Quantitative and textural analysis of magnetization transfer and diffusion images in the early detection of brain metastases

Purpose: The sensitivity of the magnetization transfer ratio (MTR) and apparent diffusion coefficient (ADC) for early detection of brain metastases was investigated in mice and humans. Methods: Mice underwent MRI twice weekly for up to 31 days following intra-cardiac injection of the brain-homing breast cancer cell line MDA-MB231-BR. Patients with small cell lung cancer underwent quarterly MRI for a year. MTR and ADC were measured in regions of metastasis and matched contralateral tissue at the final time-point and in registered regions at earlier time-points. Texture analysis and linear discriminant analysis were performed to detect metastasis-containing slices. Results: Compared with contralateral tissue, mouse metastases had significantly lower MTR and higher ADC at the final time-point. Some lesions were visible at earlier time-points on the MTR and ADC maps: 24% of these were not visible on corresponding T2-weighted images. Texture analysis using the MTR maps showed 100% specificity and 98% sensitivity for metastasis at the final time-point, with 77% sensitivity 2-4 days earlier and 46% 5-8 days earlier. Only 2/16 patients developed metastases, and their penultimate scans were normal. Conclusion: Some brain metastases may be detected earlier on MTR than conventional T2; however, the small gain is unlikely to justify ‘predictive’ MRI.The authors gratefully acknowledge the Cambridge Institute Biological Resources Unit for expert animal care and technical assistance, the Histopathology Core Facility, Drs Joe Frank and Diane Palmieri for providing the cell line, the advice of Dr. Dan Tozer, and the support of Cancer Research UK [grant number C14303/A17197], the Brian Cross Memorial Trust, the Addenbrooke’s Charitable Trust, the University of Cambridge, Hutchison Whampoa Ltd, the Cambridge Experimental Cancer Medicine Centre, and the NIHR Cambridge Biomedical Research Centre.This is the final version of the article. It first appeared from Wiley via https://doi.org/10.1002/mrm.2625

Quantitative and textural analysis of magnetization transfer and diffusion images in the early detection of brain metastases.

PURPOSE: The sensitivity of the magnetization transfer ratio (MTR) and apparent diffusion coefficient (ADC) for early detection of brain metastases was investigated in mice and humans. METHODS: Mice underwent MRI twice weekly for up to 31 d following intracardiac injection of the brain-homing breast cancer cell line MDA-MB231-BR. Patients with small cell lung cancer underwent quarterly MRI for 1 year. MTR and ADC were measured in regions of metastasis and matched contralateral tissue at the final time point and in registered regions at earlier time points. Texture analysis and linear discriminant analysis were performed to detect metastasis-containing slices. RESULTS: Compared with contralateral tissue, mouse metastases had significantly lower MTR and higher ADC at the final time point. Some lesions were visible at earlier time points on the MTR and ADC maps: 24% of these were not visible on corresponding T2 -weighted images. Texture analysis using the MTR maps showed 100% specificity and 98% sensitivity for metastasis at the final time point, with 77% sensitivity 2-4 d earlier and 46% 5-8 d earlier. Only 2 of 16 patients developed metastases, and their penultimate scans were normal. CONCLUSIONS: Some brain metastases may be detected earlier on MTR than conventional T2 ; however, the small gain is unlikely to justify "predictive" MRI. Magn Reson Med 77:1987-1995, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.The authors gratefully acknowledge the Cambridge Institute Biological Resources Unit for expert animal care and technical assistance, the Histopathology Core Facility, Drs Joe Frank and Diane Palmieri for providing the cell line, the advice of Dr. Dan Tozer, and the support of Cancer Research UK [grant number C14303/A17197], the Brian Cross Memorial Trust, the Addenbrooke’s Charitable Trust, the University of Cambridge, Hutchison Whampoa Ltd, the Cambridge Experimental Cancer Medicine Centre, and the NIHR Cambridge Biomedical Research Centre.This is the final version of the article. It first appeared from Wiley via https://doi.org/10.1002/mrm.2625

Muscle metabolism and activation heterogeneity by combined 31P chemical shift and T2 imaging, and pulmonary O2 uptake during incremental knee-extensor exercise.

The integration of skeletal muscle substrate depletion, metabolite accumulation, and fatigue during large muscle-mass exercise is not well understood. Measurement of intramuscular energy store degradation and metabolite accumulation is confounded by muscle heterogeneity. Therefore, to characterize regional metabolic distribution in the locomotor muscles, we combined 31P magnetic resonance spectroscopy, chemical shift imaging, and T2-weighted imaging with pulmonary oxygen uptake during bilateral knee-extension exercise to intolerance. Six men completed incremental tests for the following: (1) unlocalized 31P magnetic resonance spectroscopy; and (2) spatial determination of 31P metabolism and activation. The relationship of pulmonary oxygen uptake to whole quadriceps phosphocreatine concentration ([PCr]) was inversely linear, and three of four knee-extensor muscles showed activation as assessed by change in T2. The largest changes in [PCr], [inorganic phosphate] ([Pi]) and pH occurred in rectus femoris, but no voxel (72 cm3) showed complete PCr depletion at exercise cessation. The most metabolically active voxel reached 11 ± 9 mM [PCr] (resting, 29 ± 1 mM), 23 ± 11 mM [Pi] (resting, 7 ± 1 mM), and a pH of 6.64 ± 0.29 (resting, 7.08 ± 0.03). However, the distribution of 31P metabolites and pH varied widely between voxels, and the intervoxel coefficient of variation increased between rest (∼10%) and exercise intolerance (∼30-60%). Therefore, the limit of tolerance was attained with wide heterogeneity in substrate depletion and fatigue-related metabolite accumulation, with extreme metabolic perturbation isolated to only a small volume of active muscle (<5%). Regional intramuscular disturbances are thus likely an important requisite for exercise intolerance. How these signals integrate to limit muscle power production, while regional "recruitable muscle" energy stores are presumably still available, remains uncertain

A novel Atg5-shRNA mouse model enables temporal control of Autophagy in vivo.

Macroautophagy/autophagy is an evolutionarily conserved catabolic pathway whose modulation has been linked to diverse disease states, including age-associated disorders. Conventional and conditional whole-body knockout mouse models of key autophagy genes display perinatal death and lethal neurotoxicity, respectively, limiting their applications for in vivo studies. Here, we have developed an inducible shRNA mouse model targeting Atg5, allowing us to dynamically inhibit autophagy in vivo, termed ATG5i mice. The lack of brain-associated shRNA expression in this model circumvents the lethal phenotypes associated with complete autophagy knockouts. We show that ATG5i mice recapitulate many of the previously described phenotypes of tissue-specific knockouts. While restoration of autophagy in the liver rescues hepatomegaly and other pathologies associated with autophagy deficiency, this coincides with the development of hepatic fibrosis. These results highlight the need to consider the potential side effects of systemic anti-autophagy therapies

Acute tumor response to ZD6126 assessed by intrinsic susceptibility magnetic resonance imaging

AbstractThe effective magnetic resonance imaging (MRI) transverse relaxation rate R2* was investigated as an early acute marker of the response of rat GH3 prolactinomas to the vascular-targeting agent, ZD6126. Multigradient echo (MGRE) MRI was used to quantify R2*, which is sensitive to tissue deoxyhemoglobin levels. Tumor R2* was measured prior to, and either immediately for up to 35 minutes, or 24 hours following administration of 50 mg/kg ZD6126. Following MRI, tumor perfusion was assessed by Hoechst 33342 uptake. Tumor R2* significantly increased to 116 ± 4% of baseline 35 minutes after challenge, consistent with an ischemic insult induced by vascular collapse. A strong positive correlation between baseline R2* and the subsequent increase in R2* measured 35 minutes after treatment was obtained, suggesting that the baseline R2* is prognostic for the subsequent tumor response to ZD6126. In contrast, a significant decrease in tumor R2* was found 24 hours after administration of ZD6126. Both the 35-minute and 24-hour R2* responses to ZD6126 were associated with a decrease in Hoechst 33342 uptake. Interpretation of the R2* response is complex, yet changes in tumor R2* may provide a convenient and early MRI biomarker for detecting the antitumor activity of vascular-targeting agents

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

Long and short echo time proton magnetic resonance spectroscopic imaging of the healthy aging brain.

Since only short-echo spectroscopy showed a robust relationship between Cr and subject age, and detects more metabolites than long echo time, we conclude that short-echo is superior to long-echo for future aging studies. Future studies could usefully determine whether the Cr-age relationship is due to changes in concentration, T1, or both

Reduced N-acetylaspartate is consistent with axonal dysfunction in cerebral small vessel disease.

The most consistent change in SVD is a reduction in NAA, a marker of neuronal integrity. The lack of correlation with cognition does not support the use of MRS as a surrogate disease marker

Diffusion tensor imaging and MR spectroscopy in hypertension and presumed cerebral small vessel disease.

In patients with cerebral small vessel disease (SVD) diffusion tensor imaging (DTI) is sensitive to white matter damage and correlates better with cognitive function than conventional imaging. It has been proposed as a surrogate marker for treatment trials. However, the pathological changes underlying DTI are not known. The purpose of this study was to use magnetic resonance spectroscopy (MRS) to determine the pathological changes underlying DTI abnormalities in a range of patients from asymptomatic white matter hyperintensities to symptomatic cerebral SVD. 29 SVD patients, 63 hypertensive subjects, and 42 normotensive controls were recruited. The relationship between the DTI and MRS parameters in the centrum semiovale white matter was determined. There was a significant reduction in N-acetylaspartate (NAA; 2.067 +/- 0.042 vs 2.299 +/- 0.029 and 2.315 +/- 0.036, P = 9 x 10(-6)) and increase in mean diffusivity (mm2/s x 10(-3); 0.942 +/- 0.123 vs 0.822 +/- 0.064 and 0.792 +/- 0.057, P = 1 x 10(-8)) in symptomatic SVD patients compared with the other two groups. DTI parameters correlated with NAA in all three groups, in a graded manner depending on severity of disease (r -SVD -0.827, hypertensive subjects -0.457, controls -0.317). NAA is a marker of axonal loss/dysfunction. These findings are consistent with axonal loss/dysfunction being the principal process causing the DTI changes found in cerebral SVD and ageing