1H-localized broadband 13C NMR spectroscopy of the rat brain in vivo at 9.4 T

Localized (13)C NMR spectra were obtained from the rat brain in vivo over a broad spectral range (15-100 ppm) with minimal chemical-shift displacement error (<10%) using semi-adiabatic distortionless enhancement by polarization transfer (DEPT) combined with (1)H localization. A new gradient dephasing scheme was employed to eliminate unwanted coherences generated by DEPT when using surface coils with highly inhomogeneous B(1) fields. Excellent sensitivity was evident from the simultaneous detection of natural abundance signals for N-acetylaspartate, myo-inositol, and glutamate in the rat brain in vivo at 9.4 T. After infusion of (13)C-labeled glucose, up to 18 (13)C resonances were simultaneously measured in the rat brain, including glutamate C2, C3, C4, glutamine C2, C3, C4, aspartate C2, C3, glucose C1, C6, N-acetyl-aspartate C2, C3, C6, as well as GABA C2, lactate C3, and alanine C3. (13)C-(13)C multiplets corresponding to multiply labeled compounds were clearly observed, suggesting that extensive isotopomer analysis is possible in vivo. This unprecedented amount of information will be useful for metabolic modeling studies aimed at understanding brain energy metabolism and neurotransmission in the rodent brain

Developmental and regional changes in the neurochemical profile of the rat brain determined by in vivo 1H NMR spectroscopy

Sixteen metabolites were quantified from 11-24 micro l volumes in three different brain regions (hippocampus, striatum, and cerebral cortex) during postnatal development. Rat pups from the same litter were repeatedly measured on postnatal days 7, 10, 14, 21, and 28 using a completely noninvasive and longitudinal study design. Metabolite quantification was based on ultra-short echo-time (1)H NMR spectroscopy at 9.4 T and LCModel processing. Most of the brain metabolites were quantified with Cramer-Rao lower bounds (CRLB) less than 20%, which corresponded to an estimated concentration error <0.2 micro mol/g. Taurine and total creatine were quantified with CRLB < or = 5% from all 114 processed spectra. The resulting high reliability and reproducibility revealed significant regional and age-related changes in metabolite concentrations. The most sensitive markers for developmental and regional variations between hippocampus, striatum, and cerebral cortex were N-acetylaspartate, myo-inositol, taurine, glutamate, and choline compounds. Absolute values of metabolite concentrations were in very good agreement with previously published in vitro results based on chromatographic measurements of brain extracts. The current data may serve as a reference for studies focused on developmental defects and pathologies using neonatal rat models

Highly resolved in vivo 1H NMR spectroscopy of the mouse brain at 9.4 T

An efficient shim system and an optimized localization sequence were used to measure in vivo 1H NMR spectra from cerebral cortex, hippocampus, striatum, and cerebellum of C57BL/6 mice at 9.4 T. The combination of automatic first- and second-order shimming (FASTMAP) with strong custom-designed second-order shim coils (shim strength up to 0.04 mT/cm2) was crucial to achieve high spectral resolution (water line width of 11-14 Hz). Requirements for second-order shim strengths to compensate field inhomogeneities in the mouse brain at 9.4 T were assessed. The achieved spectral quality (resolution, S/N, water suppression, localization performance) allowed reliable quantification of 16 brain metabolites (LCModel analysis) from 5-10-microL brain volumes. Significant regional differences (up to 2-fold, P < 0.05) were found for all quantified metabolites but Asp, Glc, and Gln. In contrast, 1H NMR spectra measured from the striatum of C57BL/6, CBA, and CBA/BL6 mice revealed only small (<13%, P < 0.05) interstrain differences in Gln, Glu, Ins, Lac, NAAG, and PE. It is concluded that 1H NMR spectroscopy at 9.4 T can provide precise biochemical information from distinct regions of the mouse brain noninvasively that can be used for monitoring of disease progression and treatment as well as phenotyping in transgenic mice models

Assessment of adrenoleukodystrophy lesions by high field MRS in non-sedated pediatric patients

Early detection of white matter lesions in childhood-onset cerebral adrenoleukodystrophy (ALD) is important as hematopoietic cell transplantation (HCT), currently the only effective treatment, is beneficial only if performed early in the disease course

Lacunar Infarction in Type 2 Diabetes Is Associated with an Elevated Intracranial Arterial Pulsatility Index

Purpose: The arterial pulsatility index (PI) is measured by transcranial Doppler ultrasonography (TCD) and is postulated to reflect the vascular resistance distal to the artery being examined. An increased PI of the intracranial artery is often reported with diabetes mellitus (DM), old age, hypertension, intracranial hypertension, vascular dementia, and small artery disease. Microvascular complication of DM, which may contribute to cerebral infarction, involves the small perforating artery and may influence the PI of the proximal artery. Materials and Methods: We performed a TCD examination in patients with type 2 DM with acute lacunar infarction (DML, n = 35), type 2 DM without cerebral infarction (DMO, n = 69), and in control cases with no DM or cerebral infarction (control group, n = 41). We then compared the TCD findings among these groups. Results: The PI was significantly higher in the DML and DMO groups than in the control group (1.05, 0.93, 0.73. respectively, for the right middle cerebral artery; 1.04, 0.90, 0.73, respectively, for the left middle cerebral artery; 0.97, 0.89, 0.70, respectively, for the basilar artery). The PI was also significantly higher in the DML group than in the DMO group for both middle cerebral arteries. The flow velocity was comparable among the three groups. Conclusion: The elevated PI of the intracranial arteries may reflect diabetic cerebral microvascular complications. The PI measurement using TCD may be a useful predictor of lacunar infarction in type 2 DM patients

Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo

Background Tumour Carbonic Anhydrase IX (CAIX), a hypoxia-inducible tumour-associated cell surface enzyme, is thought to acidify the tumour microenvironment by hydrating CO2 to form protons and bicarbonate, but there is no definitive evidence for this in solid tumours in vivo. Methods We used 1H magnetic resonance spectroscopic imaging (MRSI) of the extracellular pH probe imidazolyl succinic acid (ISUCA) to measure and spatially map extracellular pH in HCT116 tumours transfected to express CAIX and empty vector controls in SCID mice. We also measured intracellular pH in situ with 31P MRS and measured lactate in freeze-clamped tumours. Results CAIX expressing tumours had 0.15 pH-unit lower median extracellular pH than control tumours (pH 6.71 tumour vs pH 6.86 control, P = 0.01). Importantly, CAIX expression imposed an upper limit for tumour extracellular pH at 6.93. Despite the increased lactate concentration in CAIX-expressing tumours, 31P MRS showed no difference in intracellular pH, suggesting that CAIX acidifies only the tumour extracellular space. Conclusions CAIX acidifies the tumour microenvironment, and also provides an extracellular pH control mechanism. We propose that CAIX thus acts as an extracellular pH-stat, maintaining an acidic tumour extracellular pH that is tolerated by cancer cells and favours invasion and metastasis.We are grateful for the support of CRUK [grant number C14303/A17197], the Breast Cancer Research Foundation, the Royal Society, Worldwide Cancer Research and the European Research Council [SURVIVE: 723397]. JP-T and SC received support from the Spanish Ministry of Economy and Competitiveness SAF2014-23622