800 ± 600 mm-3, P < 0.05). LIR partially restored glycemia (3.9 ± 0.6 g/L, P < 0.05 vs controls and T2D), totally prevented LVEF impairment (72 ± 7%, P = NS vs CTL), with no significant effect on capillary density. MPE was significantly increased in T2D rats (7.6 ± 0.5 vs 7.1 ± 0.5, P < 0.05), with no significant improvement in T2D-LIR rats (7.4 ± 0.4, P = NS vs controls and T2D). CONCLUSION: MPE quantification allowed the preclinical noninvasive assessment of CMVD. Both MPE and capillary density quantification suggested that LIR did not improve T2D-induced CMVD. The relevance of MPE for CMVD assessment warrants further clinical investigation.

Preclinical and clinical evaluation of a new method to assess cardiac insulin resistance using nuclear imaging.

BACKGROUND: Myocardial insulin resistance (IR) could be a predictive factor of cardiovascular events. This study aimed to introduce a new method using 123I-6-deoxy-6-iodo-D-glucose (6DIG), a pure tracer of glucose transport, for the assessment of IR using cardiac dynamic nuclear imaging. METHODS: The protocol evaluated first in rat-models consisted in two 6DIG injections and one of insulin associated with planar imaging and blood sampling. Compartmental modeling was used to analyze 6DIG kinetics in basal and insulin conditions and to obtain an index of IR. As a part of a translational approach, a clinical study was then performed in 5 healthy and 6 diabetic volunteers. RESULTS: In rodent models, the method revealed reproducible when performed twice at 7 days apart in the same animal. Rosiglitazone, an insulin-sensitizing drug, induced a significant increase of myocardial IR index in obese Zucker rats from 0.96 ± 0.18 to 2.26 ± 0.44 (P<.05) after 7 days of an oral treatment, and 6DIG IR indexes correlated with the gold standard IR index obtained through the hyperinsulinemic-euglycemic clamp (r=.68, P<.02). In human, a factorial analysis was applied on images to obtain vascular and myocardial kinetics before compartmental modeling. 1.5-fold to 2.2-fold decreases in mean cardiac IR indexes from healthy to diabetic volunteers were observed without reaching statistical significance. CONCLUSIONS: These preclinical results demonstrate the reproducibility and sensibility of this novel imaging methodology. Although this first in-human study showed that this new method could be rapidly performed, larger studies need to be planned in order to confirm its performance.

Comparison of Cadmium Zinc Telluride ECG-gated SPECT equilibrium radionuclide angiocardiography to magnetic resonance imaging to measure right ventricular volumes and ejection fraction in patients with cardiomyopathy.

AIMS: The objective of this study was to determine the accuracy of right ventricular function (RVF) assessed by Cadmium Zinc Telluride ECG-gated SPECT equilibrium radionuclide angiocardiography (CZT-ERNA). METHODS AND RESULTS: Twenty-one consecutive patients with cardiomyopathy (aged 54 ± 19 years; 62% male) were included. RV ejection fraction (EF) and volumes were analyzed by CZT-ERNA and compared with values obtained by cardiac magnetic resonance imaging (CMR). Mean values were not different between CZT-ERNA and MRI for RVEF (48.1 ± 10.4% vs 50.8 ± 10.0%; P = .23). Significant correlations (P < .0001) were observed between CZT-ERNA and MRI for RVEF, RV end-diastolic volume, and end-systolic volume (r = 0.81, r = 0.93, and r = 0.96, respectively). Bland-Altman analysis showed a mean difference (bias) between CZT-ERNA and MRI for RVEF of -2.69% (95% CI - 5.35 to - 0.42) with good agreement between the 2 techniques (limits of agreement, -14.3 to 8.99). Intraobserver and interobserver reproducibility of RVF measured by CZT-ERNA was high. CONCLUSION: CZT-ERNA provides accurate, reproducible assessment of RVF and appears as a good alternative to cardiac magnetic resonance for the evaluation of the magnitude of RVF in patients with cardiomyopathy.

Prognosis of Coronary Atherosclerotic Burden in Non-Ischemic Dilated Cardiomyopathies.

BACKGROUND: Atherosclerosis is associated with a worse prognosis in many diseases such as ischemic cardiomyopathy, but its impact in non-ischemic dilated cardiomyopathy (dCMP) is lesser known. Our aim was to study the prognostic impact of coronary atherosclerotic burden (CAB) in patients with dCMP. METHODS: Consecutive patients with dCMP and left ventricular (LV) dysfunction diagnosed by concomitant analysis of invasive coronary angiography (ICA) and CMR imaging were identified from registry-database. CAB was measured by Gensini score. The primary composite endpoint was the occurrence of major adverse cardiovascular events (MACE) defined as cardiovascular (CV) mortality, non-fatal MI and unplanned myocardial revascularization. The results of 139 patients constituting the prospective study population (mean age 59.4 ± 14.7 years old, 74% male), average LV ejection fraction was 31.1 ± 11.02%, median Gensini score was 0 (0-3), and mid-wall late gadolinium enhancement (LGE) was the most frequent LGE pattern (42%). Over a median follow-up of 2.8 years, 9% of patients presented MACE. Patients with MACE had significantly higher CAB compared to those who were free of events (0 (0-3) vs. 3.75 (2-15), p < 0.0001). CAB remained the significant predictor of MACE on multivariate logistic analysis (OR: 1.12, CI: 1.01-1.23, p = 0.02). CONCLUSION: High CAB may be a new prognostic factor in dCMP patients.

Prognostic value of SPECT myocardial perfusion entropy in high-risk type 2 diabetic patients.

PURPOSE: Risk stratification of patients with type 2 diabetes mellitus (T2D) remains suboptimal. We hypothesized that myocardial perfusion entropy (MPE) quantified from SPECT myocardial perfusion images may provide incremental prognostic value in T2D patients independently from myocardial ischemia. METHODS: T2D patients with very high and high cardiovascular risk were prospectively included (n = 166, 65 ± 12 years). Stress perfusion defect was quantified by visual evaluation of SPECT MPI. SPECT MPI was also used for the quantification of rest and stress MPE. The primary end point was major adverse cardiac events (MACEs) defined as cardiac death, myocardial infarction (MI), and myocardial revascularization > 3 months after SPECT. RESULTS: Forty-four MACEs were observed during a 4.6-year median follow-up. Significant differences in stress MPE were observed between patients with and without MACEs (4.19 ± 0.46 vs. 3.93 ± 0.40; P ≤ .01). By Kaplan-Meier analysis, the risk of MACEs was significantly higher in patients with higher stress MPE (log-rank P ≤ 01). Stress MPE and stress perfusion defect (SSS ≥ 4) were significantly associated with the risk of MACEs (hazard ratio 2.77 and 2.06, respectively, P < .05 for both) after adjustment for clinical and imaging risk predictors as identified from preliminary univariate analysis. MPE demonstrated incremental prognostic value over clinical risk factors, stress test EKG and SSS as evidenced by nested models showing improved Akaike information criterion (AIC), reclassification (global continuous net reclassification improvement [NRI]: 63), global integrated discrimination improvement (IDI: 6%), and discrimination (change in c-statistic: 0.66 vs 0.74). CONCLUSIONS: Stress MPE provided independent and incremental prognostic information for the prediction of MACEs in diabetic patients. TRIAL REGISTRATION NUMBER: NCT02316054 (12/12/2014).

99mTc-A1 as a Novel Imaging Agent Targeting Mesothelin-Expressing Pancreatic Ductal Adenocarcinoma.

Mesothelin is a membrane-associated protein overexpressed in pancreatic ductal adenocarcinoma (PDAC). Some mesothelin-targeted therapies are in clinical development but the identification of patients eligible for such therapies is still challenging. The objective of this study was to perform the imaging of mesothelin in mice models of PDAC with a technetium-labeled anti-mesothelin single-domain antibody (99mTc-A1). METHODS: The Cancer Genomic Atlas (TCGA) database was used to determine the prognostic role of mesothelin in PDAC. 99mTc-A1 was evaluated both in vitro in PDAC cells (SW1990 and AsPC-1) and in vivo in an experimental model of mesothelin-expressing PDAC (AsPC-1) in mice. RESULTS: TCGA analysis showed that PDAC patients with high mesothelin expression had a shorter overall survival (P = 0.00066). The binding of 99mTc-A1 was 2.1-fold greater in high-mesothelin-expressing AsPC-1 cells when compared to moderate-mesothelin-expressing SW1990 cells (p < 0.05). In vivo, the 99mTc-A1 uptake was 3.5-fold higher in AsPC-1-derived tumors as compared to a technetium-labeled irrelevant antibody (99mTc-Ctl) (p < 0.01). CONCLUSIONS: 99mTc-A1 accurately allows imaging of mesothelin-expressing experimental PDAC tumors. Our experiments paved the way for the development of a companion test for mesothelin-targeted therapies.

Prospective diagnostic performance of semiconductor SPECT myocardial perfusion imaging: wall thickening analysis reduces the need for an additional prone acquisition.

PURPOSE: To determine whether the assessment of regional wall thickening (WT) in addition to myocardial perfusion from stress supine acquisitions could compensate for the lack of prone acquisition and the corresponding decrease in the diagnostic performance of SPECT myocardial perfusion imaging (MPI) in patients with known or suspected coronary artery disease (CAD). METHODS: The study group comprised 41 patients (123 vessels) with known or suspected CAD prospectively recruited for systematic prone and supine 201Tl stress SPECT MPI. The diagnostic performance of SPECT MPI was determined for various image sets including nongated supine images (supine NG), nongated combined prone and supine images (prone and supine NG) and gated supine images, allowing WT evaluation from NG images in addition to perfusion (supine NG + WT) using invasive coronary angiography and fractional flow reserve as the gold standards. RESULTS: The rate of false positives was significantly higher among the supine NG images (20.8%) than among either the prone and supine NG or the supine NG + WT images (3.3% and 2.7%, respectively, P < 0.05 vs. supine NG). Consequently, specificity was higher for the prone and supine NG images than for the supine NG images (96.1% vs. 76.1%, P < 0.01) and was highest for the supine NG + WT images (96.8%, P not significant vs. prone and supine NG), without significant differences in sensitivity (80.0%, 86.6% and 73.3%, respectively, P not significant for all comparisons). CONCLUSION: The diagnostic performance of supine stress SPECT MPI is improved when WT assessment of ischaemic segments is used as an additional diagnostic criterion to values not significantly different from those with combined prone and supine acquisitions.

In Vivo Assessment of VCAM-1 Expression by SPECT/CT Imaging in Mice Models of Human Triple Negative Breast Cancer.

Recent progress in breast cancer research has led to the identification of Vascular Cell Adhesion Molecule-1 (VCAM-1) as a key actor of metastatic colonization. VCAM-1 promotes lung-metastases and is associated with clinical early recurrence and poor outcome in triple negative breast cancer (TNBC). Our objective was to perform the in vivo imaging of VCAM-1 in mice models of TNBC. The Cancer Genomic Atlas (TCGA) database was analyzed to evaluate the prognostic role of VCAM-1 in TNBC. MDA-MB-231 (VCAM-1+) and control HCC70 (VCAM-1-) TNBC cells were subcutaneously xenografted in mice and VCAM-1 expression was assessed in vivo by single-photon emission computed tomography (SPECT) imaging using 99mTc-cAbVCAM1-5. Then, MDA-MB-231 cells were intravenously injected in mice and VCAM-1 expression in lung metastasis was assessed by SPECT imaging after 8 weeks. TCGA analysis showed that VCAM-1 is associated with a poor prognosis in TNBC patients. In subcutaneous tumor models, 99mTc-cAbVCAM1-5 uptake was 2-fold higher in MDA-MB-231 than in HCC70 (p < 0.01), and 4-fold higher than that of the irrelevant control (p < 0.01). Moreover, 99mTc-cAbVCAM1-5 uptake in MDA-MB-231 lung metastases was also higher than that of 99mTc-Ctl (p < 0.05). 99mTc-cAbVCAM1-5 is therefore a suitable tool to evaluate the role of VCAM-1 as a marker of tumor aggressiveness of TNBC.

Safety, Biodistribution, and Dosimetry of 123I-6-Deoxy-6-Iodo-D-Glucose, a Tracer of Glucose Transport, in Healthy and Diabetic Volunteers.

PURPOSE: Insulin resistance is a key feature of the metabolic syndrome and type 2 diabetes, in which noninvasive assessment is not currently allowed by any methodology. We previously validated an iodinated tracer of glucose transport (6DIG) and a new methodology for the in vivo quantification of cardiac insulin resistance in rodents. The aim of this study was to investigate the safety, biodistribution, and radiation dosimetry of this method using I-6DIG in 5 healthy and 6 diabetic volunteers. METHODS: The collection of adverse effects (AEs) and medical supervision of vital parameters and biological variables allowed the safety evaluation. Biodistribution was studied by sequentially acquiring whole-body images at 1, 2, 4, 8, and 24 hours postinjection. The total number of disintegrations in each organ normalized to the injected activity was calculated as the area under the time-activity curves. Dosimetry calculations were performed using OLINDA/EXM. RESULTS: No major adverse events were observed. The average dose corresponding to the 2 injections of I-6DIG used in the protocol was 182.1 ± 7.5 MBq. A fast blood clearance of I-6DIG was observed. The main route of elimination was urinary, with greater than 50% of urine activity over 24 hours. No blood or urine metabolite was detected. I-6DIG accumulation mostly occurred in elimination organs such as kidneys and liver. Mean radiation dosimetry calculations indicated an effective whole-body absorbed dose of 3.35 ± 0.57 mSv for the whole procedure. CONCLUSIONS: I-6DIG was well tolerated in human with a dosimetry profile comparable to that of other commonly used iodinated tracers, thereby allowing further clinical development of the tracer.

Diagnostic value of stress thallium-201/rest technetium-99m-sestamibi sequential dual isotope high-speed myocardial perfusion imaging for the detection of haemodynamically relevant coronary artery stenosis.

BACKGROUND: The aim of this study was to determine the diagnostic accuracy of stress thallium-201/rest technetium-99m-sestamibi sequential dual-isotope high-speed myocardial perfusion imaging (DI-HS-MPI) against invasively determined fractional flow reserve (FFR). METHODS: Fifty-four consecutive patients prospectively underwent DI-HS-MPI before invasive coronary angiography. Perfusion was scored visually by summed stress score on a patient and coronary territory basis. Significant coronary artery disease (CAD) was defined by the presence of ≥ 90% stenosis/occlusion or fractional flow reserve ≤ 0.80 for coronary stenosis ≥ 50%. RESULTS: FFR was measured in 69 of 162 coronary vessels, with 1.28 ± 0.56 vessels assessed/patient. Sensitivity, specificity, and diagnostic accuracy of MPI for the detection of significant CAD were 92.8%, 69.2%, and 81.4%, on a patient basis, and 83.7%, 90.4%, and 88.8% by coronary territory. CONCLUSIONS: DI-HS-MPI accurately detects functionally significant CAD as defined by using FFR.

Semi-automatic detection of myocardial trabeculation using cardiovascular magnetic resonance: correlation with histology and reproducibility in a mouse model of non-compaction.

BACKGROUND: The definition of left ventricular (LV) non-compaction is controversial, and discriminating between normal and excessive LV trabeculation remains challenging. Our goal was to quantify LV trabeculation on cardiovascular magnetic resonance (CMR) images in a genetic mouse model of non-compaction using a dedicated semi-automatic software package and to compare our results to the histology used as a gold standard. METHODS: Adult mice with ventricular non-compaction were generated by conditional trabecular deletion of Nkx2-5. Thirteen mice (5 controls, 8 Nkx2-5 mutants) were included in the study. Cine CMR series were acquired in the mid LV short axis plane (resolution 0.086 × 0.086x1mm3) (11.75 T). In a sub set of 6 mice, 5 to 7 cine CMR were acquired in LV short axis to cover the whole LV with a lower resolution (0.172 × 0.172x1mm3). We used semi-automatic software to quantify the compacted mass (Mc), the trabeculated mass (Mt) and the percentage of trabeculation (Mt/Mc) on all cine acquisitions. After CMR all hearts were sliced along the short axis and stained with eosin, and histological LV contouring was performed manually, blinded from the CMR results, and Mt, Mc and Mt/Mc were quantified. Intra and interobserver reproducibility was evaluated by computing the intra class correlation coefficient (ICC). RESULTS: Whole heart acquisition showed no statistical significant difference between trabeculation measured at the basal, midventricular and apical parts of the LV. On the mid-LV cine CMR slice, the median Mt was 0.92 mg (range 0.07-2.56 mg), Mc was 12.24 mg (9.58-17.51 mg), Mt/Mc was 6.74% (0.66-17.33%). There was a strong correlation between CMR and the histology for Mt, Mc and Mt/ Mc with respectively: r2 = 0.94 (p < 0.001), r2 = 0.91 (p < 0.001), r2 = 0.83 (p < 0.001). Intra- and interobserver reproducibility was 0.97 and 0.8 for Mt; 0.98 and 0.97 for Mc; 0.96 and 0.72 for Mt/Mc, respectively and significantly more trabeculation was observed in the Mc Mutant mice than the controls. CONCLUSION: The proposed semi-automatic quantification software is accurate in comparison to the histology and reproducible in evaluating Mc, Mt and Mt/ Mc on cine CMR.

Preclinical Evaluation of Mesothelin-Specific Ligands for SPECT Imaging of Triple-Negative Breast Cancer.

Mesothelin is a cell-surface glycoprotein restricted to mesothelial cells overexpressed in several types of cancer, including triple-negative breast cancer not responding to trastuzumab or hormone-based therapies. Mesothelin-targeting therapies are currently being developed. However, the identification of patients potentially eligible for such a therapeutic strategy remains challenging. The objective of this study was to perform the radiolabeling and preclinical evaluation of 99mTc-A1 and 99mTc-C6, two antimesothelin single-domain antibody (sdAb)-derived imaging agents. Methods: A1 and C6 were radiolabeled with 99mTc and evaluated in vitro on recombinant protein and cells, as well as in vivo in xenograft mouse models of the triple-negative breast cancer cell lines HCC70 (mesothelin-positive) and MDA-MB-231 (mesothelin-negative). Results: Both 99mTc-A1 and 99mTc-C6 bound mesothelin with high affinity in vitro, with 99mTc-A1 affinity being 2.4-fold higher than that of 99mTc-C6 (dissociation constant, 43.9 ± 4.0 vs. 107 ± 16 nM, P < 0.05). 99mTc-A1 and 99mTc-C6 remained stable in vivo in murine blood (>80% at 2 h) and ex vivo in human blood (>90% at 6 h). In vivo 99mTc-A1 uptake (percentage injected dose) in HCC70 tumors was 5-fold higher than in MDA-MB-231 tumors and 1.5-fold higher than that of 99mTc-C6 (2.34% ± 0.36% vs. 0.48% ± 0.18% and 1.56% ± 0.43%, respectively, P < 0.01) and resulted in elevated tumor-to-background ratios. In vivo competition experiments demonstrated the specificity of 99mTc-A1 uptake in HCC70 tumors. Conclusion: Mesothelin-positive tumors were successfully identified by SPECT using 99mTc-A1 and 99mTc-C6. Considering its superior characteristics, 99mTc-A1 was selected as the most suitable tool for further clinical translation.

SPECT myocardial ischemia in the absence of obstructive CAD: Contribution of the invasive assessment of microvascular dysfunction.

Coronary microvascular dysfunction has recently emerged as a major independent prognostic factor and can be invasively assessed by coronary flow reserve (CFR) and the index of microvascular resistance (IMR). The incremental prognostic value of myocardial ischemia from SPECT myocardial perfusion imaging (MPI) over clinical characteristics, cardiac risk factors, and stress test data for the prediction of hard cardiac events (myocardial infarction and cardiac death) has been well demonstrated over the last two decades regardless of the absence or presence of epicardial CAD. Recently developed semi-conductor, cardiac-dedicated cameras allow for decreased acquisition times and systematic procubitus and decubitus acquisitions thereby limiting the occurrence of false positives historically attributable to artefactual motion, attenuation, and digestive artifacts. It is therefore likely that pathophysiological causes rather than acquisition artifacts might underlie SPECT perfusion abnormalities. Here, we report four representative examples of patients presenting with ischemia in the setting of no obstructive CAD and normal fractional flow reserve together with elevated IMR and low CFR. The results indicate that ischemia from SPECT MPI could result from microvascular dysfunction in patients without obstructive CAD and should be considered as a prognostic factor for hard cardiac events.

Sympathetic cardiac function in early sepsis: Noninvasive evaluation with [123I]-meta-iodobenzylguanidine (123I-MIBG) in vivo SPECT imaging.

BACKGROUND: Sympathetic system abnormalities have been reported in sepsis-related cardiac dysfunction. The present study aimed at evaluating the potential of the norepinephrine radiolabeled analogue [123I]-meta-iodobenzylguanidine (123I-MIBG) for the noninvasive assessment of modifications in cardiac sympathetic activity occurring in lipopolysaccharide (LPS)-induced experimental acute sepsis by single-photon emission computed tomographic imaging (SPECT). METHODS AND RESULTS: Sepsis was induced in male Wistar rats by intraperitoneal injection of 10 mg·kg-1 lipopolysaccharide (n = 16), whereas control animals (n = 7) were injected with vehicle (NaCl 0.9%). Echocardiography in LPS-injected animals (n = 8) demonstrated systolic and diastolic cardiac dysfunction. 123I-MIBG was injected 1 hour after LPS or vehicle administration (n = 8 and 7, respectively), and in vivo SPECT imaging was performed early and late (20 and 180 minutes) after tracer injection prior to animal euthanasia and ex vivo assessment of 123I-MIBG biodistribution. Global and 17-segment SPECT image analysis indicated that early 123I-MIBG activity was not affected by LPS treatment, whereas late cardiac tracer activity was significantly decreased in LPS-treated animals. Consequently, the cardiac washout of 123I-MIBG was significantly higher in LPS-treated (63.3% ± 4.0%) than that in control animals (56.7% ± 5.8%) (P < .05). CONCLUSION: Sepsis-induced modifications in cardiac sympathetic nervous system activity were evidenced by noninvasive in vivo 123I-MIBG SPECT imaging.