2D 1H sLASER Long-TE and 3D 31P Chemical Shift Imaging at 3 T for Monitoring Fasting-Induced Changes in Brain Tumor Tissue.

BACKGROUND: Emerging evidence suggests that fasting could play a key role in cancer treatment. Its metabolic effects on gliomas require further investigation. PURPOSE: To design a multi-voxel 1H/31P MR-spectroscopic imaging (MRSI) protocol for noninvasive metabolic monitoring of cerebral, fasting-induced changes on an individual patient/tumor level, and to assess its technical reliability/reproducibility. STUDY TYPE: Prospective. POPULATION: MRS phantom. Twenty-two patients (mean age = 61, 6 female) with suspected WHO grade II-IV glioma examined before and after 72-hour-fasting prior to biopsy/resection. FIELD STRENGTH/SEQUENCE: 3-T, 1H decoupled 3D 31P MRSI, 2D 1H sLASER MRSI at an echo time of 144 msec, 2D 1H MRSI (as water reference), T1-weighted, T1-weighted contrast-enhanced, T2-weighted, and FLAIR. sLASER and PRESS sequences were used for phantom measurements. ASSESSMENT: Phantom measurements and spectral simulations were performed with various echo-times for protocol optimization. In vivo spectral analyses were conducted using LCModel and AMARES, obtaining quality/fitting parameters (linewidth, signal-to-noise-ratio, and uncertainty measures of fitting) and metabolite intensities. The volume of glioma sub-regions was calculated and correlated with MRS findings. Ex-vivo spectra of necrotic tumor tissues were obtained using high-resolution magic-angle spinning (HR-MAS) technique. STATISTICAL TESTS: Wilcoxon signed-rank test, Bland-Altman plots, and coefficient of variation were used for repeatability analysis of quality/fitting parameters and metabolite concentrations. Spearman ρ correlation for the concentration of ketone bodies with volumes of glioma sub-regions was determined. A P-value <0.05 was considered statistically significant. RESULTS: 1H and 31P repeatability measures were highly consistent between the two sessions. ß-hydroxybutyrate and acetoacetate were detectable (fitting-uncertainty <50%) in glioma sub-regions of all patients who completed the 72-hour-fasting cycle. ß-hydroxybutyrate accumulation was significantly correlated with the necrotic/non-enhancing tumor core volume (ρ = 0.81) and validated using ex-vivo 1H HR-MAS. DATA CONCLUSION: We propose a comprehensive MRS protocol that may be used for monitoring cerebral, fasting-induced changes in patients with glioma. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 4.

Age-related changes in energy metabolism in peripheral mononuclear blood cells (PBMCs) and the brains of cognitively healthy seniors.

Mitochondrial dysfunction is a hallmark of cellular senescence and many age-related neurodegenerative diseases. We therefore investigated the relationship between mitochondrial function in peripheral blood cells and cerebral energy metabolites in young and older sex-matched, physically and mentally healthy volunteers. Cross-sectional observational study involving 65 young (26.0 ± 0.49 years) and 65 older (71.7 ± 0.71 years) women and men recruited. Cognitive health was evaluated using established psychometric methods (MMSE, CERAD). Blood samples were collected and analyzed, and fresh peripheral blood mononuclear cells (PBMCs) were isolated. Mitochondrial respiratory complex activity was measured using a Clarke electrode. Adenosine triphosphate (ATP) and citrate synthase activity (CS) were determined by bioluminescence and photometrically. N-aspartyl-aspartate (tNAA), ATP, creatine (Cr), and phosphocreatine (PCr) were quantified in brains using 1H- and 31P-magnetic resonance spectroscopic imaging (MRSI). Levels of insulin-like growth factor 1 (IGF-1) were determined using a radio-immune assay (RIA). Complex IV activity (CIV) (- 15%) and ATP levels (- 11%) were reduced in PBMCs isolated from older participants. Serum levels of IGF-1 were significantly reduced (- 34%) in older participants. Genes involved in mitochondrial activity, antioxidant mechanisms, and autophagy were unaffected by age. tNAA levels were reduced (- 5%), Cr (+ 11%), and PCr (+ 14%) levels were increased, and ATP levels were unchanged in the brains of older participants. Markers of energy metabolism in blood cells did not significantly correlate with energy metabolites in the brain. Age-related bioenergetic changes were detected in peripheral blood cells and the brains of healthy older people. However, mitochondrial function in peripheral blood cells does not reflect energy related metabolites in the brain. While ATP levels in PBMCs may be be a valid marker for age-related mitochondrial dysfunction in humans, cerebral ATP remained constant.

Impaired oxygen extraction and adaptation of intracellular energy metabolism in cerebral small vessel disease.

Background: We aimed to investigate whether combined phosphorous (31P) magnetic resonance spectroscopic imaging (MRSI) and quantitative T 2 ' mapping are able to detect alterations of the cerebral oxygen extraction fraction (OEF) and intracellular pH (pHi) as markers the of cellular energy metabolism in cerebral small vessel disease (SVD). Materials and methods: 32 patients with SVD and 17 age-matched healthy control subjects were examined with 3-dimensional 31P MRSI and oxygenation-sensitive quantitative T 2 ' mapping (1/ T 2 '  = 1/T2* - 1/T2) at 3 Tesla (T). PHi was measured within the white matter hyperintensities (WMH) in SVD patients. Quantitative T 2 ' values were averaged across the entire white matter (WM). Furthermore, T 2 ' values were extracted from normal-appearing WM (NAWM) and the WMH and compared between patients and controls. Results: Quantitative T 2 ' values were significantly increased across the entire WM and in the NAWM in patients compared to control subjects (149.51 ± 16.94 vs. 138.19 ± 12.66 ms and 147.45 ± 18.14 vs. 137.99 ± 12.19 ms, p < 0.05). WM T 2 ' values correlated significantly with the WMH load (ρ=0.441, p = 0.006). Increased T 2 ' was significantly associated with more alkaline pHi (ρ=0.299, p < 0.05). Both T 2 ' and pHi were significantly positively correlated with vascular pulsatility in the distal carotid arteries (ρ=0.596, p = 0.001 and ρ=0.452, p = 0.016). Conclusions: This exploratory study found evidence of impaired cerebral OEF in SVD, which is associated with intracellular alkalosis as an adaptive mechanism. The employed techniques provide new insights into the pathophysiology of SVD with regard to disease-related consequences on the cellular metabolic state.

A fast and novel method for amide proton transfer-chemical exchange saturation transfer multislice imaging.

Amide proton transfer-chemical exchange saturation transfer (APT-CEST) imaging provides important information for the diagnosis and monitoring of tumors. For such analysis, complete coverage of the brain is advantageous, especially when registration is performed with other magnetic resonance (MR) modalities, such as MR spectroscopy (MRS). However, the acquisition of Z-spectra across several slices via multislice imaging may be time-consuming. Therefore, in this paper, we present a new approach for fast multislice imaging, allowing us to acquire 16 slices per frequency offset within 8 s. The proposed fast CEST-EPI sequence employs a presaturation module, which drives the magnetization into the steady-state equilibrium for the first frequency offset. A second module, consisting of a single CEST pulse (for maintaining the steady-state) followed by an EPI acquisition, passes through a loop to acquire multiple slices and adjacent frequency offsets. Thus, the whole Z-spectrum can be recorded much faster than the conventional saturation scheme, which employs a presaturation for each single frequency offset. The validation of the CEST sequence parameters was performed by using the conventional saturation scheme. Subsequently, the proposed and a modified version of the conventional CEST sequence were compared in vitro on a phantom with different T1 times and in vivo on a brain tumor patient. No significant differences between both sequences could be found in vitro. The in vivo data yielded almost identical MTRasym contrasts for the white and gray matter as well as for tumor tissue. Our results show that the proposed fast CEST-EPI sequence allows for rapid data acquisition and provides similar CEST contrasts as the modified conventional scheme while reducing the scanning time by approximately 50%.

Deducing the Impact of Physical Activity, Sedentary Behavior, and Physical Performance on Cognitive Function in Healthy Older Adults.

Objectives: Participating in physical activity and maintaining physical performance as well as reducing sedentary behavior are discussed to be beneficially associated with cognitive function in older adults. The purpose of this cross-sectional analysis was to differentiate the relevance of objectively measured physical activity, physical performance, and sedentary behavior on cognitive function in healthy older adults (n = 56, age = 76 ± 7 yrs, gender = 30 female). Methods: Accelerometer based physical activity and sedentary behavior were analyzed as minutes per week spent sedentary and physically active with light or moderate to vigorous intensity. Participants' physical performance was assessed via cardiopulmonary exercise testing and analyzed as maximal workload and heart rate, heart rate reserve and peak oxygen uptake. The assessment of cognitive function included working memory, attention, executive function, and verbal memory. Data was analyzed with Spearman and partial correlations. Trial registration: NCT02343029. Results: Light physical activity was moderately associated with executive function (r = -0.339, p = 0.015). Attention was significantly associated with maximal workload (r = -0.286, p = 0.042) and peak oxygen uptake (r = -0.337, p = 0.015). Working memory was associated with maximal workload (r = 0.329, p = 0.017). Conclusion: Whereas a broad range of cognitive function were beneficially linked to physical performance, light intensity activities in particular showed an impact on executive function. Our research underlines the need to separate the impact of physical performance and physical activity on cognitive function and highlights the relevance of light physical activity.

T2 relaxation time of the normal-appearing white matter is related to the cognitive status in cerebral small vessel disease.

Previous diffusion tensor imaging (DTI) studies indicate that impaired microstructural integrity of the normal-appearing white matter (NAWM) is related to cognitive impairment in cerebral small vessel disease (SVD). This study aimed to investigate whether quantitative T2 relaxometry is a suitable imaging biomarker for the assessment of tissue changes related to cognitive abnormalities in patients with SVD. 39 patients and 18 age-matched healthy control subjects underwent 3 T magnetic resonance imaging (MRI) with T2-weighted multiple spin echo sequences for T2 relaxometry and DTI sequences, as well as comprehensive cognitive assessment. Averaged quantitative T2, fractional anisotropy (FA) and mean diffusivity (MD) were determined in the NAWM and related to cognitive parameters controlling for age, normalized brain volume, white matter hyperintensity volume and other conventional SVD markers. In SVD patients, quantitative T2 values were significantly increased compared to controls (p = 0.002) and significantly negatively correlated with the global cognitive performance (r= -0.410, p = 0.014) and executive function (r= -0.399, p = 0.016). DTI parameters did not correlate with cognitive function. T2 relaxometry of the NAWM seems to be sensitive to microstructural tissue damage associated with cognitive impairment in SVD and might be a promising imaging biomarker for evaluation of disease progression and possible effects of therapeutic interventions.

Maintenance of Energy Homeostasis during Calorically Restricted Ketogenic Diet and Fasting-MR-Spectroscopic Insights from the ERGO2 Trial.

Background: The ERGO2 (Ernaehrungsumstellung bei Patienten mit Rezidiv eines Glioblastoms) MR-spectroscopic imaging (MRSI) subtrial investigated metabolism in patients randomized to calorically restricted ketogenic diet/intermittent fasting (crKD-IF) versus standard diet (SD) in addition to re-irradiation (RT) for recurrent malignant glioma. Intracerebral concentrations of ketone bodies (KB), intracellular pH (pHi), and adenosine triphosphate (ATP) were non-invasively determined. Methods: 50 patients were randomized (1:1): Group A keeping a crKD-IF for nine days, and Group B a SD. RT was performed on day 4-8. Twenty-three patients received an extended MRSI-protocol (1H decoupled 31P MRSI with 3D chemical shift imaging (CSI) and 2D 1H point-resolved spectroscopy (PRESS)) at a 3T scanner at baseline and on day 6. Voxels were selected from the area of recurrent tumor and contralateral hemisphere. Spectra were analyzed with LCModel, adding simulated signals of 3-hydroxybutyrate (ßOHB), acetone (Acn) and acetoacetate (AcAc) to the standard basis set. Results: Acn was the only reliably MRSI-detectable KB within tumor tissue and/or normal appearing white matter (NAWM). It was detected in 4/11 patients in Group A and in 0/8 patients in Group B. MRSI results showed no significant depletion of ATP in tumor tissue of patients at day 6 during crKD-IF, even though there were a significant difference in ketone serum levels between Group A and B at day 6 and a decline in fasting glucose in Group A from baseline to day 6. The tumor specific alkaline pHi was maintained. Conclusions: Our metabolic findings suggest that tumor cells maintain energy homeostasis even with reduced serum glucose levels and may generate additional ATP through other sources.

Non-Invasive Measurement of Drug and 2-HG Signals Using 19F and 1H MR Spectroscopy in Brain Tumors Treated with the Mutant IDH1 Inhibitor BAY1436032.

BACKGROUND: BAY1436032 is a fluorine-containing inhibitor of the R132X-mutant isocitrate dehydrogenase (mIDH1). It inhibits the mIDH1-mediated production of 2-hydroxyglutarate (2-HG) in glioma cells. We investigated brain penetration of BAY1436032 and its effects using 1H/19F-Magnetic Resonance Spectroscopy (MRS). METHODS: 19F-Nuclear Magnetic Resonance (NMR) Spectroscopy was conducted on serum samples from patients treated with BAY1436032 (NCT02746081 trial) in order to analyze 19F spectroscopic signal patterns and concentration-time dynamics of protein-bound inhibitor to facilitate their identification in vivo MRS experiments. Hereafter, 30 mice were implanted with three glioma cell lines (LNT-229, LNT-229 IDH1-R132H, GL261). Mice bearing the IDH-mutated glioma cells received 5 days of treatment with BAY1436032 between baseline and follow-up 1H/19F-MRS scan. All other animals underwent a single scan after BAY1436032 administration. Mouse brains were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). RESULTS: Evaluation of 1H-MRS data showed a decrease in 2-HG/total creatinine (tCr) ratios from the baseline to post-treatment scans in the mIDH1 murine model. Whole brain concentration of BAY1436032, as determined by 19F-MRS, was similar to total brain tissue concentration determined by Liquid Chromatography with tandem mass spectrometry (LC-MS/MS), with a signal loss due to protein binding. Intratumoral drug concentration, as determined by LC-MS/MS, was not statistically different in models with or without R132X-mutant IDH1 expression. CONCLUSIONS: Non-invasive monitoring of mIDH1 inhibition by BAY1436032 in mIDH1 gliomas is feasible.

Exercise and microstructural changes in the motor cortex of older adults.

Exercise has been shown to counteract age-related volume decreases in the human brain, and in this imaging study, we ask whether the same holds true for the microstructure of the cortex. Healthy older adults (n = 47, 65-90 years old) either exercised three times a week on a stationary bike or maintained their usual physical routine over a 12-week period. Quantitative longitudinal relaxation rate (R1 ) magnetic resonance imaging (MRI) maps were made at baseline and after the 12-week intervention. R1 is commonly taken to reflect cortical myelin density. The change in R1 (ΔR1 ) was significantly increased in a region of interest (ROI) in the primary motor cortex containing motor outputs to the leg musculature in the exercise group relative to the control group (p = .04). The change in R1 in this ROI correlated with an increase in oxygen consumption at the first ventilatory threshold (VT1) (p = .04), a marker of improvement in submaximal aerobic performance. An exploratory analysis across the cortex suggested that the correlation was predominately confined to the leg representation in the motor cortex. This study suggests that microstructural declines in the cortex of older adults may be staved off by exercise.

Evaluating Magnetic Resonance Spectroscopy as a Tool for Monitoring Therapeutic Response of Whole Brain Radiotherapy in a Mouse Model for Breast-to-Brain Metastasis.

Brain metastases are the most common intracranial tumor in adults and are associated with poor patient prognosis and median survival of only a few months. Treatment options for brain metastasis patients remain limited and largely depend on surgical resection, radio- and/or chemotherapy. The development and pre-clinical testing of novel therapeutic strategies require reliable experimental models and diagnostic tools that closely mimic technologies that are used in the clinic and reflect histopathological and biochemical changes that distinguish tumor progression from therapeutic response. In this study, we sought to test the applicability of magnetic resonance (MR) spectroscopy in combination with MR imaging to closely monitor therapeutic efficacy in a breast-to-brain metastasis model. Given the importance of radiotherapy as the standard of care for the majority of brain metastases patients, we chose to monitor the post-irradiation response by magnetic resonance spectroscopy (MRS) in combination with MR imaging (MRI) using a 7 Tesla small animal scanner. Radiation was applied as whole brain radiotherapy (WBRT) using the image-guided Small Animal Radiation Research Platform (SARRP). Here we describe alterations in different metabolites, including creatine and N-acetylaspartate, that are characteristic for brain metastases progression and lactate, which indicates hypoxia, while choline levels remained stable. Radiotherapy resulted in normalization of metabolite levels indicating tumor stasis or regression in response to treatment. Our data indicate that the use of MR spectroscopy in addition to MRI represents a valuable tool to closely monitor not only volumetrical but also metabolic changes during tumor progression and to evaluate therapeutic efficacy of intervention strategies. Adapting the analytical technology in brain metastasis models to those used in clinical settings will increase the translational significance of experimental evaluation and thus contribute to the advancement of pre-clinical assessment of novel therapeutic strategies to improve treatment options for brain metastases patients.

Generation of an Atxn2-CAG100 knock-in mouse reveals N-acetylaspartate production deficit due to early Nat8l dysregulation.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder caused by CAG-expansion mutations in the ATXN2 gene, mainly affecting motor neurons in the spinal cord and Purkinje neurons in the cerebellum. While the large expansions were shown to cause SCA2, the intermediate length expansions lead to increased risk for several atrophic processes including amyotrophic lateral sclerosis and Parkinson variants, e.g. progressive supranuclear palsy. Intense efforts to pioneer a neuroprotective therapy for SCA2 require longitudinal monitoring of patients and identification of crucial molecular pathways. The ataxin-2 (ATXN2) protein is mainly involved in RNA translation control and regulation of nutrient metabolism during stress periods. The preferential mRNA targets of ATXN2 are yet to be determined. In order to understand the molecular disease mechanism throughout different prognostic stages, we generated an Atxn2-CAG100-knock-in (KIN) mouse model of SCA2 with intact murine ATXN2 expression regulation. Its characterization revealed somatic mosaicism of the expansion, with shortened lifespan, a progressive spatio-temporal pattern of pathology with subsequent phenotypes, and anomalies of brain metabolites such as N-acetylaspartate (NAA), all of which mirror faithfully the findings in SCA2 patients. Novel molecular analyses from stages before the onset of motor deficits revealed a strong selective effect of ATXN2 on Nat8l mRNA which encodes the enzyme responsible for NAA synthesis. This metabolite is a prominent energy store of the brain and a well-established marker for neuronal health. Overall, we present a novel authentic rodent model of SCA2, where in vivo magnetic resonance imaging was feasible to monitor progression and where the definition of earliest transcriptional abnormalities was possible. We believe that this model will not only reveal crucial insights regarding the pathomechanism of SCA2 and other ATXN2-associated disorders, but will also aid in developing gene-targeted therapies and disease prevention.

The pH sensitivity of APT-CEST using phosphorus spectroscopy as a reference method.

The pH value is a potential physiological marker for clinical diagnosis as it is altered in pathologies such as tumors. While intracellular pH can be measured noninvasively via phosphorus spectroscopy (31 P MRSI), Amide Proton Transfer-Chemical Exchange Saturation Transfer (APT-CEST) MRI has been suggested as an alternative method for pH quantification. To assess the suitability of APT-CEST contrast for pH quantification, two approaches (magnetization transfer ratio asymmetry [MTRasym ] and Lorentzian difference analysis [LDA]) for analyzing the Z-spectrum have been correlated with pH values obtained by 31 P MRSI. Fourteen patients with glioblastoma and 12 healthy controls were included. In contrast to MTRasym , the LDA is modeling the direct water saturation and the semi-solid magnetization transfer, allowing a separate evaluation of the aliphatic nuclear Overhauser effect and the APT-CEST. The results of our study show that the pH values obtained by 31 P MRSI correspond well with both methods describing the APT-CEST contrast. Two-sample t-test showed significant differences in MTRasym , LDA and pH obtained by 31 P MRSI for regions of interest in glioblastoma, contralateral control areas and normal appearing white matter (P < 0.001). A slightly improved correlation between the amide signal and pH was found after performing LDA (r = 0.78) compared with MTRasym (r = 0.70). While both methods can be used to monitor pH changes, the LDA approach appears to be better suited.

Revascularization of High-Grade Carotid Stenosis Restores Global Cerebral Energy Metabolism.

Background and Purpose- Chronic cerebral hemodynamic impairment due to high-grade occlusive carotid disease may lead to compromised energy metabolism. This might result in chronic subtle tissue damage, even in patients without overt brain infarction. The aim of this study was to investigate hypoperfusion-related changes of cerebral energy metabolism and their potential restitution after revascularization. For this purpose, 3-dimensional 31P magnetic resonance spectroscopy and oxygenation-sensitive T2' magnetic resonance imaging were used (with 1/T2'=1/T2*-1/T2), which were expected to cross-validate each other. Methods- Ten patients with unilateral high-grade carotid artery stenosis resulting in a transient ischemic attack or a nondisabling cerebral ischemia were included. Then, high-energy metabolites, intracellular pH, and oxygenation-sensitive quantitative (q)T2' values were determined in noninfarcted hypoperfused areas delineated on time-to-peak maps from perfusion-weighted imaging and in unaffected contralateral areas before and shortly after carotid stenting/endarterectomy. Repeated measures ANOVA was used to test for intervention effects. Results- Within dependent hypoperfused areas ipsilateral to the stenosis, qT2' was significantly decreased ( P<0.05) as compared to corresponding contralateral areas before carotid intervention. There was a significant effect of carotid intervention on qT2' values in both hemispheres ( P<0.001). No differences between hemispheres were found for qT2' after revascularization. Intracellular pH and qT2' values showed a significant negative relationship ( P=0.005) irrespective of time point and hemisphere. Conclusions- After revascularization of unilateral high-grade carotid stenosis, previously decreased qT2' in the dependent hypoperfused territory as marker of hypoxia reincreases not only in the dependent territory but also in corresponding contralateral brain tissue. This might indicate a restriction of the whole-brain oxygen metabolism in case of unilateral high-grade carotid stenosis and an improvement of whole-brain oxygenation after revascularization that goes beyond acute clinically apparent affection of the dependent territory. Furthermore, tissue oxygen supply seems to be closely linked to intracellular pH.

Complete Restitution of the Ischemic Penumbra after Successful Thrombectomy : A Pilot Study Using Quantitative MRI.

PURPOSE: Endovascular thrombectomy is highly effective in patients with proximal large artery occlusion but the relevance of reperfusion injury after recanalization is a matter of debate. The aim of this study was to investigate potential residual metabolic distress and microstructural tissue damage or edema after reperfusion using quantitative oxygen-sensitive T2' and T2-mapping in patients successfully treated by thrombectomy. METHODS: Included in this study were 11 patients (mean age 70 ± 11.4 years) with acute ischemic stroke due to internal carotid artery and/or middle cerebral artery occlusion. Quantitative T2 and T2' (1/T2' = 1/T2* - 1/T2) were determined within the ischemic core and hypoperfused but salvaged tissue with delayed time-to-peak (TTP) in patients before and after successful thrombectomy and compared to a control region within the unaffected hemisphere. RESULTS: Decreased T2' values within hypoperfused tissue before thrombectomy showed a normalization after recanalization (p < 0.01). In formerly hypoperfused but salvaged tissue, T2 values increased significantly after thrombectomy (p < 0.05) but did not differ from reference values in the control region. In salvaged tissue, increases of quantitative T2' and T2 to follow-up were more pronounced in areas with severe TTP delay. CONCLUSION: After successful recanalization, T2' re-increased back to normal in formerly hypoperfused areas as a sign of prompt normalization of oxygen metabolism. Furthermore, quantitative T2 in the formerly hypoperfused tissue did not differ from reference values in unaffected tissue. These results indicate complete restitution of salvaged tissue after reperfusion and support the overall safety of endovascular thrombectomy with respect to microstructural tissue integrity.

Lifespan leisure physical activity profile, brain plasticity and cognitive function in old age.

OBJECTIVES: Despite the evidence suggesting physical activity (PA) as a major factor for the prevention of age-related cognitive decline, only a few studies have systematically investigated the impact of leisure PA during the lifespan (LLPA). This study investigates the effects of LLPA on cognitive function (CF) and brain plasticity (BP) in old age. METHOD: Participants' (n = 50, 72 ± 5 yrs, 27 females) LLPA energy expenditure and volume was assessed via a validated questionnaire investigating five epochs (14-80 yrs). Using current WHO PA recommendations as reference, participants were stratified into energy expenditure and volume groups. CF outcomes were attention, executive functions, working memory and memory. BP was assessed using magnetic resonance spectroscopy (MRSI) and brain derived neurotropic factor (BDNF). RESULTS: Correlation analysis revealed associations of mean LLPA energy expenditure with attention (CF) and N-acetylaspartate to choline ratios (NAA/Cho) (MRSI). ANOVA revealed higher interference control performance (CF) and NAA/Cho in participants complying with current PA recommendations (2-3 h per week) compared to non-compliers. Further CF and BP outcomes including BDNF were not associated with LLPA. CONCLUSION: Lifelong adherence to minimum recommended PA seems to be associated with markers of cognitive function and neuronal integrity in old age.

In vivo Metabolic Profiles as Determined by 31P and short TE 1H MR-Spectroscopy : No Difference Between Patients with IDH Wildtype and IDH Mutant Gliomas.

PURPOSE: Previous ex vivo spectroscopic data from tissue samples revealed differences in phospholipid metabolites between isocitrate dehydrogenase mutated (IDHmut) and IDH wildtype (IDHwt) gliomas. We investigated whether these changes can be found in vivo using 1H-decoupled 31P magnetic resonance spectroscopic imaging (MRSI) with 3D chemical shift imaging (CSI) at 3 T in patients with low and high-grade gliomas. METHODS: The study included 33 prospectively enrolled, mostly untreated patients who met spectral quality criteria according to the World Health Organization (WHO II n = 7, WHO III n = 17, WHO IV n = 9; 25 patients IDHmut, 8 patients IDHwt). The MRSI protocol included 1H decoupled 31P MRSI with 3D CSI (3D 31P CSI), 2D 1H CSI and a 1H single voxel spectroscopy sequence (TE 30 ms) from the tumor area. For 1H MRS, absolute metabolite concentration values were calculated (phantom replacement method). For 31P MRS, metabolite intensity ratios were calculated for the choline (C) and ethanolamine (E)-containing metabolites. RESULTS: In our patient cohort we did not find significant differences for the ratio of phosphocholine (PC) and phosphoethanolamine (PE), PC/PE, (p = 0.24) for IDHmut compared to IDHwt gliomas. Furthermore, we found no elevated ratios of glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE), GPC/GPE, (p = 0.68) or GPC/PE (p = 0.12) for IDHmut gliomas. Even the ratio (PC+GPC)/(PE+GPE) showed no significant differences with respect to mutation status (p = 0.16). Nonetheless, changes related to tumor grade regarding intracellular pH (pHi) and phospholipid metabolism as well as absolute metabolite concentrations of co-registered 2D 1H CSI data for tumor and control tissue showed the anticipated results. CONCLUSION: Using 3D-CSI data acquisition, in vivo 31P MR spectroscopic measurement of phospholipid metabolites could not distinguish between IDHmut and IDHwt.

Fitting algorithms and baseline correction influence the results of non-invasive in vivo quantitation of 2-hydroxyglutarate with 1 H-MRS.

1 H-MRS enables non-invasive detection of 2-hydroxyglutarate (2-HG), an oncometabolite accumulating in gliomas carrying mutations in the isocitrate dehydrogenase (IDH) genes. Reliable 2-HG quantitation requires reproducible post-processing, deployment of fitting algorithms and quantitation methods. We prospectively enrolled 38 patients with suspected or recently diagnosed gliomas (IDH mutated n = 26). The MRI protocol included a 1 H single voxel PRESS sequence with volumes of usually 8 mL or more (20 × 20 × 20 mm3 ) at TE  = 97 ms and 180° pulse spacing. Our aim was to evaluate the reliability of 2-HG quantitation comparing two frequently used software tools and their respective options of baseline correction (jMRUI with the time domain methods AQSES and QUEST, and LCModel, which analyzes the frequency domain data). For AQSES, degrees of freedom for baseline correction constrains were varied. For LCModel, baseline correction was obtained with and without correction of the unknown background term (predefined macromolecules, lipids). Tissue concentrations were calculated based on the phantom replacement method. Quantitation of 2-HG levels showed similar mean 2-HG tissue concentrations for IDH mutated tumors (2.65mM, range 3.06-2.20) for all methods. Bland-Altman plots (difference plots) did not reveal a systematic bias (fixed bias) for any of the algorithms tested, and we were able to show a significant correlation regarding 2-HG concentration at the same echo time with few statistical outliers (parametric correlation). However, evaluation of outliers suggested that in vivo quantitation of 2-HG is affected not only by the fitting domain (time or frequency), but also by the baseline correction, which is a major contributing factor to the result of 2-HG fitting. Clinical application of 2-HG quantitation as a prognostic or predictive biomarker, particularly in multicenter trials, requires standardized use of fitting methods and baseline correction procedures.

Is Objectively Assessed Sedentary Behavior, Physical Activity and Cardiorespiratory Fitness Linked to Brain Plasticity Outcomes in Old Age?

The aim of this cross-sectional study was to determine the associations of objectively assessed habitual physical activity and physical performance with brain plasticity outcomes and brain-derived neurotrophic factor (BDNF) levels in cognitively healthy older adults. Physical performance was analyzed based on cardiopulmonary exercise-testing data and accelerometer-based physical activity was analyzed as total activity counts, sedentary time, light physical activity and moderate to vigorous physical activity. Brain plasticity outcomes included magnetic resonance spectroscopy (MRS)-based markers, quantitative imaging-based hippocampal volume and BDNF serum levels. The association between physical performance and hippocampal volume was strongly influenced by participants' education, sex, age and BMI. Confounder-controlled correlation revealed significant associations of brain plasticity outcomes with physical activity but not with performance. MRS-based adenosine triphosphate to phosphocreatine and glycerophosphocholine to phosphocreatine ratios were significantly associated with accelerometer total activity counts. BDNF was detrimentally associated with sedentary time but beneficially related to accelerometer total activity counts and moderate to vigorous physical activity. Exceeding the current moderate to vigorous physical activity recommendations led to significantly higher BDNF levels. Our results indicate that regular physical activity might be beneficial for preserving brain plasticity in higher age. In this study these associations were not mediated significantly by physical performance. Overall physical activity and exceeding current moderate to vigorous physical activity recommendations were positively associated with BDNF. Sedentary behavior, however, seems to be negatively related to neurotrophic factor bioavailability in the elderly.

Effects of Aging on the Human Brain: A Proton and Phosphorus MR Spectroscopy Study at 3T.

BACKGROUND AND PURPOSE: To investigate accumulative aging effects on neurometabolism in human brain and to collect a reference dataset. METHODS: Fifty-four healthy volunteers aged evenly between 22 and 73 years were studied using whole-brain 1 H-MR spectroscopic imaging in combination with 31 P-MRS at 3T. Global metabolite concentrations of brain N-acetylaspartate (NAA), total choline (tCho), and total creatine (tCr), as well as phosphocreatine (PCr), adenosine-5'-triphosphate (ATP), phosphomonoesters (PME), phosphodiesters (PDE), and inorganic phosphate (Pi) were determined. Fractional volumes of brain gray matter (FVGM), white matter (FVWM), and total tissue (FVTB, GM+WM) were also estimated. RESULTS: With age, NAA, ATP, and PME, as well as FVTB and FVGM decreased and tCho and FVWM increased linearly. Positive correlations were found between FVGM and global concentrations of NAA, ATP, PME, and Pi. CONCLUSION: Age-related accumulative metabolic changes in aging human brain correlated with reduced neuronal metabolic activity and density, reflected by decreased NAA, reduced mitochondrial activity by decreased ATP, and reduced membrane synthesis by decreased PME. These changes are associated with age-related decrease of neuronal volume. Global NAA and ATP might be used as surrogate biomarker for monitoring aging in human brain.

Ex vivo 1H MR spectroscopy and histology after experimental chronic spinal cord compression.

BACKGROUND: Proton magnetic resonance imaging (MRS) is used increasingly to image the spinal cord in compressive cervical myelopathy (CSM). However, detailed analyses of the underlying histomorphological changes leading to MRS alterations are still lacking. The aim of our study was to correlate neuroimaging and neuropathologic alterations in a rabbit myelopathy model. METHODS: Chronic spinal cord compression was induced in a rabbit model (n=16) allowing for a gradual 270° compression of the spinal cord. Spinal cord compression core areas were divided into two samples for (A) 1H MRS and (B) histopathological analyses. Postoperatively the animals underwent a neurological examination twice a day and outcome was categorized in pattern of injury and amount of recovery. RESULTS: Three groups were observed and categorized: (I) animals with severe deficits and no or minimal recovery; (II) animals with severe deficits and complete or almost complete recovery; (III) animals with mild to moderate deficits and a complete recovery. Significant differences in the lesioned spinal cords between the different recovery groups were found for N-acetyl-aspartate and choline. NAA/Cr was detected significantly (P<0.001, ANOVA) less in the group that did show permanent neurological deficits. To the contrary, choline was detected significantly (P<0.001, ANOVA) more in the group that did show permanent neurological deficits. Histologically the first group showed more apoptosis and necrosis than the second and third group. CONCLUSIONS: MR spectroscopy (MRS) may be helpful for clinicians in improving the prognostic accuracy in cervical myelopathies since this method nicely reflects the extent and severity of spinal cord damage.