The influence of anterior cingulate GABA+ and glutamate on emotion regulation and reactivity in adolescents and adults.

During adolescence, emotion regulation and reactivity are still developing and are in many ways qualitatively different from adulthood. However, the neurobiological processes underpinning these differences remain poorly understood, including the role of maturing neurotransmitter systems. We combined magnetic resonance spectroscopy in the dorsal anterior cingulate cortex (dACC) and self-reported emotion regulation and reactivity in a sample of typically developed adolescents (n = 37; 13-16 years) and adults (n = 39; 30-40 years), and found that adolescents had higher levels of glutamate to total creatine (tCr) ratio in the dACC than adults. A glutamate Í age group interaction indicated a differential relation between dACC glutamate levels and emotion regulation in adolescents and adults, and within-group follow-up analyses showed that higher levels of glutamate/tCr were related to worse emotion regulation skills in adolescents. We found no age-group differences in gamma-aminobutyric acid+macromolecules (GABA+) levels; however, emotion reactivity was positively related to GABA+/tCr in the adult group, but not in the adolescent group. The results demonstrate that there are developmental changes in the concentration of glutamate, but not GABA+, within the dACC from adolescence to adulthood, in accordance with previous findings indicating earlier maturation of the GABA-ergic than the glutamatergic system. Functionally, glutamate and GABA+ are positively related to emotion regulation and reactivity, respectively, in the mature brain. In the adolescent brain, however, glutamate is negatively related to emotion regulation, and GABA+ is not related to emotion reactivity. The findings are consistent with synaptic pruning of glutamatergic synapses from adolescence to adulthood and highlight the importance of brain maturational processes underlying age-related differences in emotion processing.

Phosphorus MRS of healthy human spleen.

Phosphorus (31 P-) MRS in vivo enables detection and quantification of important phosphorus-containing metabolites in biological tissues. 31 P-MRS of the normal spleen is challenging due to the relatively small volume and the larger distance between the spleen and surface coil. However, reference spectra of the healthy spleen are invaluable in studies of splenic malignancies and benign causes of splenomegaly, as well as in the study of its physiology. The purpose of this work was to investigate the feasibility of localized 31 P-MRS of healthy spleen in situ in a clinically acceptable measurement time using a clinical 3 T MR scanner. In this work, 31 P spectra of five healthy volunteers were measured using single-voxel image-selected in vivo spectroscopy (ISIS). The measurement sequence was augmented by broadband proton decoupling and nuclear Overhauser effect enhancement. It is demonstrated that localized 31 P-MRS of the spleen in situ using single-voxel ISIS is feasible on a clinical 3 T scanner in a clinically acceptable acquisition time. However, results have to be corrected for the transmitter excitation profile, and chemical shift displacement errors need to be taken into consideration during placement of the volume of interest. Results presented here could be used as a reference in future studies of splenomegaly caused by haematological malignancies.

Decreased renal perfusion during acute kidney injury in critical COVID-19 assessed by magnetic resonance imaging: a prospective case control study.

BACKGROUND: Renal hypoperfusion has been suggested to contribute to the development of acute kidney injury (AKI) in critical COVID-19. However, limited data exist to support this. We aim to investigate the differences in renal perfusion, oxygenation and water diffusion using multiparametric magnetic resonance imaging in critically ill COVID-19 patients with and without AKI. METHODS: A prospective case-control study where patients without prior kidney disease treated in intensive care for respiratory failure due to COVID-19 were examined. Kidney Disease: Improving Global Outcomes Creatinine criteria were used for group allocation. Main comparisons were tested using Mann-Whitney U test. RESULTS: Nineteen patients were examined, ten with AKI and nine without AKI. Patients with AKI were examined in median 1 [0-2] day after criteria fulfillment. Age and baseline Plasma-Creatinine were similar in both groups. Total renal blood flow was lower in patients with AKI compared with patients without (median 645 quartile range [423-753] vs. 859 [746-920] ml/min, p = 0.037). Regional perfusion was reduced in both cortex (76 [51-112] vs. 146 [123-169] ml/100 g/min, p = 0.015) and medulla (28 [18-47] vs. 47 [38-73] ml/100 g/min, p = 0.03). Renal venous saturation was similar in both groups (72% [64-75] vs. 72% [63-84], ns.), as was regional oxygenation (R2*) in cortex (17 [16-19] vs. 17 [16-18] 1/s, ns.) and medulla (29 [24-39] vs. 27 [23-29] 1/s, ns.). CONCLUSIONS: In critically ill COVID-19 patients with AKI, the total, cortical and medullary renal blood flows were reduced compared with similar patients without AKI, whereas no differences in renal oxygenation were demonstrable in this setting. Trial registration ClinicalTrials ID: NCT02765191 , registered May 6 2014 and updated May 7 2020.

Chronic cerebral blood flow alterations in traumatic brain injury and sports-related concussions.

PRIMARY OBJECTIVE: Traumatic brain injury (TBI) and sports-related concussion (SRC) may result in chronic functional and neuroanatomical changes. We tested the hypothesis that neuroimaging findings (cerebral blood flow (CBF), cortical thickness, and 1H-magnetic resonance (MR) spectroscopy (MRS)) were associated to cognitive function, TBI severity, and sex. RESEARCH DESIGN: Eleven controls, 12 athletes symptomatic following ≥3SRCs and 6 patients with moderate-severe TBI underwent MR scanning for evaluation of cortical thickness, brain metabolites (MRS), and CBF using pseudo-continuous arterial spin labeling (ASL). Cognitive screening was performed using the RBANS cognitive test battery. MAIN OUTCOMES AND RESULTS: RBANS-index was impaired in both injury groups and correlated with the injury severity, although not with any neuroimaging parameter. Cortical thickness correlated with injury severity (p = 0.02), while neuronal density, using the MRS marker ((NAA+NAAG)/Cr, did not. On multivariate analysis, injury severity (p = 0.0003) and sex (p = 0.002) were associated with CBF. Patients with TBI had decreased gray (p = 0.02) and white matter (p = 0.02) CBF compared to controls. CBF was significantly lower in total gray, white matter and in 16 of the 20 gray matter brain regions in female but not male athletes when compared to female and male controls, respectively. CONCLUSIONS: Injury severity correlated with CBF, cognitive function, and cortical thickness. CBF also correlated with sex and was reduced in female, not male, athletes. Chronic CBF changes may contribute to the persistent injury mechanisms in TBI and rSRC.

Circadian variation in renal blood flow and kidney function in healthy volunteers monitored with noninvasive magnetic resonance imaging.

Circadian regulation of kidney function is involved in maintaining whole body homeostasis, and dysfunctional circadian rhythm can potentially be involved in disease development. Magnetic resonance imaging (MRI) provides reliable and reproducible repetitive estimates of kidney function noninvasively without the risk of adverse events associated with contrast agents and ionizing radiation. The purpose of this study was to estimate circadian variations in kidney function in healthy human subjects with MRI and to relate the findings to urinary excretions of electrolytes and markers of kidney function. Phase-contrast imaging, arterial spin labeling, and blood oxygen level-dependent transverse relaxation rate (R2*) mapping were used to assess total renal blood flow and regional perfusion as well as intrarenal oxygenation in eight female and eight male healthy volunteers every fourth hour during a 24-h period. Parallel with MRI scans, standard urinary and plasma parameters were quantified. Significant circadian variations of total renal blood flow were found over 24 h, with increasing flow from noon to midnight and decreasing flow during the night. In contrast, no circadian variation in intrarenal oxygenation was detected. Urinary excretions of electrolytes, osmotically active particles, creatinine, and urea all displayed circadian variations, peaking during the afternoon and evening hours. In conclusion, total renal blood flow and kidney function, as estimated from excretion of electrolytes and waste products, display profound circadian variations, whereas intrarenal oxygenation displays significantly less circadian variation.

Multiparametric assessment of renal physiology in healthy volunteers using noninvasive magnetic resonance imaging.

Noninvasive methods of magnetic resonance imaging (MRI) can quantify parameters of kidney function. The main purpose of this study was to determine baseline values of such parameters in healthy volunteers. In 28 healthy volunteers (15 women and 13 men), arterial spin labeling to estimate regional renal perfusion, blood oxygen level-dependent transverse relaxation rate (R2*) to estimate oxygenation, and apparent diffusion coefficient (ADC), true diffusion (D), and longitudinal relaxation time (T1) to estimate tissue properties were determined bilaterally in the cortex and outer and inner medulla. Additionally, phase-contrast MRI was applied in the renal arteries to quantify total renal blood flow. The results demonstrated profound gradients of perfusion, ADC, and D with highest values in the kidney cortex and a decrease towards the inner medulla. R2* and T1 were lowest in kidney cortex and increased towards the inner medulla. Total renal blood flow correlated with body surface area, body mass index, and renal volume. Similar patterns in all investigated parameters were observed in women and men. In conclusion, noninvasive MRI provides useful tools to evaluate intrarenal differences in blood flow, perfusion, diffusion, oxygenation, and structural properties of the kidney tissue. As such, this experimental approach has the potential to advance our present understanding regarding normal physiology and the pathological processes associated with acute and chronic kidney disease.

Proton MR spectroscopy of human pancreas allografts.

OBJECTIVE: To estimate pancreas graft relaxation times and concentrations of total fat, and the intracellular lipids of non-adipose pancreatic cells (NAPC) using proton (1H) magnetic resonance spectroscopy (MRS) during cold preservation. MATERIALS AND METHODS: Grafts from 11 human donors were investigated. Each pancreas was perfused in situ with histidine-tryptophan-ketoglutarate (HTK) or with University of Wisconsin solution and placed into a transport container. Temperature of the grafts was maintained at 4 ± 2 °C during transport to our hospital and MR scanning. A 1.5 T clinical scanner was used for the measurements. Single-voxel PRESS spectra were acquired using transmit-receiver head coil. RESULTS: Relaxation times were measured for lipid (-CH2-)n (T1, 287 ± 60 ms; T2, 27 ± 4 ms), and tissue water (T1, 670 ± 69 ms; T2, 77 ± 17 ms). Average total fat, and intracellular lipids of NAPC concentrations were 79.2 ± 100.8 (range 2.4-304.4), and 2.9 ± 1.2 mmol/kg ww, respectively. CONCLUSION: We have shown that 1H-MRS is a useful tool for the estimation of pancreas graft lipid concentrations. Total pancreatic fat and especially content of intracellular lipids of NAPC are valuable measures for inspection of graft quality prior to transplantation or islet of Langerhans isolation.

Multiple breath-hold proton spectroscopy of human liver at 3T: Relaxation times and concentrations of glycogen, choline, and lipids.

PURPOSE: To evaluate the feasibility of an expiration multiple breath-hold 1 H-MRS technique to measure glycogen (Glycg), choline-containing compounds (CCC), and lipid relaxation times T1 , T2 , and their concentrations in normal human liver. MATERIALS AND METHODS: Thirty healthy volunteers were recruited. Experiments were performed at 3T. Multiple expiration breath-hold single-voxel point-resolved spectroscopy (PRESS) technique was used for localization. Water-suppressed spectra were used for the estimation of Glycg, CCC, lipid methylene (CH2 )n relaxation times and concentrations. Residual water lines were removed by the Hankel Lanczos singular value decomposition filter. After phase correction and frequency alignment, spectra were averaged and processed by LCModel. Summed signals of Glycg resonances H2H4', H3, and H5 between 3.6 and 4 ppm were used to estimate their apparent relaxation times and concentration. Glycg, CCC, and lipid content were estimated from relaxation corrected spectral intensity ratios to unsuppressed water line. RESULTS: Relaxation times were measured for liver Glycg (T1 , 892 ± 126 msec; T2 , 13 ± 4 msec), CCC (T1 , 842 ± 75 msec; T2 , 50 ± 5 msec), lipid (CH2 )n (T1 , 402 ± 19 msec; T2 , 52 ± 3 msec), and water (T1 , 990 ± 89 msec; T2 , 30 ± 2 msec). Mean CCC and lipid concentrations of healthy liver were 7.8 ± 1.3 mM and 15.8 ± 23.6 mM, respectively. Glycg content was found lower in the morning (48 ± 21 mM) compared to the afternoon (145 ± 50 mM). CONCLUSION: Multiple breath-hold 1 H-MRS together with dedicated postprocessing is a feasible technique for the quantification of liver Glycg, CCC, and lipid relaxation times and concentrations. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:410-417.

Assessment of cerebral perfusion and edema in preeclampsia with intravoxel incoherent motion MRI.

INTRODUCTION: Cerebral complications are the main reasons for morbidity and mortality in preeclampsia and eclampsia. As yet, we do not know whether the pathophysiology entails hypo- or hyperperfusion of the brain, or how and when edema emerges, due to the difficulty of examining the cerebral circulation. MATERIAL AND METHODS: We have used a non-invasive diffusion weighted-magnetic resonance imaging technique, intravoxel incoherent motion, to study cerebral perfusion on the capillary level and cerebral edema in women with preeclampsia (n = 30), normal pregnancy (n = 32), and non-pregnant women (n = 16). Estimates of cerebral blood volume, blood flow, and edema were measured in 5 different regions. These points were chosen to represent blood supply areas of both the carotid and vertebrobasilar arteries, and to include both white and gray matter. RESULTS: Except for the caudate nucleus, we did not detect any differences in cerebral perfusion measures on a group level. In the caudate nucleus, we found lower cerebral blood volume and lower blood flow in preeclampsia than in either normal pregnancy (P = .01 and P = .03, respectively) or non-pregnant women (both P = .02). No differences in edema were detected between study groups. CONCLUSION: The cerebral perfusion measures were comparable between the study groups, except for a portion of the basal ganglia where hypoperfusion was detected in preeclampsia but not in normal pregnancy or non-pregnant women.

An Intraprostatic Modified Release Formulation of Antiandrogen 2-Hydroxyflutamide for Localized Prostate Cancer.

PURPOSE: We investigated the tolerability, safety and antitumor effects of a novel intraprostatic depot formulation of antiandrogen 2-hydroxyflutamide (in NanoZolid®) in men with localized prostate cancer. MATERIALS AND METHODS: Two clinical trials, LPC-002 and LPC-003, were performed in a total of 47 men. The formulation was injected transrectally into the prostate under ultrasound guidance. In LPC-002 the effects on prostate specific antigen and prostate volume were measured for 6 months in 24 patients. In LPC-003 antitumor effects were evaluated by histopathology and magnetic resonance imaging including spectroscopy during 6 or 8 weeks in 23 patients. In each study testosterone and 2-hydroxyflutamide in plasma were measured as well as quality of life parameters. RESULTS: In LPC-002 (mean dose 690 mg) a reduction was observed in prostate specific antigen and prostate volume. Average nadir prostate specific antigen and prostate volume were 24.9% and 14.0% below baseline, respectively. When increasing the dose in LPC-003 to 920 and 1,740 mg, average prostate specific antigen decreased 16% and 23% after 6 and 8 weeks, respectively. Magnetic resonance imaging and magnetic resonance spectroscopy showed morphological changes and a global reduction in metabolite concentrations following treatment, indicating an antitumor response. Injections did not result in hormone related side effects. Three serious adverse events were reported and all resolved with oral antibiotic treatment. CONCLUSIONS: Intraprostatic injections of 2-hydroxyflutamide depot formulations showed antitumor effects, and proved to be safe and tolerable. However, for better anticancer effects higher doses and better dose distribution are suggested.

Quantification of metabolite concentrations in benign and malignant prostate tissues using 3D proton MR spectroscopic imaging.

PURPOSE: To estimate concentrations of choline (Cho), spermine (Spm), and citrate (Cit) in prostate tissue using 3D proton magnetic resonance spectroscopic imaging (MRSI) with water as an internal concentration reference as well as to assess the relationships between the measured metabolites and also between the metabolites and apparent diffusion coefficient (ADC). MATERIALS AND METHODS: Forty-six prostate cancer patients were scanned at 3T. Spectra were acquired with the point-resolved spectroscopy (PRESS) localization technique. Single-voxel spectra of four healthy volunteers were used to estimate T1 relaxation time of Spm. Spm, Cho concentrations, and ADC values of benign prostate tissues were correlated with Cit content. RESULTS: The T1 value, 708 ± 132 msec, was estimated for Spm. Mean concentrations in the benign peripheral zone (PZ) were Cho, 4.5 ± 1 mM, Spm, 13.0 ± 4.4 mM, Cit, 64.4 ± 16.1 mM. Corresponding values in the benign central gland (CG) were Cho, 3.6 ± 1 mM, Spm, 13.3 ± 4.5 mM, Cit, 34.3 ± 12.9 mM. Concentrations of Cit and Spm were positively correlated in the benign PZ zone (r = 0.730) and CG (r = 0.664). Positive correlation was found between Cit and Cho in the benign CG (r = 0.705). Whereas Cit and ADC were positively correlated in the benign PZ (r = 0.673), only low correlation was found in CG (r = 0.265). CONCLUSION: We have shown that it is possible to perform water-referenced quantitative 3D MRSI of the prostate at the cost of a relatively short prolongation of the acquisition time. The individual metabolite concentrations provide additional information compared to the previously used metabolite-to-citrate ratios. LEVEL OF EVIDENCE: 1 J. Magn. Reson. Imaging 2017;45:1232-1240.

Intravoxel incoherent motion MR imaging of the kidney: pilot study.

MR examinations (Achieva 3 T, Philips, Best, The Netherlands) were performed at five different occasions in a healthy volunteer (male 60 years) and in one renal cancer patient (male 78 years) with normal renal function (creatinine 88 µmol/L). Intravoxel incoherent motion (IVIM) coefficients D + D* were measured using respiratory-triggered diffusion-weighted spin-echo echo-planar imaging. Perfusion data of the patient were acquired using a saturation-recovery gradient-echo sequence and with the bolus of Gd-BOPTA (Multihance). D + D* were computed by monoexponential fitting of MR signal intensity attenuation versus b for b = 0, 50, 100, 150 s/mm(2). Perfusion parameters were evaluated with "NordicICE" software. The map of D + D* was compared qualitatively with the perfusion map computed from the Gd scan. D + D* values of the cortex and medulla were in the range 2.3-2.7 and 1.1-1.6 × 10(-3) mm(2)/s, respectively. In conclusion, in this pilot study a good qualitative relation between IVIM variables D + D* and renal perfusion has been found.

Training drills in high performance badminton-effects of interval duration on internal and external loads.

Purpose: The aim of the present study was to analyze the impact of interval duration on training loads and technical skill performance in high performance badminton drills. Methods: On three experimental days, 19 internationally ranked players (13 male: 22.7 ± 3.8 years, 180 ± 6 cm, 71.5 ± 6.1 kg; 6 females: 20.4 ± 2.5 years, 168 ± 4 cm, 59.8 ± 6.0 kg) completed one of three protocols (T10, T30, and T50) of a typical badminton specific drill, the so-called "Multifeeding" (the coach feeds shuttlecock without break in a random order) in a counterbalanced order. The protocols varied in interval duration (10, 30, and 50 s) but were matched for the rally-to-rest-ratio (1:1) and active playing time (600 s). Cardiorespiratory responses (portable spirometry, chest belt), energy metabolism (levels of blood lactate, La), rate of perceived exertion (RPE), player's kinematics (Local Positioning System), and technical skill performance (video analysis) were measured. Results: Average oxygen consumption (T10 45 ± 6; T30 46 ± 7; T50 44 ± 6 mL min-1·kg-1), Energy expenditure (886 ± 209; 919 ± 176; 870 ± 206 kcal h-1), heart rate (164 ± 13; 165 ± 11; 165 ± 10 bpm) and RPE (16 ± 2; 17 ± 2; 17 ± 2) did not differ between the protocols. Respiratory exchange ratio (RER) and La significantly increased depending on interval duration (RER: 0.90 ± 0.05; 0.93 ± 0.03; 0.96 ± 0.04 and La: 3.6 ± 2.0; 5.6 ± 3.0; 7.3 ± 2.3 mmol l-1). Stroke frequency (SF; 0.58 ± 0.05; 0.57 ± 0.05; 0.55 ± 0.06 strokes·s-1) was similar while distance covered, and average running velocity were significantly lower for T50 compared to T10 (76 ± 17; 70 ± 13; 65 ± 11 m min-1). Moreover, jump frequency in T30 was higher than in T10 (6.7 ± 3.1; 8.8 ± 3.8; 8.5 ± 4.2 jumps·min-1), whereas differences in internal and external loads were not associated with changes in stroke precision (errors: 16 ± 6; 19 ± 4; 18 ± 4%; accuracy: 22 ± 6; 24 ± 8; 23 ± 8%). Conclusion: Anaerobic metabolic stimulus increases while running distance and velocity decrease, in case of longer interval durations. Even though there was no impact on stroke precision, extending the intervals beyond 30 s might impair external training load and skill performance. Consequently, interval duration should be defined carefully depending on the training goals.

Pupil dilation during negative prediction errors is related to brain choline concentration and depressive symptoms in adolescents.

Depressive symptoms are associated with altered pupillary responses during learning and reward prediction as well as with changes in neurometabolite levels, including brain concentrations of choline, glutamate and gamma-aminobutyric acid (GABA). However, the full link between depressive symptoms, reward-learning-related pupillary responses and neurometabolites is yet to be established as these constructs have not been assessed in the same individuals. The present pilot study, investigated these relations in a sample of 24 adolescents aged 13 years. Participants completed the Revised Child Anxiety and Depression Scale (RCADS) and underwent a reward learning task while measuring pupil dilation and a single voxel dorsal anterior cingulate cortex (dACC) MEGA-PRESS magnetic resonance spectroscopy scan assessing choline, glutamate and GABA concentrations. Pupil dilation was related to prediction errors (PE) during learning, which was captured by a prediction error-weighted pupil dilation response index (PE-PDR) for each individual. Higher PE-PDR scores, indicating larger pupil dilations to negative prediction errors, were related to lower depressive symptoms and lower dACC choline concentrations. Dorsal ACC choline was positively associated with depressive symptoms, whereas glutamate and GABA were not related to PE-PDR or depressive symptoms. The findings support notions of cholinergic involvement in depressive symptoms and cholinergic influence on reward-related pupillary response, suggesting that pupillary responses to negative prediction errors may hold promise as a biomarker of depressive states.

The value of pre-operative magnetic resonance spectroscopy in the assessment of steatohepatitis in patients with colorectal liver metastasis.

BACKGROUND & AIMS: Neoadjuvant chemotherapy prior to liver surgery for colorectal metastases can cause marked steatosis (≥ 33%) and steatohepatitis defined by non-alcoholic fatty liver disease activity score (NAS) as adverse effects on liver parenchyma. The aim of this study was to evaluate the steatosis level prior to liver resection using proton magnetic resonance spectroscopy ((1)H MRS) and to compare it with digital quantification of steatosis (DQS) and "classical" histopathology. METHODS: (1)H MRS at 3T evaluated steatosis in 35 patients with colorectal liver metastasis, planned for liver resection. Non-tumorous liver parenchyma samples were obtained after surgery for classical histopathology and DQS utilising automated software for quantification of histopathological slides using image processing. RESULTS: Classical histopathology defined marked steatosis in nine patients. Histopathology was less reliable than DQS (interclass correlation coefficient - ICC 0.771) or (1)H MRS (ICC 0.722) in steatosis estimation. (1)H MRS showed very similar steatosis levels and high reliability compared to DQS (ICC 0.955). Steatohepatitis was observed in seven patients (NAS ≥ 4) and (1)H MRS was able to predict it with 100% sensitivity and 89% specificity at threshold 10.9%, without knowing lobular inflammation or hepatocyte ballooning. BMI was significantly higher in the groups with marked steatosis and steatohepatitis. Standard blood tests or chemotherapy had no predictive value. CONCLUSIONS: (1)H MRS is a reliable non-invasive tool for steatosis assessment, and interestingly, it was able to predict steatohepatitis defined by NAS ≥ 4 in patients planned for liver resection of colorectal metastases after neoadjuvant chemotherapy.

MR spectroscopy of the human prostate using surface coil at 3 T: metabolite ratios, age-dependent effects, and diagnostic possibilities.

PURPOSE: To measure prostate spectra of healthy volunteers using a surface coil, to demonstrate age-dependent effects, and to investigate diagnostic possibilities for prostate cancer detection. MATERIALS AND METHODS: Single-voxel and 2D magnetic resonance spectroscopic imaging (MRSI) spectra of 51 healthy volunteers with biopsy-proven prostate carcinoma of 20 patients for comparison were measured and processed using the LCModel. The mean normalized spectra and mean metabolite-to-citrate intensity ratios were computed. RESULTS: Metabolite-to-citrate ratios of healthy volunteers were lower in the older group (>51 years) than in the younger group (<45 years). The peripheral zone (PZ) revealed a lower metabolite-to-citrate intensity ratio than the central gland (CG). Age-related differences in metabolite-to-citrate ratio were insignificant in the voxels with predominantly CG tissue, whereas significant differences were found in the PZ. Sensitivity in detecting prostate cancer by single-voxel spectroscopy (SVS) and 2D MRSI was 75% and 80%, respectively. CONCLUSION: SVS and 2D MRSI of the prostate at 3 T, using a surface coil, are useful in situations when insertion of the endorectal coil into the rectum is difficult or impossible. Our findings of age-dependent effects may be of importance for the analysis of patient spectra.

GABA quantification in human anterior cingulate cortex.

γ-Aminobutyric acid (GABA) is a primary inhibitory neurotransmitter in the human brain. It has been shown that altered GABA concentration plays an important role in a variety of psychiatric and neurological disorders. The main purpose of this study was to propose a combination of PRESS and MEGA-PRESS acquisitions for absolute GABA quantification and to compare GABA estimations obtained using total choline (tCho), total creatine (tCr), and total N-acetyl aspartate (tNAA) as the internal concentration references with water referenced quantification. The second aim was to demonstrate the fitting approach of MEGA-PRESS spectra with QuasarX algorithm using a basis set of GABA, glutamate, glutamine, and NAA in vitro spectra. Thirteen volunteers were scanned with the MEGA-PRESS sequence at 3T. Interleaved water referencing was used for quantification, B0 drift correction and to update the carrier frequency of RF pulses in real time. Reference metabolite concentrations were acquired using a PRESS sequence with short TE (30 ms) and long TR (5000 ms). Absolute concentration were corrected for cerebrospinal fluid, gray and white matter water fractions and relaxation effects. Water referenced GABA estimations were significantly higher compared to the values obtained by metabolite references. We conclude that QuasarX algorithm together with the basis set of in vitro spectra improves reliability of GABA+ fitting. The proposed GABA quantification method with PRESS and MEGA-PRESS acquisitions enables the utilization of tCho, tCr, and tNAA as internal concentration references. The use of different concentration references have a good potential to improve the reliability of GABA estimation.

Inhibitory and excitatory neurotransmitter systems in depressed and healthy: A positron emission tomography and magnetic resonance spectroscopy study.

The Gamma-aminobutyric acid (GABA) and glutamate (Glu) neurotransmitter systems are implicated in depression. While previous studies found reduced GABA levels, and a tendency towards reduced Glu, using proton (1H) magnetic resonance spectroscopy (1H-MRS), little is known about GABAA receptor availability in depression. Here, the aim was to characterize GABA and Glu-levels in dorsal anterior cingulate cortex (dACC), whole-brain GABAA availability, and their relationship in patients with depression compared to healthy controls. Forty-two patients and 45 controls underwent 1H-MRS using a MEGA-PRESS sequence to quantify dACC GABA+ and Glu (contrasted against creatine [Cr]). Immediately preceding the 1H-MRS, a subsample of 28 patients and 15 controls underwent positron emission tomography (PET) with [11C]Flumazenil to assess whole-brain GABAA receptor availability. There were no differences in dACC GABA+/Cr or Glu/Cr ratios between patients and controls. The same was true for whole-brain GABAA receptor availability. However, there was a significant negative relationship between GABA+/Cr ratio and receptor availability in ACC, in a whole-brain voxel-wise analysis across patients and controls, controlling for group or depressive symptoms. This relatively large study did not support the GABA-deficit hypothesis in depression, but shed light on GABA-system functioning, suggesting a balance between neurotransmitter concentration and receptor availability in dACC.

Radiolabelling and positron emission tomography imaging of a high-affinity peptide binder to collagen type 1.

INTRODUCTION: Pathological formation of fibrosis, is an important feature in many diseases. Fibrosis in liver and pancreas has been associated to metabolic disease including type 1 and 2 diabetes. The current methods for detecting and diagnosing fibrosis are either invasive, or their sensitivity to detect fibrosis in early stage is limited. Therefore, it is crucial to develop non-invasive methods to detect, stage and study the molecular processes that drive the pathology of liver fibrosis. The peptide LRELHLNNN was previously identified as a selective binder to collagen type I with an affinity of 170 nM. Radiolabelled LRELHLNNN thus constitute a potential PET tracer for fibrosis. METHOD: LRELHLNNN was conjugated to a DOTA/NOTA moiety via a PEG2-linker. DOTA-PEG2-LRELHLNNN was labelled with Gallium-68 and NOTA- PEG2-LRELHLNNN with aluminium fluoride-18. Biodistribution of [68Ga]Ga-DOTA-PEG2-LRELHLNNN and [18F]AlF-NOTA-PEG2-LRELHLNNN was performed in healthy rats ex vivo and in vivo. The 68Ga-labelled analogue was evaluated in a mouse model of liver fibrosis by PET/MRI-imaging. The human predicted dosimetry of the tracers was extrapolated from rat ex vivo biodistribution studies at 10, 20, 40, 60, 120, 180 min (only fluoride-18) post-injection. RESULTS: The peptides were successfully radiolabelled with gallium-68 and aluminium fluoride-18, respectively. The biodistribution of [68Ga]Ga-DOTA-PEG2-LRELHLNNN and [18F]AlF-NOTA-PEG2-LRELHLNNN was favorable showing rapid clearance and low background binding in organs where fibrosis may develop. Binding of [68Ga]Ga-DOTA-PEG2-LRELHLNNN to fibrotic liver was higher than surrounding tissues in mice with induced hepatic fibrosis. However, the binding was in the range of SUV 0.3, indicating limited targeting of the tracer to liver. The extrapolated human predicted dosimetric profiles of [68Ga]Ga-DOTA-PEG2-LRELHLNNN and [18F]AlF-NOTA-PEG2-LRELHLNNN were beneficial, potentially allowing at least three PET examinations annually. CONCLUSIONS: We describe the modification, radiolabelling and evaluation of the collagen type I binding peptide LRELHLNNN. The resulting radiotracer analogues demonstrated suitable biodistribution and dosimetry. [68Ga]Ga-DOTA-PEG2-LRELHLNNN exhibited binding to hepatic fibrotic lesions and is a promising tool for PET imaging of fibrosis. ADVANCES IN KNOWLEDGE: Validation of a new collagen targeting PET tracer. IMPLICATIONS FOR PATIENT CARE: Early, non-invasive diagnosis and stratification of fibrosis in order to improve the diagnosis, staging and treatment of patients with diseases involving fibrosis.

The Use of a Non-Conventional Long-Lived Gallium Radioisotope 66Ga Improves Imaging Contrast of EGFR Expression in Malignant Tumours Using DFO-ZEGFR:2377 Affibody Molecule.

Epidermal growth factor receptor (EGFR) is overexpressed in many malignancies. EGFR-targeted therapy extends survival of patients with disseminated cancers. Radionuclide molecular imaging of EGFR expression would make EGFR-directed treatment more personalized and therefore more efficient. A previous study demonstrated that affibody molecule [68Ga]Ga-DFO-ZEGFR:2377 permits specific positron-emission tomography (PET) imaging of EGFR expression in xenografts at 3 h after injection. We anticipated that imaging at 24 h after injection would provide higher contrast, but this is prevented by the short half-life of 68Ga (67.6 min). Here, we therefore tested the hypothesis that the use of the non-conventional long-lived positron emitter 66Ga (T1/2 = 9.49 h, ß+ = 56.5%) would permit imaging with higher contrast. 66Ga was produced by the 66Zn(p,n)66Ga nuclear reaction and DFO-ZEGFR:2377 was efficiently labelled with 66Ga with preserved binding specificity in vitro and in vivo. At 24 h after injection, [66Ga]Ga-DFO-ZEGFR:2377 provided 3.9-fold higher tumor-to-blood ratio and 2.3-fold higher tumor-to-liver ratio than [68Ga]Ga-DFO-ZEGFR:2377 at 3 h after injection. At the same time point, [66Ga]Ga-DFO-ZEGFR:2377 provided 1.8-fold higher tumor-to-blood ratio, 3-fold higher tumor-to-liver ratio, 1.9-fold higher tumor-to-muscle ratio and 2.3-fold higher tumor-to-bone ratio than [89Zr]Zr-DFO-ZEGFR:2377. Biodistribution data were confirmed by whole body PET combined with magnetic resonance imaging (PET/MRI). The use of the positron emitter 66Ga for labelling of DFO-ZEGFR:2377 permits PET imaging of EGFR expression at 24 h after injection and improves imaging contrast.