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Differences between left and right hemispheres of the metabolite ratios, distinguish- ing between women and men; * represents higher values on the right, and ** higher values on the left side.
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Background and purpose
Phosphorous magnetic resonance spectroscopy (31P-MRS) allows a non-invasive analysis of phosphorus-containing compounds in vivo. The present study investigated the influence of brain region, hemisphere, age, sex and brain volume on 31P-MRS metabolites in healthy adults.
Materials and Methods
Supratentorial brain 31P-MRS spec...
Context in source publication
Citations
... We have identified 7 31 P-MRS studies investigating HEP variability with normal aging (Longo et al., 1993;Constans et al., 1995;Rae et al., 2003;Forester et al., 2010;Schmitz et al., 2018;Cuenoud et al., 2020;Rietzler et al., 2022), in addition to 4 studies focusing on individuals at risk for AD (e.g., family history and/or APOE4 genotype) (Mosconi et al., 2021;Jett et al., 2022aJett et al., , 2023Parasoglou et al., 2022). These studies are summarized in Table 2. 31 P-MRS studies conducted over the adult lifespan generally indicate an increase in PCr with age (Longo et al., 1993;Rae et al., 2003;Forester et al., 2010;Cuenoud et al., 2020). ...
... It is important to note that due to the high variability and standard deviation of Pi measures previous studies may be underpowered to detect significant effects. Regarding HEP metabolite ratios, increasing PCr/ATP with age across the lifespan seems to be the most consistent finding (Longo et al., 1993;Rae et al., 2003;Cuenoud et al., 2020;Parasoglou et al., 2022;Rietzler et al., 2022). Results of agerelated changes in PCr/Pi and Pi/ATP are less consistent (Longo et al., 1993;Rae et al., 2003;Cuenoud et al., 2020;Rietzler et al., 2022). ...
... Regarding HEP metabolite ratios, increasing PCr/ATP with age across the lifespan seems to be the most consistent finding (Longo et al., 1993;Rae et al., 2003;Cuenoud et al., 2020;Parasoglou et al., 2022;Rietzler et al., 2022). Results of agerelated changes in PCr/Pi and Pi/ATP are less consistent (Longo et al., 1993;Rae et al., 2003;Cuenoud et al., 2020;Rietzler et al., 2022). Further, examination of sex and APOE4 genotype status provided evidence for modulatory effects that need accounting for in lifespan investigations. ...
Many lines of evidence suggest that mitochondria have a central role in aging-related neurodegenerative diseases, such as Alzheimer's disease (AD). Mitochondrial dysfunction, cerebral energy dysmetabolism and oxidative damage increase with age, and are early event in AD pathophysiology and may precede amyloid beta (Aβ) plaques. In vivo probes of mitochondrial function and energy metabolism are therefore crucial to characterize the bioenergetic abnormalities underlying AD risk, and their relationship to pathophysiology and cognition. A majority of the research conducted in humans have used ¹⁸ F-fluoro-deoxygluose (FDG) PET to image cerebral glucose metabolism (CMRglc), but key information regarding oxidative phosphorylation (OXPHOS), the process which generates 90% of the energy for the brain, cannot be assessed with this method. Thus, there is a crucial need for imaging tools to measure mitochondrial processes and OXPHOS in vivo in the human brain. ³¹ Phosphorus-magnetic resonance spectroscopy ( ³¹ P-MRS) is a non-invasive method which allows for the measurement of OXPHOS-related high-energy phosphates (HEP), including phosphocreatine (PCr), adenosine triphosphate (ATP), and inorganic phosphate (Pi), in addition to potential of hydrogen (pH), as well as components of phospholipid metabolism, such as phosphomonoesters (PMEs) and phosphodiesters (PDEs). Herein, we provide a systematic review of the existing literature utilizing the ³¹ P-MRS methodology during the normal aging process and in patients with mild cognitive impairment (MCI) and AD, with an additional focus on individuals at risk for AD. We discuss the strengths and limitations of the technique, in addition to considering future directions toward validating the use of ³¹ P-MRS measures as biomarkers for the early detection of AD.
... Effects of sex and APOE ε4 genotype on brain mitochondrial high-energy phosphates in midlife individuals results. The largest study examined 125 individuals ages 20-85 years, reporting lower PCr/ ATP (higher ATP utilization; averaged α-, β-, and γ-ATP resonances) and PCr/Pi (energy demand) in frontal, occipital, and temporal cortices in women as compared to men [51]. The other study, totaling 34 healthy volunteers ages 21-84 (20 men and 14 women), found no sex differences in α-, β-, or γ-nucleoside di-and tri-phosphate (NTP), Pi, or PCr measures [52]. ...
... Nonetheless, from a methodological perspective, metabolite ratios are considered more reliable, as they are less prone to acquisition issues such as transmit and receive field variation, signal-to-noise ratio (SNR), and partial volume averaging concerns. By using metabolite ratios, a study of 74 cognitively normal, middle-aged post-menopausal women of known APOE4 status (48% APOE4 carriers) reported higher α-ATP utilization in temporal and frontal regions as compared to 45 age-controlled men [30], thus consistent with [51]. ...
... Previous studies of age effects in cognitively normal individuals indicate that PCr, PCr/ATP and PCr/Pi generally increase with age [51,52,59]. However, these studies examined larger age ranges (20-85 years) as compared to 40-65 years in the current study. ...
Age, female sex, and APOE epsilon 4 (APOE4) genotype are the three greatest risk factors for late-onset Alzheimer's disease (AD). The convergence of these risks creates a hypometabolic AD-risk profile unique to women, which may help explain their higher lifetime risk of AD. Less is known about APOE4 effects in men, although APOE4 positive men also experience an increased AD risk. This study uses 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) to examine effects of sex and APOE4 status on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters (PME), phosphodiesters (PDE)] in 209 cognitively normal individuals at risk for AD, ages 40-65, 80% female, 46% APOE4 carriers (APOE4+). Women exhibited lower PCr/ATP and PCr/Pi levels than men in AD-vulnerable regions, including frontal, posterior cingulate, lateral and medial temporal cortex (multi-variable adjusted p≤0.037). The APOE4+ group exhibited lower PCr/ATP and PCr/Pi in frontal regions as compared to non-carriers (APOE4-) (multi-variable adjusted p≤0.005). Sex by APOE4 status interactions were observed in frontal regions (multi-variable adjusted p≤0.046), where both female groups and APOE4+ men exhibited lower PCr/ATP and PCr/Pi than APOE4- men. Among men, APOE4 homozygotes exhibited lower frontal PCr/ATP than heterozygotes and non-carriers. There were no significant effects of sex or APOE4 status on Pi/ATP and PME/PDE measures. Among midlife individuals at risk for AD, women exhibit lower PCr/ATP (e.g. higher ATP utilization) and lower PCr/Pi (e.g. higher energy demand) than age-controlled men, independent of APOE4 status. However, a double dose of APOE4 allele shifted men's brains to a similar metabolic range as women's brains. Examination of brain metabolic heterogeneity can support identification of AD-specific pathways within at-risk subgroups, further advancing both preventive and precision medicine for AD.
... Diffusion MRS allows the measurement of metabolite diffusion properties and thus provides insights into cellular compartmentation. Phosphocreatine (PCr), adenosine triphosphate (ATP), and inorganic phosphate (Pi) are the three main 31 P MRS detectable metabolites which are essential for energy production and transport [1]. Another 31 P metabolite glycerophosphocholine (GPC) is involved in cell membrane phospholipid metabolism and reflects malignant transformation of cells [2,3]. ...
... To validate the DW-STEAM sequence, the ADCs of water, Pi, PCr, and ATP were measured in vitro at room temperature (~ 18℃). 1 H experiments were carried out with a spherical phantom containing water (1L, pH = 7.0) using a single-channel quadrature transmit and a 32-channel receive coil (Nova Medical Inc., MA, USA), with TE/TM/ TR = 15 ms/750 ms/40 s, number of averages (NA) = 4, and voxel size = 16 × 16 × 16 mm 3 . 31 P experiments were carried out with a phantom containing 31 mM PCr, 31 mM ATP, 8 mM NaH 2 PO 4 and 106 mM NaCl (0.5 L, pH = 7.2) using a home-built surface coil with a single 31 P loop (diameter of 7 cm) and two quadrature 1 H loops (diameter of 10 cm), with TE/TM/TR = 15 ms/750 ms/60 s, NA = 4, and voxel size = 40 × 46 × 46 mm 3 . ...
Purpose:
In this study, we aimed to measure the apparent diffusion coefficients (ADCs) of major phosphorous metabolites in the human calf muscle at 7 T with a diffusion-weighted (DW)-STEAM sequence.
Methods:
A DW-STEAM sequence with bipolar gradients was implemented at 7 T, and DW MR spectra were acquired in three orthogonal directions in the human calf muscle of six healthy volunteers (TE/TM/TR = 15 ms/750 ms/5 s) at three b-values (0, 800, and 1200 s/mm2). Frequency and phase alignments were applied prior to spectral averaging. Averaged DW MR spectra were analyzed with LCModel, and ADCs of 31P metabolites were estimated.
Results:
Four metabolites (phosphocreatine (PCr), adenosine triphosphate (ATP), inorganic phosphate (Pi) and glycerol phosphorylcholine (GPC)) were quantified at all b-values with mean CRLBs below 10%. The ADC values of PCr, ATP, Pi, and GPC were (0.24 ± 0.02, 0.15 ± 0.04, 0.43 ± 0.14, 0.40 ± 0.09) × 10-3 mm2/s, respectively.
Conclusion:
The ADCs of four 31P metabolites were successfully measured in the human calf muscle at 7 T, among which those of ATP, Pi and GPC were reported for the first time in humans. This study paves the way to investigate 31P metabolite diffusion properties in health and disease on the clinical MR scanner.
... Currently, only two 31 P-MRS studies have addressed this question. One study of the adult lifespan reported higher ATP utilization in frontal, temporal, and occipital cortices of women ages 20-85 years as compared to age-controlled men 36 . The other study also reported higher ATP utilization in frontal and temporal regions of post-menopausal women as compared to age-controlled men, controlling for age and APOE-4 status 12 . ...
... ATP hydrolysis 37 ) except for lower Pi/ATP in PCC of women relative to men, which did not survive correction for multiple comparisons. The only other study that investigated sex differences in Pi/ATP showed lower ratios in temporal cortex, and higher ratios in parietal cortex of women as compared to men across the adult lifespan 36 . While the previous study did not examine PCC, these results provide preliminary evidence for emergence of sex differences in ATP hydrolysis during normal aging. ...
... While the previous study did not examine PCC, these results provide preliminary evidence for emergence of sex differences in ATP hydrolysis during normal aging. The previous study also reported lower cortical energy demand in women 36 , whereas we found no sex differences in this metabolite ratio. Given the greater variability of Pi measures, resulting in greater standard deviations, it is possible that we were underpowered to detect significant effects. ...
Increasing evidence implicates sex and endocrine aging effects on brain bioenergetic aging in the greater lifetime risk of Alzheimer’s disease (AD) in women. We conducted ³¹ Phosphorus Magnetic Resonance Spectroscopy ( ³¹ P-MRS) to assess the impact of sex and menopause on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters/phosphodiesters (PME/PDE)] in 216 midlife cognitively normal individuals at risk for AD, 80% female. Ninety-seven participants completed amyloid-beta (Aβ) ¹¹ C-PiB PET. Women exhibited higher ATP utilization than men in AD-vulnerable frontal, posterior cingulate, fusiform, medial and lateral temporal regions (p < 0.001). This profile was evident in frontal cortex at the pre-menopausal and peri-menopausal stage and extended to the other regions at the post-menopausal stage (p = 0.001). Results were significant after multi-variable adjustment for age, APOE-4 status, midlife health indicators, history of hysterectomy/oophorectomy, use of menopause hormonal therapy, and total intracranial volume. While associations between ATP/PCr and Aβ load were not significant, individuals with the highest Aβ load were post-menopausal and peri-menopausal women with ATP/PCr ratios in the higher end of the distribution. No differences in Pi/PCr, Pi/ATP or PME/PDE were detected. Outcomes are consistent with dynamic bioenergetic brain adaptations that are associated with female sex and endocrine aging.
... Consequently, 31P-MRS can potentially be applied for differentiation between radionecrosis and tumor recurrence, yet, this warrants further investigations. However, the application of 31P-MRS is complicated by the fact that 31P-metabolism varies throughout the brain, with age and between sexes, which poses important practical implications for the application and interpretation of 31P-MRS especially in such complex metabolic changes as are introduced by radiation [83]. ...
Radiation necrosis represents a potentially devastating complication after radiation therapy in brain tumors. The establishment of the diagnosis and especially the differentiation from progression and pseudoprogression with its therapeutic implications requires interdisciplinary consent and monitoring. Herein, we want to provide an overview of the diagnostic modalities, therapeutic possibilities and an outlook on future developments to tackle this challenging topic. The aim of this report is to provide an overview of the current morphological, functional, metabolic and evolving imaging tools described in the literature in order to (I) identify the best criteria to distinguish radi-onecrosis from tumor recurrence after the radio-oncological treatment of malignant gliomas and cerebral metastases, (II) analyze the therapeutic possibilities and (III) give an outlook on future developments to tackle this challenging topic. Additionally, we provide the experience of a tertiary tumor center with this important issue in neuro-oncology and provide an institutional pathway dealing with this problem.
... We carried out 31 P-MRS measurements on a 3 T system with a dual-tuned 3 H/ 31 P multichannel coil array, a setup that is known to improve sensitivity over a volume coil (Brown et al., 2016a(Brown et al., , 2016bAvdievich et al., 2020;Valkovic et al., 2017;Avdievich and Hetherington, 2007), to investigate: 1) 31 P-MRS reliability by way of a two-scan repeatability study in a cohort of healthy volunteers, 2) the hypothesis that bioenergetic abnormalities are present prior to cognitive impairment in early stage AD by measuring 31 P-MRS in healthy, cognitively normal middle-aged adults at risk for AD (based on family history or genotype), 3) the relationship between bioenergetics and amyloid deposition measured with PET, and 4) the relationship between age and regional brain energy metabolism (Forester et al., 2010;Longo et al., 1993;Schmitz et al., 2018;Rietzler et al., 2021). ...
... As pointed out by others, 31 P-MRS measurements are affected by spatially variable transmit and receive field amplitudes, making it difficult to quantify metabolites in absolute terms (Rietzler et al., 2021;Meyerspeer et al., 2020). To alleviate this issue, metabolite ratios are often reported because they provide built-in normalization. ...
... Nonetheless, a range of PCr/ATP values are found in the literature. As a starting point for discussion, using the regression coefficients in Table 3 we calculated PCr/ATP of 1.2 in the AD meta region for a 49 year-old individual (selected to match the average age in the Rietzler et al. study), compared to 1.2 to 1.5 depending on region and sex in Rietzler et al. (2021), 1.7 in Schmitz et al. (2018), 1.4 to 1.6 in papers by Hattingen et al., 2009a, and 0.8 in Longo et al. (1993. While PCr/ATP is certainly influenced by study variables such as voxel size and position and cohort characteristics, a more likely explanation for the relatively low PCr/ATP value reported in this study is incomplete magnetization recovery due to the 2 s repetition time that was selected to accommodate a reasonable acquisition time (note that PCr longitudinal relaxation time is approximately 2.5 s at 3 T 27 ). ...
Background
Neurometabolic abnormalities and amyloid-beta plaque deposition are important early pathophysiologic changes in Alzheimer's disease (AD). This study investigated the relationship between high-energy phosphorus-containing metabolites, glucose uptake, and amyloid plaque using phosphorus magnetic resonance spectroscopy (³¹P-MRS) and positron emission tomography (PET).
Methods
We measured ³¹P-MRS, fluorodeoxyglucose (FDG)-PET, and Pittsburgh Compound B (PiB)-PET in a cohort of 20 cognitively normal middle-aged adults at risk for AD. We assessed ³¹P-MRS reliability by scanning a separate cohort of 13 healthy volunteers twice each. We calculated the coefficient-of-variation (CV) of metabolite ratios phosphocreatine-to-adenosine triphosphate (PCr/α-ATP), inorganic phosphate (Pi)-to-α-ATP, and phosphomonoesters-to-phosphodiesters (PME/PDE), and pH in pre-defined brain regions. We performed linear regression analysis to determine the relationship between ³¹P measurements and tracer uptake, and Dunn's multiple comparison tests to investigate regional differences in phosphorus metabolism. Finally, we performed linear regression analysis on ³¹P-MRS measurements in both cohorts to investigate the relationship of phosphorus metabolism with age.
Results
Most regional ³¹P metabolite ratio and pH inter- and intra-day CVs were well below 10%. There was an inverse relationship between FDG-SUV levels and metabolite ratios PCr/α-ATP, Pi/α-ATP, and PME/PDE in several brain regions in the AD risk group. There were also several regional differences among ³¹P metabolites and pH in the AD risk group including elevated PCr/α-ATP, depressed PME/PDE, and elevated pH in the temporal cortices. Increased PCr/α-ATP throughout the brain was associated with aging.
Conclusions
Phosphorus spectroscopy in the brain can be performed with high repeatability. Phosphorus metabolism varies with region and age, and is related to glucose uptake in adults at risk for AD. Phosphorus spectroscopy may be a valuable approach to study early changes in brain energetics in high-risk populations.
... Regional, age-and sex-dependent differences in cerebral glucose and lactate level have been observed in previous study [36]. Surprisingly, a decreasing trend of Lac was found in distal blood samples compared with that in the femoral artery. ...
Background and purpose
Endovascular treatment (EVT) is the best treatment for acute ischemic stroke with large vessel occlusion (LVO) and makes it possible to analyze the blood contents from the occluded vascular compartments. In this study, we attempted to evaluate regional changes in blood gas values and electrolytes in the occluded vessels, aiming to determine whether these changes can predict outcomes in LVO patients receiving EVT.
Materials and Methods
We prospectively observed 45 consecutive ischemic stroke patients with LVO of the anterior circulation who underwent EVT. We collected the arterial blood proximal to the occlusion site before and after EVT, and the blood within the core of the occluded vascular compartment (distal to the thrombus) and evaluated the labs for blood gas values and electrolytes. Femoral samples were obtained under physiological flow conditions to represent systemic arterial blood.
Results
Compared with the femoral arterial blood samples, significant decreases in K+, Ca2+, HCO3−, BE, HCT, tHbc, and TCO2 levels were observed in the proximal luminal blood before EVT. Decreases in K+ and Ca2+ levels were also observed in the proximal luminal blood after EVT. Proximal/femoral ratio of pH and Na+ was associated with short-term clinical outcomes at 72 hours after EVT. A higher proximal/femoral Na+ ratio was associated with successful recanalization. Further analysis after propensity score matching showed significant changes in blood gas and electrolyte among different arterial locations in ICA and MCA LVO participants. Linear regression analyses indicated that the proximal/femoral ratio of pH, Na+, pCO2, HCO3, and TCO2 before EVT were associated with decrease in NIHSS score at 72 hours in ICA-LVO group.
Conclusions
Obvious changes in several parameters of arterial blood gas and electrolyte from the ischemic vasculature occur during hyperacute stroke. Proximal/femoral pH and Na+ ratio before EVT may be associated with short-term clinical outcome, which deserve to be further investigated.
... The results were presented and analyzed as metabolite concentration ratios, since the ratio of two metabolites is independent of the scaling factor. 46 The computational analysis was performed using Python. ...
... The results are in very good agreement with the values reported using PCr as internal reference. 46,49,50 The Bland-Altman plot shows that the mean difference of the two methods was much smaller than the standard deviation and demonstrates the absence of bias. The outlier points in Subject #9 could be explained by poor B0 homogeneity during the acquisition. ...
Purpose
We have introduced an artificial intelligence framework, 31P‐SPAWNN, in order to fully analyze phosphorus‐31 (P) magnetic resonance spectra. The flexibility and speed of the technique rival traditional least‐square fitting methods, with the performance of the two approaches, are compared in this work.
Theory and Methods
Convolutional neural network architectures have been proposed for the analysis and quantification of P‐spectroscopy. The generation of training and test data using a fully parameterized model is presented herein. In vivo unlocalized free induction decay and three‐dimensional P‐magnetic resonance spectroscopy imaging data were acquired from healthy volunteers before being quantified using either 31P‐SPAWNN or traditional least‐square fitting techniques.
Results
The presented experiment has demonstrated both the reliability and accuracy of 31P‐SPAWNN for estimating metabolite concentrations and spectral parameters. Simulated test data showed improved quantification using 31P‐SPAWNN compared with LCModel. In vivo data analysis revealed higher accuracy at low signal‐to‐noise ratio using 31P‐SPAWNN, yet with equivalent precision. Processing time using 31P‐SPAWNN can be further shortened up to two orders of magnitude.
Conclusion
The accuracy, reliability, and computational speed of the method open new perspectives for integrating these applications in a clinical setting.
... This could be explained by a difference in metabolic flux between awake and anesthetized animals. Assessment of the PCr/ATP ratio in awake and anesthetized mice demonstrated that anesthetized mice had a decreased energy reserve compared to awake mice [37,38]. The Pi/ATP ratio reveals information about the rate of ATP hydrolysis. ...
... The Pi/ATP ratio reveals information about the rate of ATP hydrolysis. The larger Pi/ATP ratio in awake relative to anesthetized mice indicated an increase in ATP hydrolysis in the awake animals [37,39]. This finding indicated that there was higher energy consumption in awake mice compared to anesthetized mice. ...
... This accounts for the fact that there was no observed difference in levels of ATP between the two groups animals. The Pi/PCr ratio was decreased in anesthetized mice indicating that awake mice have an increase in brain metabolic activity and mitochondrial function compared to anesthetized mice [37,41]. The significance lies in the fact that bioenergetic impairment, in the forms of brain energy metabolism and mitochondrial function are affected in the neuropathology of certain conditions, such as Schizophrenia and Alzheimer's disease [42]. ...
Anesthesia is often used in preclinical imaging studies that incorporate mouse or rat models. However, multiple reports indicate that anesthesia has significant physiological impacts. Thus, there has been great interest in performing imaging studies in awake, unanesthetized animals to obtain accurate results without the confounding physiological effects of anesthesia. Here, we describe a newly designed mouse holder that is interfaceable with existing MRI systems and enables awake in vivo mouse imaging. This holder significantly reduces head movement of the awake animal compared to previously designed holders and allows for the acquisition of improved anatomical images. In addition to applications in anatomical T2-weighted magnetic resonance imaging (MRI), we also describe applications in acquiring 31P spectra, manganese-enhanced magnetic resonance imaging (MEMRI) transport rates and resting-state functional magnetic resonance imaging (rs-fMRI) in awake animals and describe a successful conditioning paradigm for awake imaging. These data demonstrate significant differences in 31P spectra, MEMRI transport rates, and rs-fMRI connectivity between anesthetized and awake animals, emphasizing the importance of performing functional studies in unanesthetized animals. Furthermore, these studies demonstrate that the mouse holder presented here is easy to construct and use, compatible with standard Bruker systems for mouse imaging, and provides rigorous results in awake mice.
... Boundary regions, as well as regions filled with air or bone are spared, to avoid voxel contamination. The measurements are acquired using the parameters given in Table 2, and based on a conventional sequence by Siemens and described by Hattingen et al., in order to ensure reproducibility and applicability for potential future clinical use [32][33][34]. ...
... Therefore, these parameters also have to be taken into account when investigating cerebral energy metabolism under pathological conditions. This renders the interpretation of 31P-MRS even more challenging [33]. ...
... At the moment this method is experimental and still has to be implemented in clinical investigation [33]. ...
Preoperative grade prediction is important in diagnostics of glioma. Even more important can be follow-up after chemotherapy and radiotherapy of high grade gliomas. In this review we provide an overview of MR-spectroscopy (MRS), technical aspects, and different clinical scenarios in the diagnostics and follow-up of gliomas in pediatric and adult populations. Furthermore, we provide a recap of the current research utility and possible future strategies regarding proton- and phosphorous-MRS in glioma research.
