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CSF clearance in Alzheimer Disease measured with dynamic PET.
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CSF clearance in Alzheimer Disease measured with dynamic PET.

J Nucl Med. 2017 Mar 16;:

Authors: de Leon MJ, Li Y, Okamura N, Tsui WH, Saint Louis LA, Glodzik L, Osorio RS, Fortea J, Butler T, Pirraglia E, Fossati S, Kim HJ, Carare RO, Nedergaard M, Benveniste H, Rusinek H

Abstract
Evidence supporting the hypothesis that reduced cerebrospinal fluid (CSF) clearance is involved in the pathophysiology of Alzheimer's disease (AD) comes from primarily from rodent models. However, unlike rodents where predominant extra-cranial CSF egress is via olfactory nerves traversing the cribriform plate, human CSF clearance pathways are not well characterized. Using dynamic Positron Emission Tomography (PET) with (18)F-THK5117 a tracer for tau pathology, the ventricular CSF time activity was used as a biomarker for CSF clearance. We tested three hypotheses: 1. Extra-cranial CSF is detected at the superior turbinates; 2. CSF clearance is reduced in AD; and 3. CSF clearance is inversely associated with amyloid deposition. Methods: 15 subjects, 8 with AD and 7 normal control volunteers were examined with (18)F-THK5117. 10 subjects additionally received (11)C-PiB PET scans and 8 were PiB positive. Ventricular time activity curves (TAC) of (18)F-THK5117 were used to identify highly correlated TAC from extra-cranial voxels. Results: For all subjects, the greatest density of CSF positive extra-cranial voxels was in the nasal turbinates. Tracer concentration analyses validated the superior nasal turbinate CSF signal intensity. AD patients showed ventricular tracer clearance reduced by 23% and 66% fewer superior turbinate CSF egress sites. Ventricular CSF clearance was inversely associated with amyloid deposition. Conclusion: The human nasal turbinate is part of the CSF clearance system. Lateral ventricle and superior nasal turbinates CSF clearance abnormalities are found in AD. Ventricular CSF clearance reductions are associated with increased brain amyloid depositions. These data suggest that PET measured CSF clearance is a biomarker of potential interest in AD and other neurodegenerative diseases.

PMID: 28302766 [PubMed - as supplied by publisher]




Letter: Subjecting Radiologic Imaging to the Linear No-Threshold Hypothesis: A Non Sequitur!
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Letter: Subjecting Radiologic Imaging to the Linear No-Threshold Hypothesis: A Non Sequitur!

J Nucl Med. 2017 Mar 16;:

Authors: Silberstein EB

PMID: 28302765 [PubMed - as supplied by publisher]




(18)F-GP1, a novel fluorine-18 labeled tracer designed for PET imaging of thrombi with high detection sensitivity and low background.
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(18)F-GP1, a novel fluorine-18 labeled tracer designed for PET imaging of thrombi with high detection sensitivity and low background.

J Nucl Med. 2017 Mar 16;:

Authors: Lohrke J, Siebeneicher H, Berger M, Reinhardt M, Berndt M, Mueller A, Zerna M, Koglin N, Oden F, Bauser M, Friebe M, Dinkelborg LM, Huetter J, Stephens AW

Abstract
Thromboembolic diseases such as myocardial infarction, stroke, transient ischemic attacks and pulmonary embolism are major causes of morbidity and mortality worldwide. GPIIb/IIIa is the key receptor involved in platelet aggregation and is a validated target for therapeutic approaches and diagnostic imaging. The aim of this study was to develop and characterize a specific small molecule tracer for positron emission tomography (PET) imaging that binds with high affinity to GPIIb/IIIa receptors and has suitable pharmacokinetic properties to overcome limitations of previous approaches. Methods: Binding of (18)F-GP1 to GPIIb/IIIa receptors was investigated in competition binding assays and autoradiography using a fresh cardiac thrombus from an explanted human heart. The clot-to-blood-ratio for (18)F-GP1 was investigated by an in vitro blood flow model. Biodistribution and thrombus detection was investigated in cynomolgus monkeys after insertion of a roughened catheter into either the vena cava or aorta. Results:(18)F-GP1 is a novel fluorine-18 labeled small molecule for PET imaging of thrombi. The IC50 of (18)F-GP1 to GPIIb/IIIa was determined to be 20nM. (18)F-GP1 binds to thrombi with a mean clot-to-blood ratio of 95. Binding is specific and can be displaced by excess non-radioactive derivative. Binding is not effected by anticoagulants such as aspirin or heparin. (18)F-GP1 shows rapid blood clearance and a low background after i.v. injection in cynomolgus monkeys. Small arterial, venous thrombi, thrombotic depositions on damaged endothelial surface and small cerebral emboli were detected in vivo by PET imaging. Conclusion:(18)F-GP1 binds specifically with high affinity to the GPIIb/IIIa receptor involved in platelet aggregation. Due to its favorable pre-clinical characteristics, (18)F-GP1 is currently being investigated in a human clinical study.

PMID: 28302764 [PubMed - as supplied by publisher]




Phase 2 study of (99m)Tc-trofolastat SPECT/CT to identify and localize prostate cancer in intermediate- and high-risk patients undergoing radical prostatectomy and extended pelvic lymph node dissection.
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Phase 2 study of (99m)Tc-trofolastat SPECT/CT to identify and localize prostate cancer in intermediate- and high-risk patients undergoing radical prostatectomy and extended pelvic lymph node dissection.

J Nucl Med. 2017 Mar 16;:

Authors: Goffin KE, Joniau S, Tenke P, Slawin K, Klein EA, Stambler N, Strack T, Babich J, Armor T, Wong V

Abstract
Rationale:(99m)Tc-trofolastat ((99m)Tc-MIP-1404), a small-molecule inhibitor of prostate-specific membrane antigen (PSMA), shows high potential to detect prostate cancer (PCa) non-invasively using single-photon-emission-computed-tomography (SPECT). We therefore wanted to assess the performance of (99m)Tc-trofolastat SPECT/CT in a phase 2 multi-center, multi-reader prospective study in patients with intermediate- and high-grade PCa, prior to radical prostatectomy and extended pelvic lymph node dissection, with histopathology as gold standard. Methods: 105 PCa patients with an increased risk of lymph node involvement (LNI) received a pelvic (99m)Tc-trofolastat SPECT/CT prior to radical prostatectomy with extended pelvic lymph node dissection. Sensitivity of (99m)Tc-trofolastat for detection of PCa on a patient- and lobe-basis, using visual and semi-quantitative (tumor-to-background ratio, TBR) scores and of LNI was evaluated as well as correlation of uptake within the gland to Gleason scores (GS) and assessment of the predictive potential of (99m)Tc-trofolastat-uptake for LNI. Results: PCa was detected in 98 patients (94%) with acceptable variability between readers. There was a significantly higher visual score and TBR in positive lobes compared to tumor-negative lobes. ROC analysis showed that visual scores more accurately discriminated lobes with GS ≤3+3 from ≥3+4, while TBRs discriminated high-grade disease from normal lobes better. Visual scores and TBRs correlated significantly with GS. (99m)Tc-trofolastat SPECT/CT detected LNI with sensitivity of 50%, and specificity of 87% and TBR values significantly predicted LNI with a sensitivity of 90%. Conclusion:(99m)Tc-trofolastat SPECT/CT detects PCa with high sensitivity in patients with intermediate- and high-risk PCa compared to histology. It has potential to be used as surrogate marker for Gleason scores and predict LNI.

PMID: 28302763 [PubMed - as supplied by publisher]




Brain FDG-PET metabolic abnormalities in Macrophagic Myofasciitis: Are They Stable?
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Brain FDG-PET metabolic abnormalities in Macrophagic Myofasciitis: Are They Stable?

J Nucl Med. 2017 Mar 16;:

Authors: Blanc-Durand P, Van Der Gucht A, Aoun Sebaiti M, Abulizi M, Authier FJ, Itti E

Abstract
We address this letter in addition to our recent published study (1). The aim is to add some insight to the evolution of the brain abnormalities that are observed with macrophagic myofasciitis (MMF). MMF is a chronic disease whom evolution is slow and symptoms first may occurs from months to year after a vaccination containing aluminium hydroxid adjuvants (2). Nevertheless, its evolution is not fully understood or known. MMF associated cognitive dysfunction (MACD) is based on a tripod combining dysexecutive syndrom, visual memory impairment and interhemispheric disconnection. One pilot study suggest that MACD appears clinically stable over time (3). One recent study evaluating a support vector machine classifier also suggest that the abnormalities observed with 18-fluorodeoxyglose positron emission tomography ((18)F-FDG PET) may be sensitive and could be used to monitor patients. The study population comes from cohort followed in our Reference Center for Rare Neuromuscular Diseases and data were collected retrospectively. Among those patients, 15 had two consecutives (18)F-FDG PET brain acquisitions (median age 42.1 [range 20.9 to 63.5]) following the same brain protocol acquisition as previously described (1). Median time duration between the two examinations was 2.3 years (range 0.5 to 4]. Using analysis of covariance and negative or positive contrast in SPM12, a t-test mask was generated from the comparison between the two means of the first cerebral (18)F-FDG PET images and between the mean of the second acquisition. Results of the comparison were collected at a P-value < 0.005 at the voxel level, for clusters k ≥ 200 voxels (corrected for cluster volume) with adjustment for age. Brain abnormalities maps didn't show any statistical difference between the two examinations confirming the idea that MMF is a slowly or not progressive disease and it is in concordance with the fact that neurological symptoms even if fluctuate do not worsen over time (nor ameliorate).

PMID: 28302762 [PubMed - as supplied by publisher]




Performance Characteristics of the Whole-Body Discovery IQ PET/CT System.
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Performance Characteristics of the Whole-Body Discovery IQ PET/CT System.

J Nucl Med. 2017 Mar 16;:

Authors: Reynes-Llompart G, Gámez-Cenzano C, Romero-Zayas I, Rodriguez-Bel L, Vercher-Conejero JL, Martí-Climent JM

Abstract
Purpose: The aim of this study was to assess the physical performance of a new PET/CT system Discovery IQ 5 Rings (General Electric, Milwaukee, WI). Methods: Performance measurements were obtained using the NEMA NU2-2012 methodology. Image quality was extended by accounting for different acquisition parameters (lesion-to-background ratios of 8:1, 4:1 and 2:1 and acquisition times) as well as different reconstruction algorithms (VPHD, VPHD-S and Q.Clear). Tomographic reconstruction was also assessed using a Jaszczak phantom. Additionally, a total of thirty patient lesions were analyzed to account for differences on reconstruction algorithms in terms of lesion volume and SUV quantification. Results: Spatial resolutions ranged from 4.2 mm at 1 cm to 8.5 mm at 20 cm. Sensitivity measured in the center and at 10 cm was 22.8 and 20.4 kps/kBq, respectively. The measured noise equivalent count rate (NECR) peak was 124 kcps at 9.1 kBq/cm(3) The scatter fraction was 36.2%. The accuracy of correction for the count losses and randoms was 3.9%. In the image quality test the contrast recovery for VPHD/VPHDS/Q.Clear ranged between 18/18/13% (10 mm sphere diameter, ratio of 2:1) and 68/67/81% (37 mm sphere diameter, ratio of 8:1). The background variability was between 3.4/3.0/2.1% (ratio 2:1) to 5.5/4.8/3.7% (ratio 8:1). On Q.Clear reconstruction, the decrease of the β value has the effect of increasing the contrast recovery coefficients and the background variability. The Jaszczak phantom presented an overall image quality increase when using a reconstruction algorithm that models the point-spread function (PSF), moreover Q.Clear increased signal-to-noise ratio. Lesions analyzed for VPHD-S and Q.Clear presented a SUVmean of 6.5±3 and 7±3 (p<0.01), respectively, and a SUVmax of 11±4.8 and 12±4 (p<0.01). No significant lesion mean volume differences were found between algorithms. Conclusion: Discovery IQ PET/CT with 5 ring block detectors has the highest overall performance of the Discovery BGO based scanners, with improved sensitivity and count rate performance. The Q.Clear reconstruction improves the PET image quality, with higher recovery coefficients and lower background variability.

PMID: 28302761 [PubMed - as supplied by publisher]




[(11)C]PBR28 or [(18)F]PBR111 detect white matter inflammatory heterogeneity in multiple sclerosis.
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[(11)C]PBR28 or [(18)F]PBR111 detect white matter inflammatory heterogeneity in multiple sclerosis.

J Nucl Med. 2017 Mar 16;:

Authors: Datta G, Colasanti A, Kalk N, Owen DR, Scott G, Rabiner EI, Gunn R, Lingford-Hughes A, Malik O, Ciccarelli O, Nicholas R, Nie L, Battaglini M, De Stefano N, Matthews P

Abstract
Objective: To assess microglial activation in lesions and in normal appearing white matter of multiple sclerosis (MS) patients using positron emission tomography (PET). Methods: 34 MS patients (7 with secondary progressive MS (SPMS), 27 with relapsing remitting MS (RRMS)) and 30 healthy volunteers, genetically stratified for translocator protein (TSPO), binding status underwent PET scanning with TSPO radioligands ((11)C-PBR28 or (18)F-PBR111). Regional TSPO availability was measured as a distribution volume ratio (DVR) relative to the caudate (a pseudo-reference region). White matter lesions (WML) were classified as "active" (DVR highest in the lesion), "peripherally active" (peri-lesional DVR highest), "inactive" (DVR highest in surrounding normal appearing white matter, NAWM) or "undifferentiated" (similar DVR across lesion, peri-lesional and NAWM volumes). Results: The mean DVR in NAWM of patients was greater than that of the healthy volunteer white matter for both radioligands. Uptake for individual WML in patients was heterogeneous, but the median WML DVR and NAWM DVR for individual patients were strongly correlated (ρ = 0.94, P = 4x10-11). A higher proportion of lesions were inactive in patients with SPMS (35 %) than RRMS (23 %), but active lesions were found in all patients, including those on highly efficacious treatments. Conclusion: TSPO radioligand uptake was increased in brains of MS patients relative to healthy controls with two TSPO radiotracers. WML showed heterogeneous patterns of uptake. Active lesions were found in patients with both RRMS and SPMS. Their independent prognostic significance needs further investigation.

PMID: 28302760 [PubMed - as supplied by publisher]




Preclinical evaluation of (11)C-sarcosine as a substrate of proton-coupled amino acid transporters and first human application in prostate cancer.
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Preclinical evaluation of (11)C-sarcosine as a substrate of proton-coupled amino acid transporters and first human application in prostate cancer.

J Nucl Med. 2017 Mar 16;:

Authors: Piert M, Shao X, Raffel DM, Davenport MS, Montgomery J, Kunju L, Hockley BG, Siddiqui J, Scott PJ, Chinnaiyan A, Rajandiran T

Abstract
Sarcosine is a known substrate of proton-coupled amino acid transporters (PAT), which are overexpressed in selected tissues and solid tumors. Sarcosine, an N-methyl derivative of the amino acid glycine and a metabolic product of choline, plays an important role for prostate cancer aggressiveness and progression. Methods: Carbon-11 radiolabeled sarcosine ((11)C-sarcosine) was tested as a new positron emission tomography (PET) imaging probe in comparison with (11)C-choline in two prostate cancer tumor xenograft models (DU-145 and PC-3). We characterized (11)C-sarcosine transport in PC-3 and LNCaP tumor cells and performed (11)C-sarcosine PET with computed tomography (CT) in the first human subject with localized Gleason 4+3 prostate cancer. Target metabolite analyses of sarcosine and its natural precursors, glycine and choline, were performed from independent human prostate tissues. Results: In vitro assays indicated blockage of (11)C-sarcosine uptake into PC-3 and LNCaP tumor cells by excess unlabeled ("cold") sarcosine. 5-Hydroxy-L-tryptophan (HT), but not 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), competitively inhibited (11)C-sarcosine tumor cell uptake, confirming PAT-mediated transport. In vivo tumor-to-background ratios (TBR) obtained from (11)C-sarcosine PET were significantly elevated compared to (11)C-choline in DU-145 (TBR (11)C-sarcosine: 1.92 ± 0.11 vs. 1.41 ± 0.13 for (11)C-choline (n = 10; P < 0.002), and PC-3 tumors (TBR (11)C-sarcosine: 1.89 ± 0.2 vs. 1.34 ± 0.16 for (11)C-choline (n = 7; P < 0.002). (11)C-sarcosine produced high-contrast images in one case of localized clinically significant prostate cancer. Target metabolite analyses revealed significant step-wise increases of sarcosine, glycine and choline tissue levels from benign prostate tissue to localized prostate cancer and subsequently metastatic disease. (11)C-sarcosine showed a favorable radiation dosimetry with an 'effective dose' estimate of 0.0045 mSv/MBq, resulting in 2.68 mSv for a human subject (600 MBq dose). Conclusion:(11)C-sarcosine is a novel radiotracer for PAT transporters and shows initial utility for prostate cancer imaging, with potential benefit over commonly used (11)C-choline.

PMID: 28302759 [PubMed - as supplied by publisher]




Atlas of SPECT/CT.
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Atlas of SPECT/CT.

J Nucl Med. 2017 Mar 16;:

Authors: Kim EE

PMID: 28302758 [PubMed - as supplied by publisher]




Alteration of monoamine receptor activity and glucose metabolism in paediatric patients with anticonvulsant-induced cognitive impairment.
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Alteration of monoamine receptor activity and glucose metabolism in paediatric patients with anticonvulsant-induced cognitive impairment.

J Nucl Med. 2017 Mar 16;:

Authors: Zhu Y, Feng J, Ji J, Hou H, Chen L, Wu S, Liu Q, Yao Q, Du P, Zhang K, Chen Q, Chen Z, Zhang H, Tian M

Abstract
A landmark study from the Institute of Medicine (IOM) reported that the assessment of cognitive difficulties in children with epilepsy is timely and imperative. Anticonvulsant-induced cognitive impairment could influence the quality of life more than seizure itself in patients. Although monoaminergic system is involved in the regulation of cognitive process, its role in anticonvulsant-induced cognitive impairment remains unclear. Methods: To explore in vivo monoamine receptor binding activity in patients with anticonvulsant-induced cognitive impairment, each patient had PET imaging with both monoamine receptor binding agent, (11)C-N-methylspiperone ((11)C-NMSP), and glucose metabolic agent, (18)F-fluorodeoxyglucose ((18)F-FDG). Tests of Intelligence quotient (IQ), including verbal intelligence quotient (VIQ), performance IQ (PIQ) and full-scale IQ (FSIQ) were performed in each patient. Results: Compared to the patients with mono-therapy, patients with poly-therapy had significantly lower VIQ, PIQ and FSIQ (P < 0.01 in each comparison), as well as significantly lower monoamine receptor activities detected in the caudate nucleus, prefrontal cortex, dorsal anterior cingulate cortex and amygdale (P < 0.05 in each comparison). However, regarding to the glucose metabolism, there was no significant difference was found in patients with mono-therapy or poly-therapy (P > 0.05). Conclusion: Monoamine receptor-PET imaging could be a promising in vivo imaging biomarker for mapping anticonvulsant-induced cognitive impairment.

PMID: 28302757 [PubMed - as supplied by publisher]