Abstract Background Presentations and outcomes of acute myocardial infarction (MI) differ between women and men, with the worst outcomes being reported in younger women. Mental stress induced ischemia and sympathetic activation have been suggested to play a prominent role in the pathogenesis of MI in younger women, however, the impact of sex hormones on these parameters remains unknown. Methods The effect of sex hormones and age on myocardial infarct size and myocardial sympathetic activity (MSA) was assessed in male and female, as well as young (4–6 months) and aged (20–22 months) FVB/N mice (n = 106, 60 gonadectomized and 46 sham-operated animals) who underwent in vivo [11C]meta-hydroxyephedrine ([11C]mHED) positron emission tomography (PET) and cardiac magnetic resonance (CMR) imaging 24 h after a 30 min myocardial ischemic injury. Results MSA and catecholamine levels following myocardial injury were highest in young males (p = 0.008 and p = 0.043 vs. young females, respectively) and were reduced by orchiectomy. Accordingly, testosterone serum levels correlated positively with MSA (r = 0.66, p < 0.001). Males had a larger average infarct size and lower left ventricular contractility following myocardial injury than females (p < 0.05 vs. females). These sex differences were no longer evident in gonadectomized animals (p = NS vs. females). In female animals, estrogen depletion did not affect MSA (ovariectomy effect, p = 0.892). Female animals showed an age-dependent increase in MSA (p = 0.011), which was absent in males. Conclusion Testosterone associates with an increase in sympathetic tone, contributing to adverse cardiac remodeling following MI. Conversely, females maintain sympathetic integrity, independent of sex hormones. Our results suggest a biological advantage of female sex in post MI recovery. Further research is warranted to confirm these findings in humans.

The aim of this guideline is to provide recommendations for the implementation of an effective and efficient quality control (QC) programme for SPECT and PET systems in a preclinical imaging lab. These recommendations aim to strengthen the translational power of preclinical imaging results obtained using preclinical SPECT and PET. As for clinical imaging, reliability, reproducibility, and repeatability are essential when groups of animals are used in a longitudinal imaging experiment. The larger the variability of the imaging endpoint, the more animals are needed to be able to observe statistically significant differences between groups. Therefore, preclinical imaging requires quality control procedures to maintain reliability, reproducibility, and repeatability of imaging procedures, and to ensure the accuracy and precision of SPECT and PET quantification. While the Physics Committee of the European Association of Nuclear Medicine (EANM) has already published excellent procedure guidelines for Routine Quality Control Recommendations for Nuclear Medicine Instrumentation that also includes procedures for small animal PET systems, and important steps have already been made concerning preclinical quality control aspects, this new guideline provides a review and update of these previous guidelines such that guidelines are also adapted to new technological developments.

The relationship between mechanical ventilation-induced brain volume changes and ICU-acquired weakness (ICU-AW) is not clear. We assessed brain volume change in ventilated patients and identified associations with changes in extremity muscle strength. Patients admitted to the ICU due to the need for ventilation, and who underwent at least two head CT scans during hospitalization, were included. We employed an automated segmentation method to measure brain volume, recording changes in volume from baseline. Cases with brain volume reduction > 0% were assigned to the "brain atrophy group" and those with <= 0% reduction to the "preserved brain volume group." Medical Research Council (MRC) scores as an indicator of ICU-AW at discharge were compared between groups. There were 84 eligible patients, 71 in the brain atrophy group and 13 in the preserved brain volume group. Analysis of the brain atrophy group showed a significant brain volume reduction of - 3.3% over a median of 30 days. The median MRC scores were significantly lower in the brain atrophy group than in the preserved brain volume group (36 vs. 48, difference [95% CI]: - 12 [- 19.5- - 7.1]). Many ICU patients on mechanical ventilation showed rapidly progressive brain atrophy, and most of these patients developed ICU-AW.

NeuroLF is a dedicated brain PET system with an octagonal prism shape housed in a scanner head that can be positioned around a patient's head. Because it does not have MR or CT capabilities, attenuation correction based on an estimation of the attenuation map is a crucial feature. In this article, we demonstrate this method on [18F]FDG PET brain scans performed with a low-resolution proof of concept prototype of NeuroLF called BPET. We perform an affine registration of a template PET scan to the uncorrected emission image, and then apply the resulting transform to the corresponding template attenuation map. Using a whole-body PET/CT system as reference, we quantitively show that this method yields comparable image quality (0.893 average correlation to reference scan) to using the reference µ-map as obtained from the CT scan of the imaged patient (0.908 average correlation). We conclude from this initial study that attenuation correction using template registration instead of a patient CT delivers similar results and is an option for patients undergoing brain PET.

[18F]DASA-23 Radiosynthesis

Clinical Characteristics of patients imaged with [18F]DASA-23

The effect of posterior cranial fossa stroke on changes in cerebral volume is not known. We assessed cerebral volume changes in patients with acute posterior fossa stroke using CT scans, and looked for risk factors for cerebral atrophy. Patients with cerebellar or brainstem hemorrhage/infarction admitted to the ICU, and who underwent at least two subsequent inpatient head CT scans during hospitalization were included (n = 60). The cerebral volume was estimated using an automatic segmentation method. Patients with cerebral volume reduction > 0

Background Myocardial perfusion imaging by positron emission tomography (PET-MPI) is the current gold standard for quantification of myocardial blood flow. 18 F-flurpiridaz was recently introduced as a valid alternative to currently used PET-MPI probes. Nonetheless, optimum scan duration and time interval for image analysis are currently unknown. Further, it is unclear whether rest/stress PET-MPI with 18 F-flurpiridaz is feasible in mice. Methods Rest/stress PET-MPI was performed with 18 F-flurpiridaz (0.6-3.0 MBq) in 29 mice aged 7-8 months. Regadenoson (0.1 μg/g) was used for induction of vasodilator stress. Kinetic modeling was performed using a metabolite-corrected arterial input function. Image-derived myocardial 18 F-flurpiridaz uptake was assessed for different time intervals by placing a volume of interest in the left ventricular myocardium. Results Tracer kinetics were best described by a two-tissue compartment model. K 1 ranged from 6.7-20.0 mL/cm 3 /min, while myocardial volumes of distribution ( V T ) were between 34.6 and 83.6 mL/cm 3 . Of note, myocardial 18 F-flurpiridaz uptake (%ID/g) was significantly correlated with K 1 at rest and following pharmacological stress testing for all time intervals assessed. However, while Spearman’s coefficients (r s ) ranged between 0.478 and 0.672, R 2 values were generally low. In contrast, an excellent correlation of myocardial 18 F-flurpiridaz uptake with V T was obtained, particularly when employing the averaged myocardial uptake from 20-40 min post tracer injection (R 2 ≥0.98). Notably, K 1 and V T were similarly sensitive to pharmacological stress induction. Further, mean stress-to-rest ratios of K 1 , V T , and %ID/g 18 F-flurpiridaz were virtually identical, suggesting that %ID/g 18 F-flurpiridaz can be used to estimate CFR in mice. Conclusion Our findings suggest that a simplified assessment of relative myocardial perfusion and coronary flow reserve (CFR), based on image-derived tracer uptake, is feasible with 18 F-flurpiridaz in mice, enabling high-throughput mechanistic CFR studies in rodents.

OBJECTIVES:Different computed tomography (CT) scanners, variations in acquisition protocols, and technical parameters employed for image reconstruction may introduce bias in the analysis of pericoronary adipose tissue (PCAT) attenuation derived from coronary computed tomography angiography (CCTA). Therefore, the aim of this study was to establish the effect of tube voltage, measured as kilovoltage peak (kVp), and iterative reconstruction on PCAT mean attenuation (PCATMA).METHODS:Twelve healthy ex vivo porcine hearts were injected with iodine-enriched agar-agar to allow for ex vivo CCTA imaging on a 256-slice CT and a dual-source CT system. Images were acquired at tube voltages of 80, 100, 120, and 140 kVp and reconstructed by using both filtered back projection and iterative reconstruction algorithms. PCATMA was measured semi-automatically on CCTA images in the proximal segment of coronary arteries.RESULTS:The tube voltage showed a significant effect on PCATMA measurements on both the 256-slice CT scanner (p < 0.001) and the dual-source CT system (p = 0.013), resulting in higher attenuation values with increasing tube voltage. Similarly, the use of iterative reconstructions was associated with a significant increase of PCATMA (256-slice CT: p < 0.001 and dual-source CT: p = 0.014). Averaged conversion factors to correct PCATMA measurements for tube voltage other than 120 kVp were 1.267, 1.080 and 0.947 for 80, 100, and 140 kVp, respectively.CONCLUSION:PCATMA values are significantly affected by acquisition and reconstruction parameters. The same tube voltage and reconstruction type are recommended when PCAT attenuation is used in multicenter and longitudinal studies.KEY POINTS:• The tube voltage used for CCTA acquisition affects pericoronary adipose tissue attenuation, resulting in higher attenuation values of fat with increasing tube voltage. • Conversion factors for pericoronary adipose tissue attenuation values could be used to adjust for differences in attenuation between scans performed at different tube voltages. • In longitudinal CCTA studies employing pericoronary adipose tissue attenuation as imaging endpoint, it is recommended to maintain tube voltage and image reconstruction type constant across serial scans.

A growing body of evidence highlights sex differences in the diagnostic accuracy of cardiovascular imaging modalities. Nonetheless, the role of sex hormones in modulating myocardial perfusion and coronary flow reserve (CFR) is currently unclear. The aim of our study was to assess the impact of female and male sex hormones on myocardial perfusion and CFR. Rest and stress myocardial perfusion imaging (MPI) was conducted by small animal positron emission tomography (PET) with [18F]flurpiridaz in a total of 56 mice (7–8 months old) including gonadectomized (Gx) and sham-operated males and females, respectively. Myocardial [18F]flurpiridaz uptake (% injected dose per mL, % ID/mL) was used as a surrogate for myocardial perfusion at rest and following intravenous regadenoson injection, as previously reported. Apparent coronary flow reserve (CFRApp) was calculated as the ratio of stress and rest myocardial perfusion. Left ventricular (LV) morphology and function were assessed by cardiac magnetic resonance (CMR) imaging. Orchiectomy resulted in a significant decrease of resting myocardial perfusion (Gx vs. sham, 19.4 ± 1.0 vs. 22.2 ± 0.7 % ID/mL, p = 0.034), while myocardial perfusion at stress remained unchanged (Gx vs. sham, 27.5 ± 1.2 vs. 27.3 ± 1.2 % ID/mL, p = 0.896). Accordingly, CFRApp was substantially higher in orchiectomized males (Gx vs. sham, 1.43 ± 0.04 vs. 1.23 ± 0.05, p = 0.004), and low serum testosterone levels were linked to a blunted resting myocardial perfusion (r = 0.438, p = 0.020) as well as an enhanced CFRApp (r = −0.500, p = 0.007). In contrast, oophorectomy did not affect myocardial perfusion in females. Of note, orchiectomized males showed a reduced LV mass, stroke volume, and left ventricular ejection fraction (LVEF) on CMR, while no such effects were observed in oophorectomized females. Our experimental data in mice indicate that sex differences in myocardial perfusion are primarily driven by testosterone. Given the diagnostic importance of PET-MPI in clinical routine, further studies are warranted to determine whether testosterone levels affect the interpretation of myocardial perfusion findings in patients.

Alterations in brain cholesterol homeostasis have been broadly implicated in neurological disorders. Notwithstanding the complexity by which cholesterol biology is governed in the mammalian brain, excess neuronal cholesterol is primarily eliminated by metabolic clearance via cytochrome P450 46A1 (CYP46A1). No methods are currently available for visualizing cholesterol metabolism in the living human brain; therefore, a noninvasive technology that quantitatively measures the extent of brain cholesterol metabolism via CYP46A1 could broadly affect disease diagnosis and treatment options using targeted therapies. Here, we describe the development and testing of a CYP46A1-targeted positron emission tomography (PET) tracer, 18 F-CHL-2205 ( 18 F-Cholestify). Our data show that PET imaging readouts correlate with CYP46A1 protein expression and with the extent to which cholesterol is metabolized in the brain, as assessed by cross-species postmortem analyses of specimens from rodents, nonhuman primates, and humans. Proof of concept of in vivo efficacy is provided in the well-established 3xTg-AD murine model of Alzheimer’s disease (AD), where we show that the probe is sensitive to differences in brain cholesterol metabolism between 3xTg-AD mice and control animals. Furthermore, our clinical observations point toward a considerably higher baseline brain cholesterol clearance via CYP46A1 in women, as compared to age-matched men. These findings illustrate the vast potential of assessing brain cholesterol metabolism using PET and establish PET as a sensitive tool for noninvasive assessment of brain cholesterol homeostasis in the clinic.

Glucose is the main energy source in the brain and its regulated uptake and utilization are important biomarkers of pathological brain function. Glucose Chemical Exchange Saturation Transfer (GlucoCEST) and its time-resolved version Dynamic Glucose-Enhanced MRI (DGE) are promising approaches to monitor glucose and detect tumors, since they are radioactivity-free, do not require 13C labeling and are is easily translatable to the clinics. The main principle of DGE is clear. However, what remains to be established is to which extent the signal reflects vascular, extracellular or intracellular glucose. To elucidate the compartmental contributions to the DGE signal, we coupled it with FRET-based fiber photometry of genetically encoded sensors, a technique that combines quantitative glucose readout with cellular specificity. The glucose sensor FLIIP was used with fiber photometry to measure astrocytic and neuronal glucose changes upon injection of D-glucose, 3OMG and L-glucose, in the anaesthetized murine brain. By correlating the kinetic profiles of the techniques, we demonstrate the presence of a vascular contribution to the signal, especially at early time points after injection. Furthermore, we show that, in the case of the commonly used contrast agent 3OMG, the DGE signal actually anticorrelates with the glucose concentration in neurons and astrocytes.

PurposeTo support acquisition of accurate, reproducible and high-quality preclinical imaging data, various standardisation resources have been developed over the years. However, it is unclear the impact of those efforts in current preclinical imaging practices. To better understand the status quo in the field of preclinical imaging standardisation, the STANDARD group of the European Society of Molecular Imaging (ESMI) put together a community survey and a forum for discussion at the European Molecular Imaging Meeting (EMIM) 2022. This paper reports on the results from the STANDARD survey and the forum discussions that took place at EMIM2022. ProceduresThe survey was delivered to the community by the ESMI office and was promoted through the Society channels, email lists and webpages. The survey contained seven sections organised as generic questions and imaging modality-specific questions. The generic questions focused on issues regarding data acquisition, data processing, data storage, publishing and community awareness of international guidelines for animal research. Specific questions on practices in optical imaging, PET, CT, SPECT, MRI and ultrasound were further included. ResultsData from the STANDARD survey showed that 47% of survey participants do not have or do not know if they have QC/QA guidelines at their institutes. Additionally, a large variability exists in the ways data are acquired, processed and reported regarding general aspects as well as modality-specific aspects. Moreover, there is limited awareness of the existence of international guidelines on preclinical (imaging) research practices. ConclusionsStandardisation of preclinical imaging techniques remains a challenge and hinders the transformative potential of preclinical imaging to augment biomedical research pipelines by serving as an easy vehicle for translation of research findings to the clinic. Data collected in this project show that there is a need to promote and disseminate already available tools to standardise preclinical imaging practices.

PurposeTo investigate the reproducibility of tracer uptake measurements, including volume metrics, such as metabolic tumor volume (MTV) and tumor lesion glycolysis (TLG) obtained by TOF-PET-CT and TOF-PET-MR.Materials and MethodsEighty consecutive patients with different oncologic diagnoses underwent TOF-PET-CT (Discovery 690; GE Healthcare) and TOF-PET-MR (SIGNA PET-MR; GE Healthcare) on the same day with single dose−18F-FDG injection. The scan order, PET-CT following or followed by PET-MR, was randomly assigned. A spherical volume of interest (VOI) of 30 mm was placed on the liver in accordance with the PERCIST criteria. For liver, the maximum and mean standard uptake value for body weight (SUV) and lean body mass (SUL) were obtained. For tumor delineation, VOI with a threshold of 40 and 50% of SUVmax was used (VOI40 and VOI50). The SUVmax, SUVmean, SUVpeak, MTV and TLG were calculated. The measurements were compared between the two scanners.ResultsIn total, 80 tumor lesions from 35 patients were evaluated. There was no statistical difference observed in liver regions, whereas in tumor lesions, SUVmax, SUV mean, and SUVpeak of PET-MR were significantly underestimated (p < 0.001) in both VOI40 and VOI50. Among volume metrics, there was no statistical difference observed except TLG on VOI50 (p = 0.03). Correlation between PET-CT and PET-MR of each metrics were calculated. There was a moderate correlation of the liver SUV and SUL metrics (r = 0.63–0.78). In tumor lesions, SUVmax and SUVmean had a stronger correlation with underestimation in PET-MR on VOI 40 (SUVmax and SUVmean; r = 0.92 and 0.91 with slope = 0.71 and 0.72, respectively). In the evaluation of MTV and TLG, the stronger correlations were observed both on VOI40 (MTV and TLG; r = 0.75 and 0.92) and VOI50 (MTV and TLG; r = 0.88 and 0.95) between PET-CT and PET-MR.ConclusionPET metrics on TOF-PET-MR showed a good correlation with that of TOF-PET-CT. SUVmax and SUVpeak of tumor lesions were underestimated by 16% on PET-MRI. MTV with % threshold can be regarded as identical volumetric markers for both TOF-PET-CT and TOF-PET-MR.

Abstract Purpose: Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel PET tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and patients with GBM. Experimental Design: [18F]DASA-23 was synthesized with a molar activity of 100.47 ± 29.58 GBq/μmol and radiochemical purity >95%. We performed initial testing of [18F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next, we produced [18F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers and a pilot cohort of patients with glioma. Results: In mouse imaging studies, [18F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio of 3.6 ± 0.5. In human volunteers, [18F]DASA-23 crossed the intact blood–brain barrier and was rapidly cleared. In patients with GBM, [18F]DASA-23 successfully outlined tumors visible on contrast-enhanced MRI. The uptake of [18F]DASA-23 was markedly elevated in GBMs compared with normal brain, and it identified a metabolic nonresponder within 1 week of treatment initiation. Conclusions: We developed and translated [18F]DASA-23 as a new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These results warrant further clinical evaluation of [18F]DASA-23 to assess its utility for imaging therapy–induced normalization of aberrant cancer metabolism.

Background: Recent studies indicate that enhanced neuronal stress responses are associated with adverse cardiovascular outcomes. A chronic inflammatory state seems to mediate this detrimental neuro-cardiac communication. Statins are among the most widely prescribed medications in primary and secondary cardiovascular disease (CVD) prevention and not only lower lipid levels but also exhibit strong anti-inflammatory and neuroprotective effects. We therefore sought to investigate the influence of statins on neuronal stress responses in a patient cohort at risk for CVD. Methods: 563 patients (61.5 ± 14.0 years) who underwent echocardiography and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) were retrospectively identified. Metabolic activity of the amygdala, a part of the brain’s salience network, was quantified by 18F-FDG uptake, while normal cardiac morphology and function were assured by echocardiography. Vertebral bone marrow metabolism, a marker of inflammatory activity, was measured by 18F-FDG PET. Results: Increased neuronal stress responses were associated with an increased inflammatory activity in the bone marrow (r = 0.152, p = 0.015) as well as with a subclinical reduction in left ventricular ejection fraction (LVEF, r = −0.138, p = 0.025). In a fully-adjusted linear regression model, statin treatment was identified as an independent, negative predictor of amygdalar metabolic activity (B-coefficient −0.171, p = 0.043). Conclusions: Our hypothesis-generating investigation suggests a potential link between the anti-inflammatory actions of statins and reduced neuronal stress responses which could lead to improved cardiovascular outcomes. The latter warrants further studies in a larger and prospective population.

(1) Background: Small Animal Fast Insert for MRI detector I (SAFIR-I) is a preclinical Positron Emission Tomography (PET) insert for the Bruker BioSpec 70/30 Ultra Shield Refrigerated (USR) preclinical 7T Magnetic Resonance Imaging (MRI) system. It is designed explicitly for high-rate kinetic studies in mice and rats with injected activities reaching 500MBq, enabling truly simultaneous quantitative PET and Magnetic Resonance (MR) imaging with time frames of a few seconds in length. (2) Methods: SAFIR-I has an axial field of view of 54.2mm and an inner diameter of 114mm. It employs Lutetium Yttrium OxyorthoSilicate (LYSO) crystals and Multi Pixel Photon Counter (MPPC) arrays. The Position-Energy-Timing Application Specific Integrated Circuit, version 6, Single Ended (PETA6SE) digitizes the MPPC signals and provides time stamps and energy information. (3) Results: SAFIR-I is MR-compatible. The system’s Coincidence Resolving Time (CRT) and energy resolution are between separate-uncertainty 209.0(3)ps and separate-uncertainty 12.41(02) Full Width at Half Maximum (FWHM) at low activity and separate-uncertainty 326.89(12)ps and separate-uncertainty 20.630(011) FWHM at 550MBq, respectively. The peak sensitivity is ∼1.6. The excellent performance facilitated the successful execution of first in vivo rat studies beyond 300MBq. Based on features visible in the acquired images, we estimate the spatial resolution to be ∼2mm in the center of the Field Of View (FOV). (4) Conclusion: The SAFIR-I PET insert provides excellent performance, permitting simultaneous in vivo small animal PET/MR image acquisitions with time frames of a few seconds in length at activities of up to 500MBq.

Abstract Background Sepsis is often associated with multiple organ failure; however, changes in brain volume with sepsis are not well understood. We assessed brain atrophy in the acute phase of sepsis using brain computed tomography (CT) scans, and their findings’ relationship to risk factors and outcomes. Methods Patients with sepsis admitted to an intensive care unit (ICU) and who underwent at least two head CT scans during hospitalization were included (n = 48). The first brain CT scan was routinely performed on admission, and the second and further brain CT scans were obtained whenever prolonged disturbance of consciousness or abnormal neurological findings were observed. Brain volume was estimated using an automatic segmentation method and any changes in brain volume between the two scans were recorded. Patients with a brain volume change < 0% from the first CT scan to the second CT scan were defined as the “brain atrophy group (n = 42)”, and those with ≥ 0% were defined as the “no brain atrophy group (n = 6).” Use and duration of mechanical ventilation, length of ICU stay, length of hospital stay, and mortality were compared between the groups. Results Analysis of all 42 cases in the brain atrophy group showed a significant decrease in brain volume (first CT scan: 1.041 ± 0.123 L vs. second CT scan: 1.002 ± 0.121 L, t (41) = 9.436, p < 0.001). The mean percentage change in brain volume between CT scans in the brain atrophy group was –3.7% over a median of 31 days, which is equivalent to a brain volume of 38.5 cm3. The proportion of cases on mechanical ventilation (95.2% vs. 66.7%; p = 0.02) and median time on mechanical ventilation (28 [IQR 15–57] days vs. 15 [IQR 0–25] days, p = 0.04) were significantly higher in the brain atrophy group than in the no brain atrophy group. Conclusions Many ICU patients with severe sepsis who developed prolonged mental status changes and neurological sequelae showed signs of brain atrophy. Patients with rapidly progressive brain atrophy were more likely to have required mechanical ventilation.

The gamma aminobutyric acid (GABA) neurotransmission system has been implicated in autism spectrum disorder (ASD). Molecular neuroimaging studies incorporating simultaneous acquisitions of GABA concentrations and GABAA receptor densities can identify objective molecular markers in ASD. We measured both total GABAA receptor densities by using [18F]flumazenil positron emission tomography ([18F]FMZ-PET) and GABA concentrations by using proton magnetic resonance spectroscopy (1H-MRS) in 28 adults with ASD and 29 age-matched typically developing (TD) individuals. Focusing on the bilateral thalami and the left dorsolateral prefrontal cortex (DLPFC) as our regions of interest, we found no differences in GABAA receptor densities between ASD and TD groups. However, 1H-MRS measurements revealed significantly higher GABA/Water (GABA normalized by water signal) in the left DLPFC of individuals with ASD than that of TD controls. Furthermore, a significant gender effect was observed in the thalami, with higher GABA/Water in males than in females. Hypothesizing that thalamic GABA correlates with ASD symptom severity in gender-specific ways, we stratified by diagnosis and investigated the interaction between gender and thalamic GABA/Water in predicting Autism-Spectrum Quotient (AQ) and Ritvo Autism Asperger’s Diagnostic Scale–Revised (RAADS-R) total scores. We found that gender is a significant effect modifier of thalamic GABA/Water’s relationship with AQ and RAADS-R scores for individuals with ASD, but not for TD controls. When we separated the ASD participants by gender, a negative correlation between thalamic GABA/Water and AQ was observed in male ASD participants. Remarkably, in female ASD participants, a positive correlation between thalamic GABA/Water and AQ was found.