Exercise modifies hypothalamic connectivity and brain functional networks in women after bariatric surgery: a randomized clinical trial.

BACKGROUND: Obesity is a disease that may involve disrupted connectivity of brain networks. Bariatric surgery is an effective treatment for obesity, and the positive effects on obesity-related conditions may be enhanced by exercise. Herein, we aimed to investigate the possible synergistic effects of Roux-en-Y Gastric Bypass (RYGB) and exercise training on brain functional networks. METHODS: Thirty women eligible for bariatric surgery were randomly assigned to a Roux-en-Y gastric bypass (RYGB: n = 15, age = 41.0 ± 7.3 years) or RYGB plus Exercise Training (RYGB + ET: n = 15, age = 41.9 ± 7.2 years). Clinical, laboratory, and brain functional connectivity parameters were assessed at baseline, and 3 (POST3) and 9 months (POST9) after surgery. The 6-month, three-times-a-week, exercise intervention (resistance plus aerobic exercise) was initiated 3 months post-surgery (for RYGB + ET). RESULTS: Exercise superimposed on bariatric surgery (RYGB + ET) increased connectivity between hypothalamus and sensorial regions (seed-to-voxel analyses of hypothalamic connectivity), and decreased default mode network (DMN) and posterior salience (pSAL) network connectivity (ROI-to-ROI analyses of brain networks connectivity) when compared to RYGB alone (all p-FDR < 0.05). Increases in basal ganglia (BG) network connectivity were only observed in the exercised training group (within-group analyses). CONCLUSION: Exercise training is an important component in the management of post-bariatric patients and may improve the hypothalamic connectivity and brain functional networks that are involved in controlling food intake. TRIAL REGISTRATION: Clinicaltrial.gov: NCT02441361.

Inverse Association Between Hypothalamic N-Acetyl Aspartate/Creatine Ratio and Indices of Body Mass in Adolescents with Obesity.

BACKGROUND: Approximately 10% of adolescents worldwide are overweight or obese, hence the urgent and universal need to elucidate possible mechanisms that lead to obesity in the adolescent population. OBJECTIVES: We examined the hypothalamic metabolism and its relationship with physical development in obese and eutrophic adolescents. METHODS: We performed a case-control study with 115 adolescents between 11 and 18 years of age, to compare obese (BMI z-score ≥ 2) and nonobese individuals (eutrophic controls; BMI z-score ≤ 1). The following hypothalamic metabolite ratios were examined as primary outcomes: glutamate/creatine (Cr), the sum of glutamate and glutamine/Cr, N-acetylaspartate (NAA)/Cr, myoinositol/Cr, and total choline/Cr (glycerophosphocholine +  phosphocholine/Cr), quantified by magnetic resonance spectroscopy. BMI z-scores, pubertal status, and scores on the Yale Food Addiction Scale, the Binge Eating Scale, and the Child Depression Inventory were assessed as secondary outcomes. Pearson coefficients (r) or nonparametric Spearman correlation (rho) analyses were performed between hypothalamic metabolite ratios and other parameters, such as BMI z-scores, physical development, food habits, depression symptoms, and serum protein concentrations (cytokines, hormones, and neuropeptides). RESULTS: Adolescents with obesity showed a lower hypothalamic NAA/Cr ratio (0.70 ± 0.19) compared to their eutrophic counterparts (0.84 ± 0.20; P = 0.004). The NAA/Cr ratio was negatively correlated with BMI z-scores (r = -0.25; P = 0.03) and serum insulin (rho = -0.27; P = 0.04), C-peptide (rho = -0.26; P = 0.04), amylin (r = -0.27; P = 0.04), ghrelin (rho = -0.30; P = 0.02), and neuropeptide Y (r = -0.27; P = 0.04). Also, the NAA/Cr ratio was positively correlated with circulating IL-8 levels (rho = 0.26; P = 0.04). CONCLUSIONS: High BMI z-scores are associated with lower hypothalamic NAA/Cr ratios. The negative correlations found between the NAA/Cr ratio and serum cytokines, hormones, and neuropeptides suggest a broad cross-talk linking hormonal imbalances, neurohumoral alterations, and hypothalamic functions in adolescents with obesity.

DTI-derived parameters differ between moderate and severe traumatic brain injury and its association with psychiatric scores.

BACKGROUND AND AIM: Diffusion tensor imaging (DTI) parameters in the corpus callosum have been suggested to be a biomarker for prognostic outcomes in individuals with diffuse axonal injury (DAI). However, differences between the DTI parameters on moderate and severe trauma in DAI over time are still unclear. A secondary goal was to study the association between the changes in the DTI parameters, anxiety, and depressive scores in DAI over time. METHODS: Twenty subjects were recruited from a neurological outpatient clinic and evaluated at 2, 6, and 12 months after the brain injury and compared to matched age and sex healthy controls regarding the DTI parameters in the corpus callosum. State-Trace Anxiety Inventory and Beck Depression Inventory were used to assess psychiatric outcomes in the TBI group over time. RESULTS: Differences were observed in the fractional anisotropy and mean diffusivity of the genu, body, and splenium of the corpus callosum between DAI and controls (p < 0.02). Differences in both parameters in the genu of the corpus callosum were also detected between patients with moderate and severe DAI (p < 0.05). There was an increase in the mean diffusivity values and the fractional anisotropy decrease in the DAI group over time (p < 0.02). There was no significant correlation between changes in the fractional anisotropy and mean diffusivity across the study and psychiatric outcomes in DAI. CONCLUSION: DTI parameters, specifically the mean diffusivity in the corpus callosum, may provide reliable characterization and quantification of differences determined by the brain injury severity. No correlation was observed with DAI parameters and the psychiatric outcome scores.

Decompose quantitative susceptibility mapping (QSM) to sub-voxel diamagnetic and paramagnetic components based on gradient-echo MRI data.

PURPOSE: A method named DECOMPOSE-QSM is developed to decompose bulk susceptibility measured with QSM into sub-voxel paramagnetic and diamagnetic components based on a three-pool complex signal model. METHODS: Multi-echo gradient echo signal is modeled as a summation of three weighted exponentials corresponding to three types of susceptibility sources: reference susceptibility, diamagnetic and paramagnetic susceptibility relative to the reference. Paramagnetic component susceptibility (PCS) and diamagnetic component susceptibility (DCS) maps are constructed to represent the sub-voxel compartments by solving for linear and nonlinear parameters in the model. RESULTS: Numerical forward simulation and phantom validation confirmed the ability of DECOMPOSE-QSM to separate the mixture of paramagnetic and diamagnetic components. The PCS obtained from temperature-variant brainstem imaging follows the Curie's Law, which further validated the model and the solver. Initial in vivo investigation of human brain images showed the ability to extract sub-voxel PCS and DCS sources that produce visually enhanced contrast between brain structures comparing to threshold QSM.

ACC Glu/GABA ratio is decreased in euthymic bipolar disorder I patients: possible in vivo neurometabolite explanation for mood stabilization.

Bipolar disorder (BD) is characterized by unstable mood states ranging from mania to depression. Although there is some evidence that mood instability may result from an imbalance between excitatory glutamatergic and inhibitory GABA-ergic neurotransmission, few proton magnetic resonance spectroscopy (1H-MRS) studies have measured these two neurometabolites simultaneously in BD. The enzyme glutamic acid decarboxylase (GAD1) catalyzes the decarboxylation of glutamate (Glu) to GABA, and its single nucleotide polymorphisms (SNPs) might influence Glu/GABA ratio. Thus, we investigated Glu/GABA ratio in the dorsal anterior cingulate cortex (dACC) of euthymic BD type I patients and healthy controls (HC), and assessed the influence of both mood stabilizers and GAD1 SNPs on this ratio. Eighty-eight subjects (50 euthymic BD type I patients and 38 HC) underwent 3T 1H-MRS in the dACC (2 × 2 × 4.5 cm3) using a two-dimensional JPRESS sequence and all subjects were genotyped for 4 SNPs in the GAD1 gene. BD patients had lower dACC Glu/GABA ratio compared to HC, where this was influenced by anticonvulsant and antipsychotic medications, but not lithium. The presence of GAD1 rs1978340 allele A was associated with higher Glu/GABA ratio in BD, while patients without this allele taking mood stabilizers had a lower Glu/GABA ratio. The lowering of dACC Glu/GABA could be one explanation for the mood stabilizing action of anticonvulsants and antipsychotics in BD type I euthymia. Therefore, this putative role of Glu/GABA ratio and the influence of GAD1 genotype interacting with mood stabilization medication should be confirmed by further studies involving larger samples and other mood states.ClincalTrials.gov registration: NCT01237158.

Dynamic changes in white matter following traumatic brain injury and how diffuse axonal injury relates to cognitive domain.

Objective: The goal is to evaluate longitudinally with diffusion tensor imaging (DTI) the integrity of cerebral white matter in patients with moderate and severe DAI and to correlate the DTI findings with cognitive deficits.Methods: Patients with DAI (n = 20) were scanned at three timepoints (2, 6 and 12 months) after trauma. A healthy control group (n = 20) was evaluated once with the same high-field MRI scanner. The corpus callosum (CC) and the bilateral superior longitudinal fascicles (SLFs) were assessed by deterministic tractography with ExploreDTI. A neuropschychological evaluation was also performed.Results: The CC and both SLFs demonstrated various microstructural abnormalities in between-groups comparisons. All DTI parameters demonstrated changes across time in the body of the CC, while FA (fractional anisotropy) increases were seen on both SLFs. In the splenium of the CC, progressive changes in the mean diffusivity (MD) and axial diffusivity (AD) were also observed. There was an improvement in attention and memory along time. Remarkably, DTI parameters demonstrated several correlations with the cognitive domains.Conclusions: Our findings suggest that microstructural changes in the white matter are dynamic and may be detectable by DTI throughout the first year after trauma. Likewise, patients also demonstrated improvement in some cognitive skills.

Toward identifying reproducible brain signatures of obsessive-compulsive profiles: rationale and methods for a new global initiative.

BACKGROUND: Obsessive-compulsive disorder (OCD) has a lifetime prevalence of 2-3% and is a leading cause of global disability. Brain circuit abnormalities in individuals with OCD have been identified, but important knowledge gaps remain. The goal of the new global initiative described in this paper is to identify robust and reproducible brain signatures of measurable behaviors and clinical symptoms that are common in individuals with OCD. A global approach was chosen to accelerate discovery, to increase rigor and transparency, and to ensure generalizability of results. METHODS: We will study 250 medication-free adults with OCD, 100 unaffected adult siblings of individuals with OCD, and 250 healthy control subjects at five expert research sites across five countries (Brazil, India, Netherlands, South Africa, and the U.S.). All participants will receive clinical evaluation, neurocognitive assessment, and magnetic resonance imaging (MRI). The imaging will examine multiple brain circuits hypothesized to underlie OCD behaviors, focusing on morphometry (T1-weighted MRI), structural connectivity (Diffusion Tensor Imaging), and functional connectivity (resting-state fMRI). In addition to analyzing each imaging modality separately, we will also use multi-modal fusion with machine learning statistical methods in an attempt to derive imaging signatures that distinguish individuals with OCD from unaffected siblings and healthy controls (Aim #1). Then we will examine how these imaging signatures link to behavioral performance on neurocognitive tasks that probe these same circuits as well as to clinical profiles (Aim #2). Finally, we will explore how specific environmental features (childhood trauma, socioeconomic status, and religiosity) moderate these brain-behavior associations. DISCUSSION: Using harmonized methods for data collection and analysis, we will conduct the largest neurocognitive and multimodal-imaging study in medication-free subjects with OCD to date. By recruiting a large, ethno-culturally diverse sample, we will test whether there are robust biosignatures of core OCD features that transcend countries and cultures. If so, future studies can use these brain signatures to reveal trans-diagnostic disease dimensions, chart when these signatures arise during development, and identify treatments that target these circuit abnormalities directly. The long-term goal of this research is to change not only how we conceptualize OCD but also how we diagnose and treat it.

Dorsal Anterior Cingulate Lactate and Glutathione Levels in Euthymic Bipolar I Disorder: 1H-MRS Study.

OBJECTIVE: Oxidative stress and mitochondrial dysfunction are 2 closely integrated processes implicated in the physiopathology of bipolar disorder. Advanced proton magnetic resonance spectroscopy techniques enable the measurement of levels of lactate, the main marker of mitochondrial dysfunction, and glutathione, the predominant brain antioxidant. The objective of this study was to measure brain lactate and glutathione levels in bipolar disorder and healthy controls. METHODS: Eighty-eight individuals (50 bipolar disorder and 38 healthy controls) underwent 3T proton magnetic resonance spectroscopy in the dorsal anterior cingulate cortex (2x2x4.5cm(3)) using a 2-D JPRESS sequence. Lactate and glutathione were quantified using the ProFit software program. RESULTS: Bipolar disorder patients had higher dorsal anterior cingulate cortex lactate levels compared with controls. Glutathione levels did not differ between euthymic bipolar disorder and controls. There was a positive correlation between lactate and glutathione levels specific to bipolar disorder. No influence of medications on metabolites was observed. CONCLUSION: This is the most extensive magnetic resonance spectroscopy study of lactate and glutathione in bipolar disorder to date, and results indicated that euthymic bipolar disorder patients had higher levels of lactate, which might be an indication of altered mitochondrial function. Moreover, lactate levels correlated with glutathione levels, indicating a compensatory mechanism regardless of bipolar disorder diagnosis.

Efficacy and safety of creatine supplementation in juvenile dermatomyositis: A randomized, double-blind, placebo-controlled crossover trial.

INTRODUCTION: It has been suggested that creatine supplementation is safe and effective for treating idiopathic inflammatory myopathies, but no pediatric study has been conducted to date. The objective of this study was to examine the efficacy and safety of creatine supplementation in juvenile dermatomyositis (JDM) patients. METHODS: In this study, JDM patients received placebo or creatine supplementation (0.1 g/kg/day) in a randomized, crossover, double-blind design. Subjects were assessed at baseline and after 12 weeks. The primary outcome was muscle function. Secondary outcomes included body composition, aerobic conditioning, health-related quality of life, and muscle phosphocreatine (PCr) content. Safety was assessed by laboratory parameters and kidney function measurements. RESULTS: Creatine supplementation did not affect muscle function, intramuscular PCr content, or any other secondary outcome. Kidney function was not affected, and no side effects were reported. CONCLUSIONS: Twelve weeks of creatine supplementation in JDM patients were well-tolerated and free of adverse effects, but treatment did not affect muscle function, intramuscular PCr, or any other parameter.

Surface-Based Probabilistic Fiber Tracking in Superficial White Matter.

The short association fibers or U-fibers travel in the superficial white matter (SWM) beneath the cortical layer. While the U-fibers play a crucial role in various brain disorders, there is a lack of effective tools to reconstruct their highly curved trajectory from diffusion MRI (dMRI). In this work, we propose a novel surface-based framework for the probabilistic tracking of fibers on the triangular mesh representation of the SWM. By deriving a closed-form solution to transform the spherical harmonics (SPHARM) coefficients of 3D fiber orientation distributions (FODs) to local coordinate systems on each triangle, we develop a novel approach to project the FODs onto the tangent space of the SWM. After that, we utilize parallel transport to realize the intrinsic propagation of streamlines on SWM following probabilistically sampled fiber directions. Our intrinsic and surface-based method eliminates the need to perform the necessary but challenging sharp turns in 3D compared with conventional volume-based tractography methods. Using data from the Human Connectome Project (HCP), we performed quantitative comparisons to demonstrate the proposed algorithm can more effectively reconstruct the U-fibers connecting the precentral and postcentral gyrus than previous methods. Quantitative validations were then performed on post-mortem MRIs to show the reconstructed U-fibers from our method more faithfully follow the SWM than volume-based tractography. Finally, we applied our algorithm to study the parietal U-fiber connectivity changes in autosomal dominant Alzheimer's disease (ADAD) patients and successfully detected significant associations between U-fiber connectivity and disease severity.

Central Vein Sign and Paramagnetic Rim Lesions: Susceptibility Changes in Brain Tissues and Their Implications for the Study of Multiple Sclerosis Pathology.

Multiple sclerosis (MS) is the most common acquired inflammatory and demyelinating disease in adults. The conventional diagnostic of MS and the follow-up of inflammatory activity is based on the detection of hyperintense foci in T2 and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) and lesions with brain-blood barrier (BBB) disruption in the central nervous system (CNS) parenchyma. However, T2/FLAIR hyperintense lesions are not specific to MS and the MS pathology and inflammatory processes go far beyond focal lesions and can be independent of BBB disruption. MRI techniques based on the magnetic susceptibility properties of the tissue, such as T2*, susceptibility-weighted images (SWI), and quantitative susceptibility mapping (QSM) offer tools for advanced MS diagnostic, follow-up, and the assessment of more detailed features of MS dynamic pathology. Susceptibility-weighted techniques are sensitive to the paramagnetic components of biological tissues, such as deoxyhemoglobin. This capability enables the visualization of brain parenchymal veins. Consequently, it presents an opportunity to identify veins within the core of multiple sclerosis (MS) lesions, thereby affirming their venocentric characteristics. This advancement significantly enhances the accuracy of the differential diagnostic process. Another important paramagnetic component in biological tissues is iron. In MS, the dynamic trafficking of iron between different cells, such as oligodendrocytes, astrocytes, and microglia, enables the study of different stages of demyelination and remyelination. Furthermore, the accumulation of iron in activated microglia serves as an indicator of latent inflammatory activity in chronic MS lesions, termed paramagnetic rim lesions (PRLs). PRLs have been correlated with disease progression and degenerative processes, underscoring their significance in MS pathology. This review will elucidate the underlying physical principles of magnetic susceptibility and their implications for the formation and interpretation of T2*, SWI, and QSM sequences. Additionally, it will explore their applications in multiple sclerosis (MS), particularly in detecting the central vein sign (CVS) and PRLs, and assessing iron metabolism. Furthermore, the review will discuss their role in advancing early and precise MS diagnosis and prognostic evaluation, as well as their utility in studying chronic active inflammation and degenerative processes.

Bearded capuchin monkeys as a model for Alzheimer's disease.

The absence of a natural animal model is one of the main challenges in Alzheimer's disease research. Despite the challenges of using nonhuman primates in studies, these animals can bridge mouse models and humans, as nonhuman primates are phylogenetically closer to humans and can spontaneously develop AD-type pathology. The capuchin monkey, a New World primate, has recently attracted attention due to its skill in creating and using instruments. We analyzed one capuchin brain using structural 7 T MRI and performed a neuropathological evaluation of three animals. Alzheimer-type pathology was found in the two of the capuchins. Widespread ß-amyloid pathology was observed, mainly in focal deposits with variable morphology and a high density of mature plaques. Notably, plaque-associated dystrophic neurites associated with disruption of axonal transport and early cytoskeletal alteration were frequently found. Unlike in other species of New World monkeys, cerebral arterial angiopathy was not the predominant form of ß-amyloid pathology. Additionally, abnormal aggregates of hyperphosphorylated tau, resembling neurofibrillary pathology, were observed in the temporal and frontal cortex. Astrocyte hypertrophy surrounding plaques was found, suggesting a neuroinflammatory response. These findings indicate that aged capuchin monkeys can spontaneously develop Alzheimer-type pathology, indicating that they may be an advantageous animal model for research in Alzheimer's disease.

BDNF rs6265 differentially influences neurometabolites in the anterior cingulate of healthy and bipolar disorder subjects.

Brain-derived neurotrophic factor (BDNF) is the most abundant brain neurotrophin and plays a critical role in neuronal growth, survival and plasticity, implicated in the pathophysiology of Bipolar Disorders (BD). The single-nucleotide polymorphism in the BDNF gene (BDNF rs6265) has been associated with decreased hippocampal BDNF secretion and volume in met carriers in different populations, although the val allele has been reported to be more frequent in BD patients. The anterior cingulate cortex (ACC) is a key center integrating cognitive and affective neuronal connections, where consistent alterations in brain metabolites such as Glx (Glutamate + Glutamine) and N-acetylaspartate (NAA) have been consistently reported in BD. However, little is known about the influence of BDNF rs6265 on neurochemical profile in the ACC of Healthy Controls (HC) and BD subjects. The aim of this study was to assess the influence of BDNF rs6265 on ACC neurometabolites (Glx, NAA and total creatine- Cr) in 124 euthymic BD type I patients and 76 HC, who were genotyped for BDNF rs6265 and underwent a 3-Tesla proton magnetic resonance imaging and spectroscopy scan (1 H-MRS) using a PRESS ACC single-voxel (8cm3) sequence. BDNF rs6265 polymorphism showed a significant two-way interaction (diagnosis × genotype) in relation to NAA/Cr and total Cr. While met carriers presented increased NAA/Cr in HC, BD-I subjects with the val allele revealed higher total Cr, denoting an enhanced ACC metabolism likely associated with increased glutamatergic metabolites observed in BD-I val carriers. However, these results were replicated only in men. Therefore, our results support evidences that the BDNF rs6265 polymorphism exerts a complex pleiotropic effect on ACC metabolites influenced by the diagnosis and sex.

Evaluation of multi-channel phase reconstruction methods for quantitative susceptibility mapping on postmortem human brain.

Quantitative Susceptibility Mapping (QSM) is an established Magnetic Resonance Imaging (MRI) technique with high potential in brain iron studies associated to several neurodegenerative diseases. Unlike other MRI techniques, QSM relies on phase images to estimate tissue's relative susceptibility, therefore requiring a reliable phase data. Phase images from a multi-channel acquisition should be reconstructed in a proper way. On this work it was compared the performance of combination of phase matching algorithms (MCPC3D-S and VRC) and phase combination methods based on a complex weighted sum of phases, considering the magnitude at different powers (k = 0 to 4) as the weighting factor. These reconstruction methods were applied in two datasets: a simulated brain dataset for a 4-coil array and data of 22 postmortem subjects acquired at a 7T scanner using a 32 channels coil. For the simulated dataset, differences between the ground truth and the Root Mean Squared Error (RMSE) were evaluated. For both simulated and postmortem data, the mean (MS) and standard deviation (SD) of susceptibility values of five deep gray matter regions were calculated. For the postmortem subjects, MS and SD were statistically compared across all subjects. A qualitative analysis indicated no differences between methods, except for the Adaptive approach on postmortem data, which showed intense artifacts. In the 20% noise level case, the simulated data showed increased noise in central regions. Quantitative analysis showed that both MS and SD were not statistically different when comparing k = 1 and k = 2 on postmortem brain images, however visual inspection showed some boundaries artifacts on k = 2. Furthermore, the RMSE decreased (on regions near the coils) and increased (on central regions and on overall QSM) with increasing k. In conclusion, for reconstruction of phase images from multiple coils with no reference available, alternative methods are needed. In this study it was found that overall, the phase combination with k = 1 is preferred over other powers of k.

Brain Spectroscopy Analysis in Retired Soccer Players With Chronic Exposure to Mild Traumatic Brain Injuries.

Soccer players are at risk of suffering cranial injuries in the short and long term. There is growing concern that this may lead to traumatic brain injury in soccer players. Magnetic resonance spectroscopy (MRS) is an analytical method that enables the measurement of changes in brain metabolites that usually occur before significant structural changes. This study aimed to use MRS to compare variations in brain metabolite levels between retired soccer players and a control group. Twenty retired professional soccer players and 22 controls underwent magnetic resonance imaging, including MRS sequences and Mini-Mental State Examination (MMSE). Metabolite analysis was conducted based on absolute concentration and relative ratios. N-acetyl-aspartate, choline, glutamate, glutamine, and myoinositol were the metabolites of interest for the statistical analysis. Retired soccer players had an average age of 57.8 years, whereas the control group had an average age of 63.2 years. Median cognitive evaluation score, assessed using the MMSE, was 28 [26-29] for athletes and 29 [28-30] for controls (p = 0.01). Uni- and multi-variate analyses of the absolute concentration of metabolites (mM) between former athletes and controls did not yield any statistically significant results. Comparison of metabolites to creatine ratio concentrations did not yield any statistically significant results. There were no changes in concentrations of brain metabolites that indicated brain metabolic changes in retired soccer players compared with controls.

Bearded capuchin monkey as a model for Alzheimer's disease research.

The absence of a natural animal model is one of the main challenges in Alzheimer's disease research. Despite the challenges of using non-human primates in studies, they can bridge mouse models and humans, as non-human primates are phylogenetically close to humans and can spontaneously develop AD-type pathology. The capuchin monkey, a New World primate, has recently attracted attention due to its skill in creating and using instruments. We analyzed three capuchin brains using structural 7T MRI and neuropathological evaluation. Alzheimer-type pathology was found in one case. Widespread ß-amyloid pathology mainly in the form of focal deposits with variable morphology and high density of mature plaques. Noteworthy, plaque-associated dystrophic neurites, associated with disrupted of axonal transport and early cytoskeletal alteration, were frequently found. Unlike other species of New World monkeys, cerebral arterial angiopathy was not the predominant form of ß-amyloid pathology. Additionally, abnormal aggregates of hyperphosphorylated tau, resembling neurofibrillary pathology, were observed in the temporal and frontal cortex. Besides, astrocyte hypertrophy surrounding plaques was found, suggesting a neuroinflammatory response. Aged capuchin monkeys can spontaneously develop Alzheimer-type pathology, indicating that they may be an advantageous animal model for research in Alzheimer's disease.

Creatine but not betaine supplementation increases muscle phosphorylcreatine content and strength performance.

We aimed to investigate the role of betaine supplementation on muscle phosphorylcreatine (PCr) content and strength performance in untrained subjects. Additionally, we compared the ergogenic and physiological responses to betaine versus creatine supplementation. Finally, we also tested the possible additive effects of creatine and betaine supplementation. This was a double-blind, randomized, placebo-controlled study. Subjects were assigned to receive betaine (BET; 2 g/day), creatine (CR; 20 g/day), betaine plus creatine (BET+CR; 2+20 g/day, respectively) or placebo (PL). At baseline and after 10 days of supplementation, we assessed muscle strength and power, muscle PCr content, and body composition. The CR and BET+CR groups presented greater increase in muscle PCr content than PL (p=0.004 and p=0.006, respectively). PCr content was comparable between BET versus PL (p=0.78) and CR versus BET+CR (p=0.99). CR and BET+CR presented greater muscle power output than PL in the squat exercise following supplementation (p=0.003 and p=0.041, respectively). Similarly, bench press average power was significantly greater for the CR-supplemented groups. CR and BET+CR groups also showed significant pre- to post-test increase in 1-RM squat and bench press (CR: p=0.027 and p<0.0001; BET+CR: p=0.03 and p<0.0001 for upper- and lower-body assessments, respectively) No significant differences for 1-RM strength and power were observed between BET versus PL and CR versus BET+CR. Body composition did not differ between the groups. In conclusion, we reported that betaine supplementation does not augment muscle PCr content. Furthermore, we showed that betaine supplementation combined or not with creatine supplementation does not affect strength and power performance in untrained subjects.

Reduced muscle carnosine content in type 2, but not in type 1 diabetic patients.

Carnosine is present in high concentrations in skeletal muscle where it contributes to acid buffering and functions also as a natural protector against oxidative and carbonyl stress. Animal studies have shown an anti-diabetic effect of carnosine supplementation. High carnosinase activity, the carnosine degrading enzyme in serum, is a risk factor for diabetic complications in humans. The aim of the present study was to compare the muscle carnosine concentration in diabetic subjects to the level in non-diabetics. Type 1 and 2 diabetic patients and matched healthy controls (total n=58) were included in the study. Muscle carnosine content was evaluated by proton magnetic resonance spectroscopy (3 Tesla) in soleus and gastrocnemius. Significantly lower carnosine content (-45%) in gastrocnemius muscle, but not in soleus, was shown in type 2 diabetic patients compared with controls. No differences were observed in type 1 diabetic patients. Type II diabetic patients display a reduced muscular carnosine content. A reduction in muscle carnosine concentration may be partially associated with defective mechanisms against oxidative, glycative and carbonyl stress in muscle.

Beta-alanine (Carnosyn™) supplementation in elderly subjects (60-80 years): effects on muscle carnosine content and physical capacity.

The aim of this study was to investigate the effects of beta-alanine supplementation on exercise capacity and the muscle carnosine content in elderly subjects. Eighteen healthy elderly subjects (60-80 years, 10 female and 4 male) were randomly assigned to receive either beta-alanine (BA, n=12) or placebo (PL, n=6) for 12 weeks. The BA group received 3.2 g of beta-alanine per day (2×800 mg sustained-release Carnosyn™ tablets, given 2 times per day). The PL group received 2× (2×800 mg) of a matched placebo. At baseline (PRE) and after 12 weeks (POST-12) of supplementation, assessments were made of the muscle carnosine content, anaerobic exercise capacity, muscle function, quality of life, physical activity and food intake. A significant increase in the muscle carnosine content of the gastrocnemius muscle was shown in the BA group (+85.4%) when compared with the PL group (+7.2%) (p=0.004; ES: 1.21). The time-to-exhaustion in the constant-load submaximal test (i.e., TLIM) was significantly improved (p=0.05; ES: 1.71) in the BA group (+36.5%) versus the PL group (+8.6%). Similarly, time-to-exhaustion in the incremental test was also significantly increased (p=0.04; ES 1.03) following beta-alanine supplementation (+12.2%) when compared with placebo (+0.1%). Significant positive correlations were also shown between the relative change in the muscle carnosine content and the relative change in the time-to-exhaustion in the TLIM test (r=0.62; p=0.01) and in the incremental test (r=0.48; p=0.02). In summary, the current data indicate for the first time, that beta-alanine supplementation is effective in increasing the muscle carnosine content in healthy elderly subjects, with subsequent improvement in their exercise capacity.

Association between CACNA1C gene rs100737 polymorphism and glutamatergic neurometabolites in bipolar disorder.

Abnormalities in Ca2+ homeostasis in Bipolar Disorders (BD) have been associated with impairments in glutamatergic receptors and voltage-gated calcium channels. Increased anterior cingulate cortex (ACC) glutamatergic neurometabolites have been consistently disclosed in BD by proton magnetic resonance spectroscopy (1H-MRS). A single nucleotide polymorphism (SNP) in the CACNA1C gene (rs1006737), which encodes the alpha 1-C subunit of the L-type calcium channel, has been associated with BD and is reported to modulate intra-cellular Ca2+. Thus, this study aimed to explore the association of the CACNA1C genotype with ACC glutamatergic metabolites measured by 1H-MRS in both BD and HC subjects. A total of 194 subjects (121 euthymic BD type I patients and 73 healthy controls (HC) were genotyped for CACNA1C rs1006737, underwent a 3-Tesla 1H-MRS imaging examination and ACC glutamatergic metabolite were assessed. We found overall increased glutamatergic metabolites in AA carriers in BD. Specifically, higher Glx/Cr was observed in subjects with the AA genotype compared to both AG and GG in the overall sample (BD + HC). Also, female individuals in the BD group with AA genotype were found to have higher Glx/Cr compared to those with other genotypes. CACNA1C AA carriers in use of anticonvulsant medication had higher estimated Glutamine (Glx-Glu) than the other genotypes. Thus, this study suggest an association between calcium channel genetics and increased glutamatergic metabolites in BD, possibly playing a synergic role in intracellular Ca2+ overload and excitotoxicity.