Structural and functional connectivity phenotype in the neocortex of Fmr1 ^−/y mice supports a prominent hypothesis of autism.

Increased glucose and choline uptake are hallmarks of cancer. We investigated whether the uptake and conversion of [²H₉]choline alone and together with that of [6,6′-²H₂]glucose can be assessed in tumors via deuterium metabolic imaging (DMI) after administering these compounds. Therefore, tumors with human renal carcinoma cells were grown subcutaneously in mice. Isoflurane anesthetized mice were IV infused in the MR magnet for ~20 s with ~0.2 mL solutions containing either [²H₉]choline (0.05 g/kg) alone or together with [6,6′-²H₂]glucose (1.3 g/kg). ²H MR was performed on a 11.7T MR system with a home-built ²H/¹H coil using a 90° excitation pulse and 400 ms repetition time. 3D DMI was recorded at high resolution (2 × 2 × 2 mm) in 37 min or at low resolution (3.7 × 3.7 × 3.7 mm) in 2:24 min. Absolute tissue concentrations were calculated assuming natural deuterated water [HOD] = 13.7 mM. Within 5 min after [²H₉]choline infusion, its signal appeared in tumor spectra representing a concentration increase to 0.3–1.2 mM, which then slowly decreased or remained constant over 100 min. In plasma, [²H₉]choline disappeared within 15 min post-infusion, implying that its signal arises from tumor tissue and not from blood. After infusing a mixture of [²H₉]choline and [6,6′-²H₂]glucose, their signals were observed separately in tumor ²H spectra. Over time, the [²H₉]choline signal broadened, possibly due to conversion to other choline compounds, [[6,6′-²H₂]glucose] declined, [HOD] increased and a lactate signal appeared, reflecting glycolysis. Metabolic maps of ²H compounds, reconstructed from high resolution DMIs, showed their spatial tumor accumulation. As choline infusion and glucose DMI is feasible in patients, their simultaneous detection has clinical potential for tumor characterization.

Synaptic dysfunction contributes to cognitive impairment in Alzheimer’s disease and may be countered by increased intake of nutrients that target brain phospholipid metabolism. In this study, we explored whether the medical food Souvenaid affects brain phospholipid metabolism in patients with Alzheimer’s disease. Thirty-four drug-naive patients with mild Alzheimer’s disease (Mini Mental State Examination score ≥20) were enrolled in this exploratory, double-blind, randomized controlled study. Before and after 4-week intervention with Souvenaid or an isocaloric control product, phosphorus and proton magnetic resonance spectroscopy (MRS) was performed to assess surrogate measures of phospholipid synthesis and breakdown (phosphomonoesters [PME] and phosphodiesters [PDEs]), neural integrity (N-acetyl aspartate), gliosis (myo-inositol), and choline metabolism (choline-containing compounds [tCho]). The main outcome parameters were PME and PDE signal intensities and the PME/PDE ratio. MRS data from 33 patients (60–86 years old; 42% males; Souvenaid arm n = 16; control arm n = 17) were analyzed. PME/PDE and tCho were higher after 4 weeks of Souvenaid compared with control (PME/PDE least squares [LS] mean difference [95% CI] 0.18 [0.06–0.30], p = 0.005; tCho LS mean difference [95% CI] 0.01 [0.00–0.02], p = 0.019). No significant differences were observed in the other MRS outcome parameters. MRS reveals that Souvenaid affects brain phospholipid metabolism in mild Alzheimer’s disease, in line with findings in preclinical studies. Netherlands Trial Register, NTR3346 . Registered on 13 March 2012.

Mutations in isocitrate dehydrogenase 1 (IDH1) occur in various types of cancer and induce metabolic alterations resulting from the neomorphic activity that causes production of D-2-hydroxyglutarate (D-2-HG) at the expense of α-ketoglutarate (α-KG) and NADPH. To overcome metabolic stress induced by these alterations, IDH-mutated (IDHmut) cancers utilize rescue mechanisms comprising pathways in which glutaminase and glutamate dehydrogenase (GLUD) are involved. We hypothesized that inhibition of glutamate processing with the pleiotropic GLUD-inhibitor epigallocatechin-3-gallate (EGCG) would not only hamper D-2-HG production, but also decrease NAD(P)H and α-KG synthesis in IDHmut cancers, resulting in increased metabolic stress and increased sensitivity to radiotherapy. We performed 13C-tracing studies to show that HCT116 colorectal cancer cells with an IDH1R132H knock-in allele depend more on glutaminolysis than on glycolysis for the production of D-2-HG. We treated HCT116 cells, HCT116-IDH1R132H cells, and HT1080 cells (carrying an IDH1R132C mutation) with EGCG and evaluated D-2-HG production, cell proliferation rates, and sensitivity to radiotherapy. Significant amounts of 13C from glutamate accumulate in D-2-HG in HCT116-IDH1wt/R132H but not in HCT116-IDH1wt/wt. Preventing glutamate processing in HCT116-IDH1wt/R132H cells with EGCG resulted in reduction of D-2-HG production. In addition, EGCG treatment decreased proliferation rates of IDH1mut cells and at high doses sensitized cancer cells to ionizing radiation. Effects of EGCG in IDH-mutated cell lines were diminished by treatment with the IDH1mut inhibitor AGI-5198. This work shows that glutamate can be directly processed into D-2-HG and that reduction of glutamatolysis may be an effective and promising new treatment option for IDHmut cancers.

Background: Facioscapulohumeral dystrophy (FSHD) is a major muscular dystrophy characterized by asymmetric fatty replacement of muscles. We aimed to determine the initiation site and progression profile of the disease in lower extremity muscles of FSHD patients by assessing fat infiltration along their full proximo-distal axis using quantitative MRI. Methods: Nine patients underwent MRI of lower extremities to assess end-to-end muscle fat fractions (FFs) and inflammatory lesions. Seven patients underwent the same MRI ~3.5 years later. Individual muscles (n = 396) were semi-automatically segmented to calculate average FFs over all slices covering whole muscles. To assess disease progression we determined FF changes in 5 adjacent muscle segments. Results: We provide evidence that fat replacement commonly starts at the distal end of affected muscles where the highest FFs occur (p < 0.001). It progresses in a wave-like manner in the proximal direction at an increasing rate with the highest value (4.9 ± 2.7%/year) for muscles with baseline FFs of 30–40%. Thereafter it proceeds at a slower pace towards the proximal muscle end. In early phases of disease, inflammatory lesions preferentially occur at the distal muscle end. Compared with whole-muscle analysis, the common FF assessments using only few MR slices centrally placed in muscles are significantly biased (~50% in progression rate). Conclusions: These findings identify the distal end of leg muscles as a prime location for disease initiation in FSHD and demonstrate a wave-like progression towards the proximal end, consistent with proposed disease mechanisms. End-to-end whole-muscle fat assessment is essential to properly diagnose FSHD and its progression.