Deficits in brain glucose transport among younger adults with obesity.

OBJECTIVE: Obesity is associated with alterations in eating behavior and neurocognitive function. In this study, we investigate the effect of obesity on brain energy utilization, including brain glucose transport and metabolism. METHODS: A total of 11 lean participants and 7 young healthy participants with obesity (mean age, 27 years) underwent magnetic resonance spectroscopy scanning coupled with a hyperglycemic clamp (target, ~180 mg/dL) using [1-13C] glucose to measure brain glucose uptake and metabolism, as well as peripheral markers of insulin resistance. RESULTS: Individuals with obesity demonstrated an ~20% lower ratio of brain glucose uptake to cerebral glucose metabolic rate (Tmax/CMRglucose) than lean participants (2.12 ± 0.51 vs. 2.67 ± 0.51; p = 0.04). The cerebral tricarboxylic acid cycle flux (VTCA) was similar between the two groups (p = 0.64). There was a negative correlation between total nonesterified fatty acids and Tmax/CMRglucose (r = -0.477; p = 0.045). CONCLUSIONS: We conclude that CMRglucose is unlikely to differ between groups due to similar VTCA, and, therefore, the glucose transport Tmax is lower in individuals with obesity. These human findings suggest that obesity is associated with reduced cerebral glucose transport capacity even at a young age and in the absence of other cardiometabolic comorbidities, which may have implications for long-term brain function and health.

Short symmetric and highly selective asymmetric first and second order gradient modulated offset independent adiabaticity (GOIA) pulses for applications in clinical MRS and MRSI.

Gradient modulated RF pulses, especially gradient offset independent adiabaticity (GOIA) pulses, are increasingly gaining attention for high field clinical magnetic resonance spectroscopy and spectroscopic imaging (MRS/MRSI) due to the lower peak B1 amplitude and associated power demands achievable relative to its non-modulated adiabatic full passage counterparts. In this work we describe the development of two GOIA RF pulses: 1) A power efficient, 3.0 ms wideband uniform rate with smooth truncation (WURST) modulated RF pulse with 15 kHz bandwidth compatible with a clinically feasible peak B1 amplitude of 0.87 kHz (or 20 µT), and 2) A highly selective asymmetric 6.66 ms RF pulse with 20 kHz bandwidth designed to achieve a single-sided, fractional transition width of only 1.7%. Effects of potential asynchrony between RF and gradient-modulated (GM) waveforms for 3 ms GOIA-WURST RF pulses was evaluated by simulation and experimentally. Results demonstrate that a 20+ µs asynchrony between RF and GM functions substantially degrades inversion performance when using large RF offsets to achieve translation. A projection-based method is presented that allows a quick calibration of RF and GM asynchrony on pre-clinical/clinical MR systems. The asymmetric GOIA pulse was implemented within a multi-pulse OVS sequence to achieve power efficient, highly-selective, and B1 and T1-independent signal suppression for extracranial lipid suppression. The developed GOIA pulses were utilized with linear gradient modulation (X, Y, Z gradient fields), and with second-order-field modulations (Z2, X2Y2 gradient fields) to provide elliptically-shaped regions-of-interest for MRS and MRSI acquisitions. Both described GOIA-RF pulses have substantial clinical value; specifically, the 3.0 ms GOIA-WURST pulse is beneficial to realize short TE sLASER localized proton MRS/MRSI sequences, and the asymmetric GOIA RF pulse has applications in highly selective outer volume signal suppression to allow interrogation of tissue proximal to extracranial lipids with full-intensity.

Prefrontal Glutamate Neurotransmission in PTSD: A Novel Approach to Estimate Synaptic Strength in Vivo in Humans.

Background: Trauma and chronic stress are believed to induce and exacerbate psychopathology by disrupting glutamate synaptic strength. However, in vivo in human methods to estimate synaptic strength are limited. In this study, we established a novel putative biomarker of glutamatergic synaptic strength, termed energy-per-cycle (EPC). Then, we used EPC to investigate the role of prefrontal neurotransmission in trauma-related psychopathology. Methods: Healthy controls (n = 18) and patients with posttraumatic stress (PTSD; n = 16) completed 13C-acetate magnetic resonance spectroscopy (MRS) scans to estimate prefrontal EPC, which is the ratio of neuronal energetic needs per glutamate neurotransmission cycle (VTCA/VCycle). Results: Patients with PTSD were found to have 28% reduction in prefrontal EPC (t = 3.0; df = 32, P = .005). There was no effect of sex on EPC, but age was negatively associated with prefrontal EPC across groups (r = -0.46, n = 34, P = .006). Controlling for age did not affect the study results. Conclusion: The feasibility and utility of estimating prefrontal EPC using 13C-acetate MRS were established. Patients with PTSD were found to have reduced prefrontal glutamatergic synaptic strength. These findings suggest that reduced glutamatergic synaptic strength may contribute to the pathophysiology of PTSD and could be targeted by new treatments.

Reversibility of brain glucose kinetics in type 2 diabetes mellitus.

AIMS/HYPOTHESIS: We have previously shown that individuals with uncontrolled type 2 diabetes have a blunted rise in brain glucose levels measured by 1H magnetic resonance spectroscopy. Here, we investigate whether reductions in HbA1c normalise intracerebral glucose levels. METHODS: Eight individuals (two men, six women) with poorly controlled type 2 diabetes and mean ± SD age 44.8 ± 8.3 years, BMI 31.4 ± 6.1 kg/m2 and HbA1c 84.1 ± 16.2 mmol/mol (9.8 ± 1.4%) underwent 1H MRS scanning at 4 Tesla during a hyperglycaemic clamp (~12.21 mmol/l) to measure changes in cerebral glucose at baseline and after a 12 week intervention that improved glycaemic control through the use of continuous glucose monitoring, diabetes regimen intensification and frequent visits to an endocrinologist and nutritionist. RESULTS: Following the intervention, mean ± SD HbA1c decreased by 24.3 ± 15.3 mmol/mol (2.1 ± 1.5%) (p=0.006), with minimal weight changes (p=0.242). Using a linear mixed-effects regression model to compare glucose time courses during the clamp pre and post intervention, the pre-intervention brain glucose level during the hyperglycaemic clamp was significantly lower than the post-intervention brain glucose (p<0.001) despite plasma glucose levels during the hyperglycaemic clamp being similar (p=0.266). Furthermore, the increases in brain glucose were correlated with the magnitude of improvement in HbA1c (r = 0.71, p=0.048). CONCLUSION/INTERPRETATION: These findings highlight the potential reversibility of cerebral glucose transport capacity and metabolism that can occur in individuals with type 2 diabetes following improvement of glycaemic control. Trial registration ClinicalTrials.gov NCT03469492.