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Initial definitions of sarcopenia included the age-associated loss of skeletal muscle mass that was presumed to be associated with late-life reduced functional capacity, disability and loss of independence. Because no method for determination of muscle mass was available for large cohort studies of aging men and women, lean body mass determined by dual X-ray absorptiometry or bioelectrical impedance was used as a surrogate measure of muscle mass. The data from these studies showed either no or a poor relationship between LBM and functional capacity and health related outcomes, leading to the conclusion of many that the amount of muscle may not be associated with these age-associated outcomes. It was assumed that some undefined index of muscle quality is the critical contributor. These studies also consistently showed that muscle strength is lost more quickly than lean mass. Total body muscle mass can now be measured directly, accurately and non-invasively using the D3creatine (D3Cr) dilution method. D3Cr muscle mass, but not DXA derived LBM, is strongly associated with functional capacity, falls and insulin resistance in older men and women. In addition, D3Cr muscle mass is associated with risk of disability, hip fracture and mortality. New and emerging data demonstrate that low muscle mass may serve as a diagnostic criterion for sarcopenia.

Cigarette smoking has a major impact on global health and morbidity, and positron emission tomographic research has provided evidence for reduced inflammation in the human brain associated with cigarette smoking. Given the consequences of inflammatory dysfunction for health, the question of whether cigarette smoking affects neuroinflammation warrants further investigation. The goal of this project therefore was to validate and extend evidence of hypoinflammation related to smoking, and to examine the potential contribution of inflammation to clinical features of smoking. Using magnetic resonance spectroscopy, we measured levels of neurometabolites that are putative neuroinflammatory markers. N-acetyl compounds (N-acetylaspartate + N-acetylaspartylglutamate), glutamate, creatine, choline-compounds (phosphocholine + glycerophosphocholine), and myo-inositol, have all been linked to neuroinflammation, but they have not been examined as such with respect to smoking. We tested whether people who smoke cigarettes have brain levels of these metabolites consistent with decreased neuroinflammation, and whether clinical features of smoking are associated with levels of these metabolites. The dorsal anterior cingulate cortex was chosen as the region-of-interest because of previous evidence linking it to smoking and related states. Fifty-four adults who smoked daily maintained overnight smoking abstinence before testing and were compared with 37 nonsmoking participants. Among the smoking participants, we tested for associations of metabolite levels with tobacco dependence, smoking history, craving, and withdrawal. Levels of N-acetyl compounds and glutamate were higher, whereas levels of creatine and choline compounds were lower in the smoking group as compared with the nonsmoking group. In the smoking group, glutamate and creatine levels correlated negatively with tobacco dependence, and creatine correlated negatively with lifetime smoking, but none of the metabolite levels correlated with craving or withdrawal. The findings indicate a link between smoking and a hypoinflammatory state in the brain, specifically in the dorsal anterior cingulate cortex. Smoking may thereby increase vulnerability to infection and brain injury.

BackgroundGiven limited experience in applying the creatine-(methyl-D3) (D3Cr) dilution method to measure skeletal muscle mass (SMM) in young children, the feasibility of deployment in a fielding setting and performance of the method was assessed in a cohort of 4-year-old children in Dhaka, Bangladesh.MethodsFollowing D3Cr oral dose (10 mg) administration, single fasting urine samples were collected at 2-4 days (n = 100). Twenty-four-hour post-dose collections and serial spot urine samples on days 2, 3 and 4 were obtained in a subset of participants (n = 10). Urinary creatine, creatinine, D3Cr and D3-creatinine enrichment were analyzed by liquid chromatography-tandem mass spectrometry. Appendicular lean mass (ALM) was measured by dual-energy x-ray absorptiometry and grip strength was measured by a hand-held dynamometer.ResultsSMM was measured successfully in 91% of participants, and there were no adverse events. Mean ± SD SMM was greater than ALM (4.5 ± 0.4 and 3.2 ± 0.6 kg, respectively). Precision of SMM was low (intraclass correlation = 0.20; 95% CI: 0.02, 0.75; n = 10). Grip strength was not associated with SMM in multivariable analysis (0.004 kg per 100 g of SMM; 95% CI: -0.031, 0.038; n = 91).ConclusionsThe D3Cr dilution method was feasible in a community setting. However, high within-child variability in SMM estimates suggests the need for further optimization of this approach.ImpactThe D3-creatine (D3Cr) stable isotope dilution method was considered a feasible method for the estimation of skeletal muscle mass (SMM) in young children in a community setting and was well accepted among participants. SMM was weakly associated with both dual-energy x-ray absorptiometry-derived values of appendicular lean mass and grip strength. High within-child variability in estimated values of SMM suggests that further optimization of the D3Cr stable isotope dilution method is required prior to implementation in community research settings.

Developing accurate methods to quantify age-related muscle loss (sarcopenia) could greatly accelerate development of therapies to treat muscle loss in the elderly, as current methods are inaccurate or expensive. The current gold standard method for quantifying sarcopenia is dual-energy X-ray absorptiometry (DXA) but does not measure muscle directly-it is a composite measure quantifying lean mass (muscle) excluding fat and bone. In humans, DXA overestimates muscle mass, which has led to erroneous conclusions about the importance of skeletal muscle in human health and disease. In animal models, DXA is a popular method for measuring lean mass. However, instrumentation is expensive and is potentially limited by anesthesia concerns. Recently, the D3 -creatine (D3 Cr) dilution method for quantifying muscle mass was developed in humans and rats. This method is faster, cheaper, and more accurate than DXA. Here, we demonstrate that the D3 Cr method is a specific assay for muscle mass in mice, and we test associations with DXA and body weight. We evaluated the D3 Cr method compared to DXA-determined lean body mass (LBM) in aged mice and reported that DXA consistently overestimates muscle mass with age. Overall, we provide evidence that the D3 Cr dilution method directly measures muscle mass in mice. Combined with its ease of use, accessibility, and non-invasive nature, the method may prove to more quickly advance development of preclinical therapies targeting sarcopenia.

BackgroundAlthough proton magnetic resonance spectroscopy (MRS) has been used to study metabolite alterations in stimulant (methamphetamine and cocaine) substance use disorders (SUDs) for over 25 years, data-driven consensus regarding the nature and magnitude of these alterations is lacking.MethodIn this meta-analysis, we examined associations between SUD and regional metabolites (N-acetyl aspartate (NAA), choline, myo-inositol, creatine, glutamate, and glutamate+glutamine (glx)) in the medial prefrontal cortex (mPFC), frontal white matter (FWM), occipital cortex, and basal ganglia as measured by 1 H-MRS. We also examined moderating effects of MRS acquisition parameters (echo time (TE), field strength), data quality (coefficient of variation (COV)), and demographic/clinical variables.ResultsA MEDLINE search revealed 28 articles that met meta-analytic criteria. Significant effects included lower mPFC NAA, higher mPFC myo-inositol, and lower mPFC creatine in SUD relative to people without SUD. mPFC NAA effects were moderated by TE, with larger effects at longer TEs. For choline, although no group effects were observed, effect sizes in the mPFC were related to MRS technical indicators (field strength, COV). No effects of age, sex, primary drug of use (methamphetamine vs. cocaine), duration of use, or duration of abstinence were observed. Evidence for moderating effects of TE and COV may have implications for future MRS studies in SUDs.ConclusionsThe observed metabolite profile in methamphetamine and cocaine SUD (lower NAA and creatine with higher myo-inositol) parallels that observed in Alzheimer's disease and mild cognitive impairment, suggesting these drugs are associated with neurometabolic differences similar to those characterizing these neurodegenerative conditions.

BackgroundThe medial prefrontal cortex (mPFC) plays an important role in depression and addiction. Previous studies have shown alterations in glutamatergic activity in the mPFC following the administration of ketamine in patients with depression and healthy controls. However, it remains unclear whether chronic, nonmedical use of ketamine affects metabolites in the mPFC.MethodsUsing proton magnetic resonance spectroscopy, we measured metabolites (glutamate and glutamine [Glx]; phosphocreatine and creatine [PCr+Cr]; myo-inositol; N-acetyl-aspartate; and glycerophosphocholine and phosphocholine [GPC+PC]) in the mPFC of chronic ketamine users (n = 20) and healthy controls (n = 43). Among ketamine users, 60% consumed ketamine once per day or more, 10% consumed it every 2 days and 30% consumed it every 3 or more days. Using analysis of covariance, we evaluated between-group differences in the ratios of Glx:PCr+Cr, myo-inositol:PCr+Cr, N-acetyl-aspartate:PCr+Cr and GPC+PC:PCr+Cr.ResultsChronic ketamine users showed significantly higher Glx:PCr+Cr ratios than healthy controls (median 1.05 v. 0.95, p = 0.008). We found no significant differences in myoinositol:PCr+Cr, N-acetyl-aspartate:PCr+Cr or GPC+PC:PCr+Cr ratios between the 2 groups. We found a positive relationship between N-acetyl-aspartate:PCr+Cr and Glx:PCr+Cr ratios in the healthy control group (R = 0.345, p = 0.023), but the ketamine use group failed to show such an association (ρ = 0.197, p = 0.40).LimitationsThe cross-sectional design of this study did not permit causal inferences related to higher Glx:PCr+Cr ratios and chronic ketamine use.ConclusionThis study provides the first evidence that chronic ketamine users have higher glutamatergic activity in the mPFC than healthy controls; this finding may provide new insights relevant to the treatment of depression with ketamine.

Ibudilast, a neuroimmune modulator, shows promise as a pharmacotherapy for alcohol use disorder (AUD). In vivo administration of ibudilast reduces the expression of pro-inflammatory cytokines in animal models, but its effects on markers of inflammation in humans are unknown. This preliminary study examined the effect of ibudilast on peripheral and potential central markers of inflammation in individuals with AUD. This study also explored the predictive relationship of neurometabolite markers with subsequent drinking in the trial. Non-treatment-seeking individuals with an AUD (n = 52) were randomized to receive oral ibudilast (n = 24) or placebo (n = 28) for 2 weeks. Plasma levels of peripheral inflammatory markers were measured at baseline and after 1 and 2 weeks of medication. At study mid-point, proton magnetic resonance spectroscopy was performed to measure potential neurometabolite markers of inflammation: choline-compounds (Cho), myo-inositol (MI) and creatine + phosphocreatine (Cr) in frontal and cingulate cortices from 43 participants (ibudilast: n = 20; placebo: n = 23). The treatment groups were compared on peripheral and central markers. Ibudilast-treated participants had lower Cho in superior frontal white matter and nominally lower MI in pregenual anterior cingulate cortex. Ibudilast-treated participants had nominally lower C-reactive protein levels at visit 2 and nominally lower TNF-α/IL-10 ratios, relative to placebo. C-reactive protein and Cho levels were correlated, controlling for medication. Superior frontal white matter Cho predicted drinking in the following week. Micro-longitudinal ibudilast treatment may induce peripheral and putative central anti-inflammatory responses in patients with AUD. The neurometabolite responses may be associated with reduction in drinking, suggesting an anti-inflammatory component to the therapeutic action of ibudilast.

BackgroundAbnormalities in cardiac energy metabolism occur in heart failure (HF) and contribute to contractile dysfunction, but their role, if any, in HF-related pathologic remodeling is much less established. CK (creatine kinase), the primary muscle energy reserve reaction which rapidly provides ATP at the myofibrils and regenerates mitochondrial ADP, is down-regulated in experimental and human HF. We tested the hypotheses that pathologic remodeling in human HF is related to impaired cardiac CK energy metabolism and that rescuing CK attenuates maladaptive hypertrophy in experimental HF.MethodsFirst, in 27 HF patients and 14 healthy subjects, we measured cardiac energetics and left ventricular remodeling using noninvasive magnetic resonance 31P spectroscopy and magnetic resonance imaging, respectively. Second, we tested the impact of metabolic rescue with cardiac-specific overexpression of either Ckmyofib (myofibrillar CK) or Ckmito (mitochondrial CK) on HF-related maladaptive hypertrophy in mice.ResultsIn people, pathologic left ventricular hypertrophy and dilatation correlate closely with reduced myocardial ATP levels and rates of ATP synthesis through CK. In mice, transverse aortic constriction-induced left ventricular hypertrophy and dilatation are attenuated by overexpression of CKmito, but not by overexpression of CKmyofib. CKmito overexpression also attenuates hypertrophy after chronic isoproterenol stimulation. CKmito lowers mitochondrial reactive oxygen species, tissue reactive oxygen species levels, and upregulates antioxidants and their promoters. When the CK capacity of CKmito-overexpressing mice is limited by creatine substrate depletion, the protection against pathologic remodeling is lost, suggesting the ADP regenerating capacity of the CKmito reaction rather than CK protein per se is critical in limiting adverse HF remodeling.ConclusionsIn the failing human heart, pathologic hypertrophy and adverse remodeling are closely related to deficits in ATP levels and in the CK energy reserve reaction. CKmito, sitting at the intersection of cardiac energetics and redox balance, plays a crucial role in attenuating pathologic remodeling in HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00181259.

A complete characterization of neurometabolite profiles in the dorsolateral prefrontal cortex (DLPFC) in recent onset schizophrenia (SZ) remains elusive. Filling in this knowledge gap is essential in order to better understand how the neurochemistry of this region contributes to SZ pathology. To that end, DLPFC N-acetyl aspartate (NAA), myo-inositol, glutamate, choline, and creatine levels were examined by 3 T magnetic resonance spectroscopy (MRS) in recent onset individuals with SZ (n = 40) and healthy controls (HC) (n = 47). Metabolite levels were also examined in the visual cortex (VC) as a control region. People with SZ showed significantly higher choline in both the DLPFC and VC, but no differences in NAA, myo-inositol, glutamate, or creatine in either region. A trend-level negative correlation was also observed between DLPFC NAA and negative symptoms in SZ. Our results suggest that choline is increased in both the prefrontal and occipital cortices in recent onset SZ, and that DLPFC NAA levels may be inversely related to negative symptoms in the illness. The observed increase in choline-containing compounds in both DLPFC and VC in recent onset SZ could reflect increased membrane remodeling such as occurs in activated microglia and astrocytes in response to neuroinflammation.

Colorectal cancer (CRC) is a leading cause of cancer mortality. Creatine metabolism was previously shown to critically regulate colon cancer progression. We report that RGX-202, an oral small-molecule SLC6A8 transporter inhibitor, robustly inhibits creatine import in vitro and in vivo, reduces intracellular phosphocreatine and ATP levels, and induces tumor apoptosis. RGX-202 suppressed CRC growth across KRAS wild-type and KRAS mutant xenograft, syngeneic, and patient-derived xenograft (PDX) tumors. Antitumor efficacy correlated with tumoral expression of creatine kinase B. Combining RGX-202 with 5-fluorouracil or the DHODH inhibitor leflunomide caused regressions of multiple colorectal xenograft and PDX tumors of distinct mutational backgrounds. RGX-202 also perturbed creatine metabolism in patients with metastatic CRC in a phase 1 trial, mirroring pharmacodynamic effects on creatine metabolism observed in mice. This is, to our knowledge, the first demonstration of preclinical and human pharmacodynamic activity for creatine metabolism targeting in oncology, thus revealing a critical therapeutic target.

BACKGROUND: The D3-creatine (D3Cr) dilution method provides a direct measure of skeletal muscle. The aim of this study was to compare the association of D3Cr muscle mass with lean body mass (LBM) measured by dual-energy x-ray absorptiometry (DXA) and examine its relation with physical function in postmenopausal women. METHODS: Seventy-four community-dwelling women (mean age 82.3 ± 5.4) participated in this pilot study from the Buffalo, New York clinical site of the Womens Health Initiative (WHI). Participants attended a clinic visit which included anthropometric measures, blood draw, DXA scan, measures of physical function, and initiated the D3Cr protocol. Physical function was evaluated using hand grip strength, short physical performance battery (SPPB), and RAND-36 physical function scale. Descriptive statistics and logistic regression models were used to examine the associations of D3Cr muscle mass with functional outcomes. RESULTS: D3-creatine muscle mass was moderately correlated with DXA LBM (r = 0.50) and DXA appendicular lean mass (ALM) (r = 0.50). Individuals with high D3Cr muscle mass (%) had higher physical function compared to individuals with low muscle mass (%), indicated by high scores on SPPB (odds ratio [OR] = 5.24; 95% confidence interval [CI]: 1.40, 19.58). We observed stronger relationships between high D3Cr and physical function than either DXA LBM (OR = 3.40; 95% CI: 0.88, 13.11) or DXA ALM (OR = 4.15; 95% CI: 1.10, 15.68) and physical function. CONCLUSIONS: Our findings provide strong preliminary data for the associations of D3Cr muscle mass with measures of physical function in older women. These findings support and extend prior work on D3Cr muscle mass in older men.

Obesity increases the risk of mortality because of metabolic sequelae such as type 2 diabetes and cardiovascular disease1. Thermogenesis by adipocytes can counteract obesity and metabolic diseases2,3. In thermogenic fat, creatine liberates a molar excess of mitochondrial ADP-purportedly via a phosphorylation cycle4-to drive thermogenic respiration. However, the proteins that control this futile creatine cycle are unknown. Here we show that creatine kinase B (CKB) is indispensable for thermogenesis resulting from the futile creatine cycle, during which it traffics to mitochondria using an internal mitochondrial targeting sequence. CKB is powerfully induced by thermogenic stimuli in both mouse and human adipocytes. Adipocyte-selective inactivation of Ckb in mice diminishes thermogenic capacity, increases predisposition to obesity, and disrupts glucose homeostasis. CKB is therefore a key effector of the futile creatine cycle.

BackgroundWhether low muscle mass is a risk factor for disability and mortality is unclear. Associations between approximations of muscle mass (including lean mass from dual-energy x-ray absorptiometry [DXA]), and these outcomes are inconsistent.MethodsMuscle mass measured by deuterated creatine (D3Cr) dilution and appendicular lean mass (ALM, by DXA) were assessed at the Year 14 Visit (2014-2016) of the prospective Osteoporotic Fractures in Men study (N = 1,425, age 77-101 years). Disability in activities of daily living (ADLs), instrumental ADLs, and mobility tasks was self-reported at the Year 14 visit and 2.2 years later; deaths were centrally adjudicated over 3.3 years. Relative risks and 95% confidence intervals (CI) were estimated per standard deviation decrement with negative binomial, logistic regression, or proportional hazards models.ResultsIn age- and clinical center-adjusted models, the relative risks per decrement in D3Cr muscle mass/wgt was 1.9 (95% CI: 1.2, 3.1) for incident self-reported ADL disability; 1.5 (95% CI: 1.3, 1.9) for instrumental ADL disability; and 1.8 (95% CI: 1.5, 2.2) for mobility disability. In age-, clinical center-, and weight-adjusted models, the relative risks per decrement in D3Cr muscle mass was 1.8 (95% CI: 1.5, 2.2) for all-cause mortality. In contrast, lower DXA ALM was not associated with any outcome. Associations of D3Cr muscle mass with these outcomes were slightly attenuated after adjustment for confounding factors and the potentially mediating effects of strength and physical performance.ConclusionsLow muscle mass as measured by D3Cr dilution is a novel risk factor for clinically meaningful outcomes in older men.

Proton magnetic resonance spectroscopy (1H-MRS) of the fetal brain can be used to study emerging metabolite profiles in the developing brain. Identifying early deviations in brain metabolic profiles in high-risk fetuses may offer important adjunct clinical information to improve surveillance and management during pregnancy.ObjectiveTo investigate the normative trajectory of the fetal brain metabolites during the second half of gestation, and to determine the impact of using different Cramer-Rao Lower Bounds (CRLB) threshold on metabolite measurements using magnetic resonance spectroscopy.Study designWe prospectively enrolled 219 pregnant women with normal fetal ultrasound and biometric measures. We performed a total of 331 fetal 1H-MRS studies with gestational age in the rage of 18-39 weeks with 112 of the enrolled participants scanned twice. All the spectra in this study were acquired on a GE 1.5 T scanner using long echo-time of 144 ​ms and analyzed in LCModel.ResultsWe successfully acquired and analyzed fetal 1H-MRS with a success rate of 93%. We observed increases in total NAA, total creatine, total choline, scyllo inositol and total NAA-to-total choline ratio with advancing GA. Our results also showed faster increases in total NAA and total NAA-to-total choline ratio during the third trimester compared to the second trimester. We also observed faster increases in total choline and total NAA in female fetuses. Increasing the Cramer-Rao lower bounds threshold progressively from 100% to 40%-20% increased the mean metabolite concentrations and decreased the number of observations available for analysis.ConclusionWe report serial fetal brain biochemical profiles in a large cohort of health fetuses studied twice in gestation with a high success rate in the second and third trimester of pregnancy. We present normative in-vivo fetal brain metabolite trajectories over a 21-week gestational period which can be used to non-invasively measure and monitor brain biochemistry in the healthy and high-risk fetus.

The pathophysiology of sickle cell disease (SCD) includes vasculopathy as well as anaemia. Elevated plasma homocysteine is a risk factor for vascular disease and may be associated with increased risk of vascular complications in SCD patients. In the present study, microvascular characteristics were assessed in the bulbar conjunctiva of 18 paediatric and 18 adult SCD patients, using the non-invasive technique of computer-assisted intravital microscopy. A vasculopathy severity index (SI) was computed to quantify the degree of microvasculopathy in each patient. Plasma homocysteine and several of its determinants [serum folate and vitamin B12, plasma pyridoxal-5'-phosphate (vitamin B6 status) and creatinine (kidney function)] were measured. Age was strongly correlated with microvasculopathy in the SCD patients, with the SI increasing about 0·1 unit per one-year increase in age (P

BackgroundWe examined cross-sectional associations between dietary patterns, macronutrient intake, and measures of muscle mass and lean mass in older men.MethodsParticipants in the Osteoporotic Fractures in Men (MrOS) cohort (n = 903; mean ± SD age 84.2 ± 4 years) completed brief Block food frequency questionnaires (May 2014-May 2016); factor analysis was used to derive dietary patterns. The D3-creatine (D3Cr) dilution method was used to measure muscle mass; dual-energy x-ray absorptiometry (DXA) was used to measure appendicular lean mass (ALM). Generalized linear models were used to report adjusted means of outcomes by dietary pattern. Multiple linear regression models were used to determine associations between macronutrients and D3Cr muscle mass and DXA ALM. Multivariable models were adjusted for age, race, clinic site, education, depression, total energy intake, height, and percent body fat.ResultsGreater adherence to a Western dietary pattern (high factor loadings for red meat, fried foods, and high-fat dairy) was associated with higher D3Cr muscle mass (p-trend = .026). Adherence to the Healthy dietary pattern (high factor loadings for fruit, vegetables, whole grains, and lean meats) was not associated with D3Cr muscle mass or DXA ALM. Total protein (β = 0.09, 95% CI = 0.03, 0.14) and nondairy animal protein (β = 0.16, 95% CI = 0.10, 0.21) were positively associated with D3Cr muscle mass. Nondairy animal protein (β = 0.06, 95% CI = 0.002, 0.11) was positively associated with DXA ALM. Associations with other macronutrients were inconsistent.ConclusionsNondairy animal protein intake (within a Western dietary pattern and alone) was positively associated with D3Cr muscle mass in older men.

T cells demand massive energy to combat cancer; however, the metabolic regulators controlling antitumor T cell immunity have just begun to be unveiled. When studying nutrient usage of tumor-infiltrating immune cells in mice, we detected a sharp increase of the expression of a CrT (Slc6a8) gene, which encodes a surface transporter controlling the uptake of creatine into a cell. Using CrT knockout mice, we showed that creatine uptake deficiency severely impaired antitumor T cell immunity. Supplementing creatine to WT mice significantly suppressed tumor growth in multiple mouse tumor models, and the combination of creatine supplementation with a PD-1/PD-L1 blockade treatment showed synergistic tumor suppression efficacy. We further demonstrated that creatine acts as a "molecular battery" conserving bioenergy to power T cell activities. Therefore, our results have identified creatine as an important metabolic regulator controlling antitumor T cell immunity, underscoring the potential of creatine supplementation to improve T cell-based cancer immunotherapies.

ObjectiveTo determine the frontal lobe proton magnetic resonance spectroscopy (1H MRS) abnormalities in asymptomatic and symptomatic carriers of microtubule-associated protein tau (MAPT) mutations.MethodsWe recruited patients with MAPT mutations from 5 individual families, who underwent single voxel 1H MRS from the medial frontal lobe at 3T (n = 19) from the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Study at the Mayo Clinic site. Asymptomatic MAPT mutation carriers (n = 9) had Frontotemporal Lobar Degeneration Clinical Dementia Rating Sum of Boxes (FTLD-CDR SOB) score of zero, and symptomatic MAPT mutation carriers (n = 10) had a median FTLD-CDR SOB score of 5. Noncarriers from healthy first-degree relatives of the patients were recruited as controls (n = 25). The demographic aspects and 1H MRS metabolite ratios were compared by use of the Fisher exact test for sex and linear mixed models to account for within-family correlations. We used Tukey contrasts for pair-wise comparisons.ResultsAsymptomatic MAPT mutation carriers had lower neuronal marker N-acetylaspartate (NAA)/creatine (Cr) (p = 0.001) and lower NAA/myo-inositol (mI) (p = 0.026) than noncarriers after adjustment for age. Symptomatic MAPT mutation carriers had lower NAA/Cr (p = 0.01) and NAA/mI (p = 0.01) and higher mI/Cr (p = 0.02) compared to noncarriers after adjustment for age. Furthermore, NAA/Cr (p = 0.006) and NAA/mI (p < 0.001) ratios decreased, accompanied by an increase in mI/Cr ratio (p = 0.001), as the ages of carriers approached and passed the age at symptom onset.ConclusionFrontal lobe neurochemical alterations measured with 1H MRS precede the symptom onset in MAPT mutation carriers. Frontal lobe 1H MRS is a potential biomarker for early neurodegenerative processes in MAPT mutation carriers.

1H magnetic resonance spectroscopy (MRS) can reveal changes in brain biochemistry in vivo in humans and has been applied to late onset Alzheimer disease (AD). Carriers of mutations for autosomal dominant Alzheimer disease (ADAD) may show changes in levels of metabolites prior to the onset of clinical symptoms. Proton MR spectra were acquired at 1.5 T for 16 cognitively asymptomatic or mildly symptomatic mutation carriers (CDR

Metastasis is the major cause for breast cancer related mortality. The combination of miRNA-based therapy and chemotherapy represents a promising approach against breast cancer lung metastasis. The goal of this study is to develop an improved therapy that co-delivers a novel bioengineered miRNA prodrug (tRNA-mir-34a) and doxorubicin (DOX) via a multifunctional nanomicellar carrier that is based on a conjugate of amphiphilic copolymer POEG-VBC backbone with creatine, a naturally occurring cationic molecule. Co-delivery of DOX leads to more effective processing of tRNA-mir-34a into mature miR-34a and down-regulation of target genes. DOX + tRNA-mir-34a/POEG-PCre exhibits potent synergistic anti-tumor and anti-metastasis activity in vitro and in vivo. Interestingly, the enhanced immune response contributes to the overall antitumor efficacy. POEG-PCre may represent a safe and effective delivery system for an optimal chemo-gene combination therapy.

Sarcopenia has been described as the age-associated decrease in skeletal muscle mass. However, virtually every study of sarcopenia has measured lean body mass (LBM) or fat free mass (FFM) rather than muscle mass, specifically. In a number of published sarcopenia studies, LBM or FFM is referred to as muscle mass, leading to an incorrect assumption that measuring LBM or FFM is an accurate measure of muscle mass. As a result, the data on the effects of changes in LBM or FFM in older populations on outcomes such as functional capacity, disability, and risk of injurious falls have been inconsistent resulting in the conclusion that muscle mass is only weakly related to these outcomes. We review and describe the assumptions for the most commonly used measurements of body composition. Dual-energy X-ray absorptiometry (DXA) has become an increasingly common tool for the assessment of LBM or FFM and appendicular lean mass as a surrogate, but inaccurate, measurement of muscle mass. Other previously used methods (total body water, bioelectric impedance, and imaging) also have significant limitations. D3 -Creatine (D3 -Cr) dilution provides a direct and accurate measurement of creatine pool size and skeletal muscle mass. In a recent study in older men (MrOS cohort), D3 -Cr muscle mass was associated with functional capacity and risk of injurious falls and disability, while assessments of LBM or appendicular lean mass by DXA were only weakly or not associated with these outcomes. Inaccurate measurements of muscle mass by DXA and other methods have led to inconsistent results and potentially erroneous conclusions about the importance of skeletal muscle mass in health and disease. The assessment of skeletal muscle mass using the D3 -Cr dilution method in prospective cohort studies may reveal sarcopenia as a powerful risk factor for late life disability and chronic disease.

HIV-associated neurocognitive disorders (HANDs) persist even with virologic suppression on combination antiretroviral therapy (cART), and the underlying pathophysiological mechanisms are not well understood. We performed structural magnetic resonance imaging and MR spectroscopy (MRS) in HIV+ individuals without major neurocognitive comorbidities. Study participants were classified as neurocognitively unimpaired (NU), asymptomatic (ANI), mild neurocognitive disorder (MND), or HIV-associated dementia (HAD). Using structural MRI, we measured volumes of cortical and subcortical gray matter and total and abnormal white matter (aWM). Using single-voxel MRS, we estimated metabolites in frontal gray matter (FGM) and frontal white matter (FWM) and basal ganglia (BG) regions. Adjusted odds ratios were used to compare HAND to NU. Among 253 participants, 40% met HAND criteria (21% ANI, 15% MND, and 4% HAD). Higher risk of HAND was associated with more aWM. Both HAD and MND also had smaller gray and white matter volumes than NU. Among individuals with undetectable plasma HIV RNA, structural volumetric findings were similar to the overall sample. MND had lower FWM creatine and higher FGM choline relative to NU, whereas HAD and ANI had lower BG N-acetyl aspartate relative to NU. In the virologically suppressed subgroup, however, ANI and MND had higher FGM choline compared to NU. Overall, HAND showed specific alterations (more aWM and inflammation; less gray matter volume and lower NAA). Some MR measures differentiated less severe subtypes of HAND from HAD. These MR alterations may represent legacy effects or accumulating changes, possibly related to medical comorbidities, antiretroviral therapy, or chronic effects of HIV brain infection.

BackgroundDetection of chronic kidney disease (CKD) with urine albumin-to-creatinine ratio (UACR) among patients with hypertension (HTN) provides an opportunity for early treatment, potentially mitigating risk of CKD progression and cardiovascular complications. Differences in UACR testing patterns among racial/ethnic populations at risk for CKD could contribute to known disparities in CKD complications.MethodsWe examined the prevalence of UACR testing among low-income adult primary care patients with HTN, defined by a new administrative code for HTN or 2 clinic blood pressures >140/90 mm Hg between January 1, 2014, and January 1, 2017, in one public health-care delivery system with a high prevalence of end-stage kidney disease among race/ethnic minorities. Logistic regression was used to identify odds of UACR testing within 1 year of a HTN diagnosis, overall, and by racial/ethnic subgroup, adjusted for demographic factors, estimated glomerular filtration rate, and HTN severity. Models were also stratified by diabetes status.ResultsThe cohort (n = 16,414) was racially/ethnically diverse (16% White, 21% Black, 34% Asian, 19% Hispanic, and 10% other) and 51% female. Only 35% of patients had UACR testing within 1 year of a HTN diagnosis. Among individuals without diabetes, odds of UACR testing were higher among Asians, Blacks, and Other subgroups compared to Whites (adjusted OR [aOR] 1.19; 95% CI 1.00-1.42 for Blacks; aOR 1.33; 1.13-1.56 for Asians; aOR 1.30; 1.04-1.60 for Other) but were not significantly different between Hispanics and Whites (aOR 1.17; 0.97-1.39). Among individuals with diabetes, only Asians had higher odds of UACR testing compared to Whites (aOR 1.35; 1.12-1.63).ConclusionsPrevalence of UACR testing among low-income patients with HTN is low in one public health-care delivery system, with higher odds of UACR testing among racial/ethnic minority subgroups compared to Whites without diabetes and similar odds among those with diabetes. If generalizable, less albuminuria testing may not explain higher prevalence of kidney failure in racial/ethnic minorities.

BackgroundRenal insufficiency is associated with pregnancy complications including fetal growth restriction, preterm birth (PTB), and pre-eclampsia.ObjectiveTo determine the effect of preconception kidney function within the normal range on pregnancy outcome.Method1043 (50% black, 50% white) women who participated in the CARDIA study who had kidney function and biochemical analyses measured before at least one pregnancy delivered during the 20 years post-baseline period were included in analysis. Kidney function estimated as glomerular filtration rate (eGFR) via modified CKD-EPI equations, serum creatinine, and urinary albumin/creatinine ratio were evaluated as predictors of infant birthweight, gestational age, birthweight-for-gestational-age, and hypertensive disorders of pregnancy via self-report, using multiple regression with adjustment for confounders (age, race, smoking, BMI, center, parity, systolic blood pressure at baseline). Serum uric acid was also examined at both baseline and year 10.ResultsUnadjusted pre-pregnancy eGFR (baseline) was associated with lower average birthweight-for-gestational-age, but this disappeared after adjustment for confounders. A decline in GFR from baseline to year 10 was associated with lower birthweight (adjusted estimate -195 g, p = 0.03 overall), especially among whites. After adjustment for confounders, no association was found with gestational age or hypertensive disorders.ConclusionsNo strong evidence for an association between preconception kidney function in the normal range and birthweight or gestational age was found. Possible racial differences in these relationships warrant further examination.

BACKGROUND:Previous studies have linked cardiac dysfunction to loss of metabolites in the creatine kinase system. Chemical exchange saturation transfer (CEST) is a promising metabolic cardiovascular magnetic resonance (CMR) imaging technique and has been applied in the heart for creatine mapping. However, current limitations include: (a) long scan time, (b) residual cardiac and respiratory motion, and (c) B0 field variations induced by respiratory motion. An improved CEST CMR technique was developed to address these problems. METHODS:Animals with chronic myocardial infarction (N = 15) were scanned using the proposed CEST CMR technique and a late gadolinium enhancement (LGE)  sequence as reference. The major improvements of the CEST CMR technique are: (a) Images were acquired by single-shot FLASH, significantly increasing the scan efficiency. (b) All images were registered to reduce the residual motion. (c) The acquired Z-spectrum was analyzed using 3-pool-model Lorentzian-line fitting to generate CEST signal, reducing the impact of B0 field shifting due to respiratory motion. Feasibility of the technique was tested in a porcine model with chronic myocardial infarction. CEST signal was measured in the scar, border zone and remote myocardium. Initial studies were performed in one patient. RESULTS:In all animals, healthy remote myocardial CEST signal was elevated (0.16 ± 0.02) compared to infarct CEST signal (0.09 ± 0.02, P

ObjectiveTo explore the association between metabolic syndrome and the Unified Parkinson's Disease Rating Scale (UPDRS) scores and, secondarily, the Symbol Digit Modalities Test (SDMT).MethodsThis is a secondary analysis of data from 1,022 of 1,741 participants of the National Institute of Neurological Disorders and Stroke Exploratory Clinical Trials in Parkinson Disease Long-Term Study 1, a randomized, placebo-controlled trial of creatine. Participants were categorized as having or not having metabolic syndrome on the basis of modified criteria from the National Cholesterol Education Program Adult Treatment Panel III. Those who had the same metabolic syndrome status at consecutive annual visits were included. The change in UPDRS and SDMT scores from randomization to 3 years was compared in participants with and without metabolic syndrome.ResultsParticipants with metabolic syndrome (n = 396) compared to those without (n = 626) were older (mean [SD] 63.9 [8.1] vs 59.9 [9.4] years; p < 0.0001), were more likely to be male (75.3% vs 57.0%; p < 0.0001), and had a higher mean uric acid level (men 5.7 [1.3] vs 5.3 [1.1] mg/dL, women 4.9 [1.3] vs 3.9 [0.9] mg/dL, p < 0.0001). Participants with metabolic syndrome experienced an additional 0.6- (0.2) unit annual increase in total UPDRS (p = 0.02) and 0.5- (0.2) unit increase in motor UPDRS (p = 0.01) scores compared with participants without metabolic syndrome. There was no difference in the change in SDMT scores.ConclusionsPersons with Parkinson disease meeting modified criteria for metabolic syndrome experienced a greater increase in total UPDRS scores over time, mainly as a result of increases in motor scores, compared to those who did not. Further studies are needed to confirm this finding.Clinicaltrialsgov identifierNCT00449865.

Study designA single-center magnetic resonance spectroscopy (MRS) imaging and surgical outcome study involving 16 patients with cervical spondylotic myelopathy (CSM).ObjectiveIn the present study, we assess the utility of MRS to quantify metabolic changes within the spinal cord and predict surgical outcome in CSM patients.Summary of background dataMRS is an advanced spinal imaging modality that can provide pertinent metabolic and biochemical information regarding spinal cord function. Previous studies have demonstrated significant abnormalities in specific cellular metabolite concentrations in CSM patients.MethodsSixteen patients with CSM were evaluated. Single voxel MRS was performed in the cervical cord. N-acetyl-aspartate (NAA) and choline metabolite concentration ratios with respect to creatine were quantified, as well as the presence or absence of a lactate peak. The modified Japanese Orthopaedic Association (mJOA) scale was used as the functional assessment measure. Correlation of MRS metabolites with change in mJOA score was performed.ResultsThe mean follow-up time was 19 months. There was a statistically significant improvement between mean preoperative and postoperative mJOA score after surgery (P

Caffeine is neuroprotective in animal models of Parkinson's disease (PD) and caffeine intake is inversely associated with the risk of PD. This association may be influenced by the genotype of GRIN2A, which encodes an NMDA-glutamate-receptor subunit. In two placebo-controlled studies, we detected no association of caffeine intake with the rate of clinical progression of PD, except among subjects taking creatine, for whom higher caffeine intake was associated with more rapid progression. We now have analyzed data from 420 subjects for whom DNA samples and caffeine intake data were available from a placebo-controlled study of creatine in PD. The GRIN2A genotype was not associated with the rate of clinical progression of PD in the placebo group. However, there was a 4-way interaction between GRIN2A genotype, caffeine, creatine and the time since baseline. Among subjects in the creatine group with high levels of caffeine intake, but not among those with low caffeine intake, the GRIN2A T allele was associated with more rapid progression (p=0.03). These data indicate that the deleterious interaction between caffeine and creatine with respect to rate of progression of PD is influenced by GRIN2A genotype. This example of a genetic factor interacting with environmental factors illustrates the complexity of gene-environment interactions in the progression of PD.

BackgroundThe heterogeneous biology of glioblastoma (GBM) emphasizes the need for imaging methods to assess tumor burden and assist in evaluating individual patients. The purpose of this study was to investigate early changes in metrics from 3D 1H magnetic resonance spectroscopic imaging (MRSI) data, compare them with anatomic lesion volumes, and determine whether they were associated with survival for patients with newly diagnosed GBM receiving a multimodality treatment regimen.MethodsSerial MRI and MRSI scans provided estimates of anatomic lesion volumes and levels of choline, creatine, N-acetylaspartate, lactate, and lipid. The association of metrics derived from these data with survival was assessed using Cox proportional hazards models with adjustments for age, Karnofsky performance score, and extent of resection. Temporal changes in parameters were evaluated using a Wilcoxon signed rank test.ResultsAnatomic lesion volumes at the post-radiotherapy (RT) scan, metabolic lesion volume at mid-RT and post-RT scans, as well as metrics describing levels of choline, lactate, and lipid were associated with overall survival. There was a significant reduction in the enhancing lesion volume, increase in T2 lesion volume from mid-RT to post-RT, and decrease in parameters describing metabolite levels during these early time points.ConclusionThe MRSI data provided metrics that described the effects of treatment on the metabolic lesion burden and were associated with overall survival. This suggests that adding these parameters to standard assessments of changes in anatomic lesion volumes could contribute to making early decisions about the efficacy of such combination therapies.

A single center magnetic resonance spectroscopy (MRS) imaging and surgical outcome study involving sixteen patients with cervical spondylotic myelopathy (CSM).In the present study, we assess the utility of MRS to quantify metabolic changes within the spinal cord and predict surgical outcome in CSM patients.MRS is an advanced spinal imaging modality that can provide pertinent metabolic and biochemical information regarding spinal cord function. Previous studies have demonstrated significant abnormalities in specific cellular metabolite concentrations in CSM patients.Sixteen patients with CSM were evaluated. Single voxel MRS was performed in the cervical cord. NAA and choline metabolite concentration ratios with respect to creatine were quantified, as well as the presence or absence of a lactate peak. The mJOA scale was used as the functional assessment measure. Correlation of MRS metabolites with change in mJOA score was performed.The mean follow-up time was 19 months. There was a statistically significant improvement between mean preoperative and postoperative mJOA score following surgery (P

Hodgkin lymphoma post-transplant lymphoproliferative disorder (HL-PTLD) is an uncommon PTLD with unclear prognosis and differences between HL-PTLD and immunocompetent HL are not well defined. Patient characteristics were compared among 192 patients with HL-PTLD from the Scientific Registry of Transplant Recipients and 13,847 HL patients in SEER (HL-SEER). Overall survival (OS) and disease-specific survival (DSS) were compared after exact matching. Additionally, multivariable analyses were used to identify prognostic markers of survival and associations between treatment and survival. Median time from transplant to HL-PTLD diagnosis was 88 months. When compared with HL-SEER, patients with HL-PTLD were older (median age, 52 vs. 36 years, P = 0.001), more likely male (73% vs. 54%, P

Several different pathologies, including many neurodegenerative disorders, affect the energy metabolism of the brain. Glutamate, a neurotransmitter in the brain, can be used as a biomarker to monitor these metabolic processes. One method that is capable of quantifying glutamate concentration reliably in several regions of the brain is TE-averaged (1) H spectroscopic imaging. However, this type of method requires the acquisition of multiple TE lines, resulting in long scan durations. The goal of this experiment was to use non-uniform sampling, compressed sensing reconstruction and an echo planar readout gradient to reduce the scan time by a factor of eight to acquire TE-averaged spectra in three spatial dimensions. Simulation of glutamate and glutamine showed that the 2.2-2.4 ppm spectral region contained 95% glutamate signal using the TE-averaged method. Peak integration of this spectral range and home-developed, prior-knowledge-based fitting were used for quantitation. Gray matter brain phantom measurements were acquired on a Siemens 3 T Trio scanner. Non-uniform sampling was applied retrospectively to these phantom measurements and quantitative results of glutamate with respect to creatine 3.0 (Glu/Cr) ratios showed a coefficient of variance of 16% for peak integration and 9% for peak fitting using eight-fold acceleration. In vivo scans of the human brain were acquired as well and five different brain regions were quantified using the prior-knowledge-based algorithm. Glu/Cr ratios from these regions agreed with previously reported results in the literature. The method described here, called accelerated TE-averaged echo planar spectroscopic imaging (TEA-EPSI), is a significant methodological advancement and may be a useful tool for categorizing glutamate changes in pathologies where affected brain regions are not known a priori. Copyright © 2016 John Wiley & Sons, Ltd.

PurposeTo measure cerebral metabolite levels in perinatally HIV-infected youths and healthy controls using the accelerated five dimensional (5D) echo planar J-resolved spectroscopic imaging (EP-JRESI) sequence, which is capable of obtaining two dimensional (2D) J-resolved spectra from three spatial dimensions (3D).Materials and methodsAfter acquisition and reconstruction of the 5D EP-JRESI data, T1-weighted MRIs were used to classify brain regions of interest for HIV patients and healthy controls: right frontal white (FW), medial frontal gray (FG), right basal ganglia (BG), right occipital white (OW), and medial occipital gray (OG). From these locations, respective J-resolved and TE-averaged spectra were extracted and fit using two different quantitation methods. The J-resolved spectra were fit using prior knowledge fitting (ProFit) while the TE-averaged spectra were fit using the advanced method for accurate robust and efficient spectral fitting (AMARES).ResultsQuantitation of the 5D EP-JRESI data using the ProFit algorithm yielded significant metabolic differences in two spatial locations of the perinatally HIV-infected youths compared to controls: elevated NAA/(Cr+Ch) in the FW and elevated Asp/(Cr+Ch) in the BG. Using the TE-averaged data quantified by AMARES, an increase of Glu/(Cr+Ch) was shown in the FW region. A strong negative correlation (r < -0.6) was shown between tCh/(Cr+Ch) quantified using ProFit in the FW and CD4 counts. Also, strong positive correlations (r > 0.6) were shown between Asp/(Cr+Ch) and CD4 counts in the FG and BG.ConclusionThe complimentary results using ProFit fitting of J-resolved spectra and AMARES fitting of TE-averaged spectra, which are a subset of the 5D EP-JRESI acquisition, demonstrate an abnormal energy metabolism in the brains of perinatally HIV-infected youths. This may be a result of the HIV pathology and long-term combinational anti-retroviral therapy (cART). Further studies of larger perinatally HIV-infected cohorts are necessary to confirm these findings.

ObjectiveIncreased caffeine intake is associated with a lower risk of Parkinson disease (PD) and is neuroprotective in mouse models of PD. However, in a previous study, an exploratory analysis suggested that, in patients taking creatine, caffeine intake was associated with a faster rate of progression. In the current study, we investigated the association of caffeine with the rate of progression of PD and the interaction of this association with creatine intake.MethodsData were analyzed from a large phase 3 placebo-controlled clinical study of creatine as a potentially disease-modifying agent in PD. Subjects were recruited for this study from 45 movement disorders centers across the United States and Canada. A total of 1741 subjects with PD participated in the primary clinical study, and caffeine intake data were available for 1549 of these subjects. The association of caffeine intake with rate of progression of PD as measured by the change in the total Unified Parkinson Disease Rating Scale score and the interaction of this association with creatine intake were assessed.ResultsCaffeine intake was not associated with the rate of progression of PD in the main analysis, but higher caffeine intake was associated with significantly faster progression among subjects taking creatine.ConclusionsThis is the largest and longest study conducted to date that addresses the association of caffeine with the rate of progression of PD. These data indicate a potentially deleterious interaction between caffeine and creatine with respect to the rate of progression of PD.

ImportanceThere are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies.ObjectiveTo determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease.Design, setting, and patientsThe Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013.InterventionsParticipants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years).Main outcomes and measuresThe primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5-4775) indicate worse outcomes.ResultsThe trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249-2470) and for creatine was 2414 (95% CI, 2304-2524). The global statistical test yielded t1865.8 = -0.75 (2-sided P = .45). There were no detectable differences (P

Posttraumatic stress disorder (PTSD) patients have low cortical concentrations of γ-aminobutyric acid (GABA) and elevated glutamate (Glu) as measured by proton magnetic resonance spectroscopy ((1)H MRS). Alcohol use disorder (AUD) is highly comorbid with PTSD, but the neurobiological underpinnings are largely unknown. We wanted to determine if PTSD patients with AUD have normalized cortical GABA and Glu levels in addition to metabolite alterations common to AUD. We compared brain metabolite concentrations in 10 PTSD patients with comorbid AUD (PAUD) with concentrtations in 28 PTSD patients without AUD and in 20 trauma-exposed controls (CON) without PTSD symptoms. We measured concentrations of GABA, Glu, N-acetylaspartate (NAA), creatine- (Cr) and choline-containing metabolites (Cho), and myo-Inositol (mI) in three cortical brain regions using (1)H MRS and correlated them with measures of neurocognition, insomnia, PTSD symptoms, and drinking severity. In contrast to PTSD, PAUD exhibited normal GABA and Glu concentrations in the parieto-occipital and temporal cortices, respectively, but lower Glu and trends toward higher GABA levels in the anterior cingulate cortex (ACC). Temporal NAA and Cho as well as mI in the ACC were lower in PAUD than in both PTSD and CON. Within PAUD, more cortical GABA and Glu correlated with better neurocognition. Heavy drinking in PTSD is associated with partially neutralized neurotransmitter imbalance, but also with neuronal injury commonly observed in AUD.

Autonomic, pain, and neuropsychologic comorbidities appear in heart failure (HF), likely resulting from brain changes, indicated as loss of structural integrity and functional deficits. Among affected brain sites, the anterior insulae are prominent in serving major regulatory roles in many of the disrupted functions commonly seen in HF. Metabolite levels, including N-acetylaspartate (NAA), creatine (Cr), choline (Cho), and myo-inositol (MI), could indicate the nature of anterior insula tissue injury in HF. The study aim was to assess anterior insular metabolites to determine processes mediating autonomic, pain, and neuropsychologic disruptions in HF. We performed magnetic resonance spectroscopy in bilateral anterior insulae in 11 HF and 53 controls, using a 3.0-Tesla magnetic resonance imaging scanner. Peaks for NAA at 2.02 ppm, Cr at 3.02 ppm, Cho at 3.2 ppm, and MI at 3.56 ppm were assigned, peak areas were calculated, and metabolites were expressed as ratios, including NAA/Cr, Cho/Cr, and MI/Cr. HF patients showed significantly increased Cho/Cr ratios, indicative of glial proliferation or injury, on the left anterior insula, and reduced NAA/Cr levels, suggesting neuronal loss/dysfunction, on the right anterior insula over controls. No differences in MI/Cr ratios appeared between groups. Right anterior insular neuronal loss and left glial alterations may contribute to distorted autonomic, pain, and neuropsychologic functions found in HF.

A current limitation of MR spectroscopic imaging of multiple skeletal muscles is prolonged scan duration. A significant reduction in the total scan duration using the echo-planar correlated spectroscopic imaging (EP-COSI) sequence was accomplished using two bipolar readout trains with different phase-encoded echoes for one of two spatial dimensions within a single repetition time (TR). The second bipolar readout was used for spatially encoding the outer k-space, whereas the first readout was used for the central k-space only. The performance of this novel sequence, called multi-echo based echo-planar correlated spectroscopic imaging (ME-EPCOSI), was demonstrated by localizing specific key features in calf muscles and bone marrow of 11 healthy volunteers and five subjects with type 2 diabetes (T2D). A 3 T MRI-MRS scanner equipped with a transmit-receive extremity coil was used. Localization of the ME-EPCOSI sequence was in good agreement with the earlier single-readout based EP-COSI sequence and the required scan time was reduced by a factor of two. In agreement with an earlier report using single-voxel based 2D MRS, significantly increased unsaturated pools of intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) and decreased IMCL and EMCL unsaturation indices (UIs) were observed in the soleus and tibialis anterior muscle regions of subjects with T2D compared with healthy controls. In addition, significantly decreased choline content was observed in the soleus of T2D subjects compared with healthy controls. Multi-voxel characterization of IMCL and EMCL ratios and UI in the calf muscle may be useful for the non-invasive assessment of altered lipid metabolism in the pathophysiology of T2D.

Study objectiveAdults with obstructive sleep apnea (OSA) show significant autonomic and neuropsychologic deficits, which may derive from damage to insular regions that serve those functions. The aim was to assess glial and neuronal status from anterior insular metabolites in OSA versus controls, using proton magnetic resonance spectroscopy (PMRS), and thus to provide insights for neuroprotection against tissue changes, and to reduce injury consequences.DesignCross-sectional study.SettingUniversity-based medical center.ParticipantsThirty-six patients with OSA, 53 controls.InterventionsNone.Measurements and resultsWe performed PMRS in bilateral anterior insulae using a 3.0-Tesla magnetic resonance imaging scanner, calculated N-acetylaspartate/creatine (NAA/Cr), choline/creatine (Cho/Cr), myo-inositol/creatine (MI/Cr), and MI/NAA metabolite ratios, and examined daytime sleepiness (Epworth Sleepiness Scale, ESS), sleep quality (Pittsburgh Sleep Quality Index, PSQI), and neuropsychologic status (Beck Depression Inventory II [BDI-II] and Beck Anxiety Inventory [BAI]). Body mass index, BAI, BDI-II, PSQI, and ESS significantly differed between groups. NAA/ Cr ratios were significantly reduced bilaterally, and left-sided MI/Cr and MI/NAA ratios were increased in OSA over controls. Significant positive correlations emerged between left insular MI/Cr ratios and apnea-hypopnea index values, right insular Cho/Cr ratios and BDI-II and BAI scores, and negative correlations appeared between left insular NAA/Cr ratios and PSQI scores and between right-side MI/Cr ratios and baseline and nadir change in O2 saturation.ConclusionsAdults with obstructive sleep apnea showed bilaterally reduced N-acetylaspartate and left-side increased myo-inositol anterior insular metabolites, indicating neuronal damage and increased glial activation, respectively, which may contribute to abnormal autonomic and neuropsychologic functions in the condition. The activated glial status likely indicates increased inflammatory action that may induce more neuronal injury, and suggests separate approaches for glial and neuronal protection.

PurposeAdvances in supportive care and ventilator management for acute respiratory distress syndrome (ARDS) have resulted in declines in short-term mortality, but risks of death after survival to hospital discharge have not been well described. Our objective was to quantify the difference between short-term and long-term mortality in ARDS and to identify risk factors for death and causes of death at 1 year among hospital survivors.MethodsThis multi-intensive care unit, prospective cohort included patients with ARDS enrolled between January 2006 and February 2010. We determined the clinical characteristics associated with in-hospital and 1-year mortality among hospital survivors and utilized death certificate data to identify causes of death.ResultsOf 646 patients hospitalized with ARDS, mortality at 1 year was substantially higher (41 %, 95% CI 37-45%) than in-hospital mortality (24%, 95% CI 21-27%), P < 0.0001. Among 493 patients who survived to hospital discharge, the 110 (22%) who died in the subsequent year were older (P < 0.001) and more likely to have been discharged to a nursing home, other hospital, or hospice compared to patients alive at 1 year (P < 0.001). Important predictors of death among hospital survivors were comorbidities present at the time of ARDS, and not living at home prior to admission. ARDS-related measures of severity of illness did not emerge as independent predictors of mortality in hospital survivors.ConclusionsDespite improvements in short-term ARDS outcomes, 1-year mortality is high, mostly because of the large burden of comorbidities, which are prevalent in patients with ARDS.

The goal of this study was to correlate prostatic metabolite concentrations from snap-frozen patient biopsies of recurrent cancer after failed radiation therapy with histopathological findings, including Ki-67 immunohistochemistry and pathologic grade, in order to identify quantitative metabolic biomarkers that predict for residual aggressive versus indolent cancer. A total of 124 snap-frozen transrectal ultrasound (TRUS)-guided biopsies were acquired from 47 men with untreated prostate cancer and from 39 men with a rising prostate-specific antigen and recurrent prostate cancer following radiation therapy. Biopsy tissues with Ki-67 labeling index ≤ 5% were classified as indolent cancer, while biopsy tissues with Ki-67 labeling index > 5% were classified as aggressive cancer. The majority (15 out of 17) of cancers classified as aggressive had a primary Gleason 4 pattern (Gleason score ≥ 4 + 3). The concentrations of choline-containing phospholipid metabolites (PC, GPC, and free Cho) and lactate were significantly elevated in recurrent cancer relative to surrounding benign tissues. There was also a significant increase in [PC] and reduction in [GPC] between untreated and irradiated prostate cancer biopsies. The concentration of the choline-containing phospholipid metabolites was significantly higher in recurrent aggressive (≈ twofold) than in recurrent indolent cancer biopsies, and the receiver operating characteristic (ROC) curve analysis of total choline to creatine ratio (tCho/Cr) demonstrated an accuracy of 95% (confidence interval = 0.88-1.00) for predicting aggressive recurrent disease. The tCho/Cr was significantly higher for identifying recurrent aggressive versus indolent cancer (tCho/Cr = 2.4 ± 0.4 versus 1.5 ± 0.2), suggesting that use of a higher threshold tCho/Cr ratio in future in vivo (1)H MRSI studies could improve the selection and therapeutic planning for patients who would benefit most from salvage focal therapy after failed radiation therapy.

Study designA single-center magnetic resonance imaging and spectroscopic study involving 21 patients with advanced cervical spondylosis and 11 healthy controls.ObjectiveWe assessed the utility of magnetic resonance spectroscopy (MRS) to quantify biochemical changes within the spinal cord and serve as a potential biomarker in patients with cervical spondylosis with or without T2 hyperintensity within the cord.SettingLos Angeles, California, USA.MethodsTwenty-one patients with cervical spondylosis and eleven healthy controls were evaluated. Single-voxel MRS was performed in the cervical cord. Morphometry of the spinal canal space was measured. N-Acetyl aspartylglutamic acid (NAA), choline (Cho), myo-inositol (Myo-I), glutamine-glutamate complex (Glx) and lactate metabolite concentration ratios with respect to total creatine (Cr) were quantified using an LC model algorithm and compared between healthy controls and spondylosis patients. Correlation of MRS metabolites with modified Japanese Orthopaedic Association (mJOA) score was also performed.ResultsThe spinal canal space was significantly different between patients and controls (analysis of variance (ANOVA), P

BackgroundStudies have shown that individuals with schizophrenia suffer from memory impairments. In this study, we combined proton magnetic resonance spectroscopy (¹H-MRS) and functional magnetic resonance imaging (fMRI) to clarify the neurobiology of memory deficits in schizophrenia.MethodsWe used single-voxel MRS acquired in the left hippocampus and fMRI during performance of a memory task to obtain measures of neurochemistry and functional response in 28 stable, medicated participants with schizophrenia (SZ) and 28 matched healthy controls (HC).ResultsThe SZ group had significantly decreased blood oxygen level-dependent (BOLD) signal in left inferior frontal gyrus (IFG) during encoding and in the anterior cingulate cortex (ACC) and superior temporal gyrus (STG) during retrieval. We did not find significant differences in N-acetylaspartate/creatine (NAA/Cr) or glutamate+glutamine (Glx/Cr) levels between the groups, but did find a significant positive correlation between NAA/Cr and Glx/Cr in the HC group that was absent in the SZ group. There were no significant correlations between BOLD and MRS measured in the hippocampus. Further analyses revealed a negative correlation between left IFG BOLD and task performance in the SZ group. Finally, in the HC group, the left IFG BOLD was positively correlated with Glx/Cr.ConclusionsWe replicated findings of reduced BOLD signal in left IFG and of an altered relationship between IFG BOLD response and task performance in the SZ. The absence of correlation between NAA/Cr and Glx/Cr levels in patients might suggest underlying pathologies of the glutamate-glutamine cycle and/or mitochondria.