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.

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.

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.

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.

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.

Longitudinal whole-brain analysis of multi-subject diffusion data in diffuse axonal injury.

BACKGROUND: Diffuse axonal injury occurs with high acceleration and deceleration forces in traumatic brain injury (TBI). This lesion leads to disarrangement of the neuronal network, which can result in some degree of deficiency. The Extended Glasgow Outcome Scale (GOS-E) is the primary outcome instrument for the evaluation of TBI victims. Diffusion tensor imaging (DTI) assesses white matter (WM) microstructure based on the displacement distribution of water molecules. OBJECTIVE: To investigate WM microstructure within the first year after TBI using DTI, the patient's clinical outcomes, and associations. METHODS: We scanned 20 moderate and severe TBI victims at 2 months and 1 year after the event. Imaging processing was done with the FMRIB software library; we used the tract-based spatial statistics software yielding fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) for statistical analyses. We computed the average difference between the two measures across subjects and performed a one-sample t-test and threshold-free cluster enhancement, using a corrected p-value < 0.05. Clinical outcomes were evaluated with the GOS-E. We tested for associations between outcome measures and significant mean FA clusters. RESULTS: Significant clusters of altered FA were identified anatomically using the JHU WM atlas. We found increasing spotted areas of FA with time in the right brain hemisphere and left cerebellum. Extensive regions of increased MD, RD, and AD were observed. Patients presented an excellent overall recovery. CONCLUSIONS: There were no associations between FA and outcome scores, but we cannot exclude the existence of a small to moderate association.

Longitudinal assessment of magnetization transfer ratio, brain volume, and cognitive functions in diffuse axonal injury.

BACKGROUND: Diffuse axonal injury (DAI) is a frequent mechanism of traumatic brain injury (TBI) that triggers a sequence of parenchymal changes that progresses from focal axonal shear injuries up to inflammatory response and delayed axonal disconnection. OBJECTIVE: The main purpose of this study is to evaluate changes in the axonal/myelinic content and the brain volume up to 12 months after TBI and to correlate these changes with neuropsychological results. METHODS: Patients with DAI (n = 25) were scanned at three time points after trauma (2, 6, and 12 months), and the total brain volume (TBV), gray matter volume, and white matter volume (WMV) were calculated in each time point. The magnetization transfer ratio (MTR) for the total brain (TB MTR), gray matter (GM MTR), and white matter (WM MTR) was also quantified. In addition, Hopkins verbal learning test (HVLT), Trail Making Test (TMT), and Rey-Osterrieth Complex Figure test were performed at 6 and 12 months after the trauma. RESULTS: There was a significant reduction in the mean TBV, WMV, TB MTR, GM MTR, and WM MTR between time points 1 and 3 (p < .05). There was also a significant difference in HVLT-immediate, TMT-A, and TMT-B scores between time points 2 and 3. The MTR decline correlated more with the cognitive dysfunction than the volume reduction. CONCLUSION: A progressive axonal/myelinic rarefaction and volume loss were characterized, especially in the white matter (WM) up to 1 year after the trauma. Despite that, specific neuropsychological tests revealed that patients' episodic verbal memory, attention, and executive function improved during the study. The current findings may be valuable in developing long-term TBI rehabilitation management programs.

Postmortem brain 7T MRI with minimally invasive pathological correlation in deceased COVID-19 subjects.

BACKGROUND: Brain abnormalities are a concern in COVID-19, so we used minimally invasive autopsy (MIA) to investigate it, consisting of brain 7T MR and CT images and tissue sampling via transethmoidal route with at least three fragments: the first one for reverse transcription polymerase chain reaction (RT-PCR) analysis and the remaining fixed and stained with hematoxylin and eosin. Two mouse monoclonal anti-coronavirus (SARS-CoV-2) antibodies were employed in immunohistochemical (IHC) reactions. RESULTS: Seven deceased COVID-19 patients underwent MIA with brain MR and CT images, six of them with tissue sampling. Imaging findings included infarcts, punctate brain hemorrhagic foci, subarachnoid hemorrhage and signal abnormalities in the splenium, basal ganglia, white matter, hippocampi and posterior cortico-subcortical. Punctate brain hemorrhage was the most common finding (three out of seven cases). Brain histological analysis revealed reactive gliosis, congestion, cortical neuron eosinophilic degeneration and axonal disruption in all six cases. Other findings included edema (5 cases), discrete perivascular hemorrhages (5), cerebral small vessel disease (3), perivascular hemosiderin deposits (3), Alzheimer type II glia (3), abundant corpora amylacea (3), ischemic foci (1), periventricular encephalitis foci (1), periventricular vascular ectasia (1) and fibrin thrombi (1). SARS-CoV-2 RNA was detected with RT-PCR in 5 out of 5 and IHC in 6 out 6 patients (100%). CONCLUSIONS: Despite limited sampling, MIA was an effective tool to evaluate underlying pathological brain changes in deceased COVID-19 patients. Imaging findings were varied, and pathological features corroborated signs of hypoxia, alterations related to systemic critically ill and SARS-CoV-2 brain invasion.

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.

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.

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.

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.

Longitudinal analysis of verbal episodic memory in patients with relapsing-remitting multiple sclerosis.

OBJECTIVE: A 4.5-year follow-up study was conducted to characterize baseline verbal episodic memory (VEM) and its behavior and to assess the effects of relapsing-remitting multiple sclerosis (RRMS) on this domain. METHODS: Twenty-nine patients with RRMS underwent two neuropsychological assessments performed an average of 4.5 years apart. Twenty-six control participants underwent a single neuropsychological assessment. A significance level of p < 0.005 was adopted to denote a significant difference between the groups on the Mann Whitney and Wilcoxon paired statistical analyses. RESULTS: No statistical difference was found in the results of the VEM tests between the first and second neuropsychological assessments of the patients. However, a statistical difference was evident between the patient and control groups in the results of the VEM tests. CONCLUSION: The patient group showed changes in the VEM relative to the control group. After approximately 4.5 years of disease, the patient performance on the VEM stabilized or improved.

Longitudinal analysis of verbal episodic memory in patients with relapsing-remitting multiple sclerosis / Análise longitudinal da memória episódica verbal em pacientes com esclerose múltipla remitente-recorrente

ABSTRACT Objective: A 4.5-year follow-up study was conducted to characterize baseline verbal episodic memory (VEM) and its behavior and to assess the effects of relapsing-remitting multiple sclerosis (RRMS) on this domain. Methods: Twenty-nine patients with RRMS underwent two neuropsychological assessments performed an average of 4.5 years apart. Twenty-six control participants underwent a single neuropsychological assessment. A significance level of p < 0.005 was adopted to denote a significant difference between the groups on the Mann Whitney and Wilcoxon paired statistical analyses. Results: No statistical difference was found in the results of the VEM tests between the first and second neuropsychological assessments of the patients. However, a statistical difference was evident between the patient and control groups in the results of the VEM tests. Conclusion: The patient group showed changes in the VEM relative to the control group. After approximately 4.5 years of disease, the patient performance on the VEM stabilized or improved.

RESUMO Objetivo: Neste estudo, propomos a caracterização da Memória Episódica Verbal (MEV) basal e o seu comportamento após o período de 4,5 anos de doença, a fim de avaliar o efeito da EMRR neste domínio. Métodos: Vinte e nove pacientes com EMRR foram submetidos a duas avaliações neuropsicológicas realizadas entre um intervalo de tempo médio de 4,5 anos. Vinte e seis controles foram submetidos à avaliação neuropsicológica única. Considerou-se nível de significância p <0,005 para delinear diferença significante entre os grupos nas análises estatísticas Mann Whitney e Wilcoxon pareado. Resultados: Não houve diferença estatística nos resultados dos testes de MEV entre a primeira e segunda avaliação neuropsicológica realizada pelos pacientes. Houve discrepância estatística nos resultados dos testes de MEV entre o grupo dos pacientes e controles. Conclusão: O grupo de pacientes apresentou alterações de MEV quando comparado aos controles. Após 4,5 anos aproximadamente os pacientes estabilizaram ou melhoraram seu desempenho em MEV.

Proton spectroscopy of the thalamus in a homogeneous sample of patients with easy-to-control juvenile myoclonic epilepsy.

OBJECTIVE: Juvenile myoclonic epilepsy (JME) is a subtype of genetically determined generalized epilepsy that does not present abnormalities on conventional magnetic resonance imaging. The aim of this study was to identify metabolic alterations in the thalamus in a clinically homogeneous sample of patients with easy-to-control JME, using short-echo time proton magnetic resonance spectroscopy (MRS). MATERIALS AND METHODS: We performed single-voxel (2 cm × 2 cm × 2 cm), short-echo time (TE = 35 ms) proton MRS of the thalamus in 21 patients with JME and in 14 healthy age-matched controls. We quantified N-acetylaspartate (NAA), total NAA, creatine (Cr), choline, and myo-inositol (MI), as well as the sum of glutamate and glutamine signals, all scaled to internal water content, and we calculated metabolite ratios using Cr as a reference. Values of p < 0.05 were considered significant. RESULTS: The MI level and the MI/Cr ratio were significantly lower in the thalami of patients diagnosed with JME than in those of the controls. Other metabolites and their ratios did not differ significantly between the two groups. CONCLUSION: In our sample of 21 JME patients, we identified lower levels of MI in the thalamus. No significant abnormalities were observed in the concentrations or ratios of other metabolites.

OBJETIVO: A epilepsia mioclônica juvenil (EMJ) é um dos subtipos da epilepsia generalizada geneticamente determinada que não apresenta alterações na ressonância magnética convencional. O objetivo deste estudo foi determinar se há alterações metabólicas no tálamo de pacientes com EMJ de fácil controle de uma amostra clinicamente homogênea utilizando espectroscopia de prótons por ressonância magnética (ERM) com tempo de eco curto. MATERIAIS E MÉTODOS: Nós realizamos ERM com voxel único (2 cm × 2 cm × 2 cm) e tempo de eco curto (TE = 35 ms) no tálamo de 21 pacientes com EMJ e 14 controles saudáveis pareados por idade. N-acetil-aspartato (NAA), NAA total, creatina (Cr), colina, mio-inositol (MI) e a soma de glutamato e glutamina foram quantificados em relação ao conteúdo de água interna e as razões dos metabólitos foram calculadas utilizando Cr como referência. Valor de p < 0,05 foi considerado como significante. RESULTADOS: Houve redução estatisticamente significante de MI e MI/Cr no tálamo dos pacientes diagnosticados como EMJ em relação aos controles. Outros metabólitos e suas razões não apresentaram alterações significantes. Conclusão: No tálamo do nosso grupo de 21 pacientes com EMJ foi observada redução de MI e da relação MI/Cr. Não foi observada diferença nos outros metabólitos ou suas relações.

Proton spectroscopy of the thalamus in a homogeneous sample of patients with easy-to-control juvenile myoclonic epilepsy / Espectroscopia de prótons do tálamo em uma amostra homogênea de pacientes com epilepsia mioclônica juvenil de fácil controle

Abstract Objective: Juvenile myoclonic epilepsy (JME) is a subtype of genetically determined generalized epilepsy that does not present abnormalities on conventional magnetic resonance imaging. The aim of this study was to identify metabolic alterations in the thalamus in a clinically homogeneous sample of patients with easy-to-control JME, using short-echo time proton magnetic resonance spectroscopy (MRS). Materials and Methods: We performed single-voxel (2 cm × 2 cm × 2 cm), short-echo time (TE = 35 ms) proton MRS of the thalamus in 21 patients with JME and in 14 healthy age-matched controls. We quantified N-acetylaspartate (NAA), total NAA, creatine (Cr), choline, and myo-inositol (MI), as well as the sum of glutamate and glutamine signals, all scaled to internal water content, and we calculated metabolite ratios using Cr as a reference. Values of p < 0.05 were considered significant. Results: The MI level and the MI/Cr ratio were significantly lower in the thalami of patients diagnosed with JME than in those of the controls. Other metabolites and their ratios did not differ significantly between the two groups. Conclusion: In our sample of 21 JME patients, we identified lower levels of MI in the thalamus. No significant abnormalities were observed in the concentrations or ratios of other metabolites.

Resumo Objetivo: A epilepsia mioclônica juvenil (EMJ) é um dos subtipos da epilepsia generalizada geneticamente determinada que não apresenta alterações na ressonância magnética convencional. O objetivo deste estudo foi determinar se há alterações metabólicas no tálamo de pacientes com EMJ de fácil controle de uma amostra clinicamente homogênea utilizando espectroscopia de prótons por ressonância magnética (ERM) com tempo de eco curto. Materiais e Métodos: Nós realizamos ERM com voxel único (2 cm × 2 cm × 2 cm) e tempo de eco curto (TE = 35 ms) no tálamo de 21 pacientes com EMJ e 14 controles saudáveis pareados por idade. N-acetil-aspartato (NAA), NAA total, creatina (Cr), colina, mio-inositol (MI) e a soma de glutamato e glutamina foram quantificados em relação ao conteúdo de água interna e as razões dos metabólitos foram calculadas utilizando Cr como referência. Valor de p < 0,05 foi considerado como significante. Resultados: Houve redução estatisticamente significante de MI e MI/Cr no tálamo dos pacientes diagnosticados como EMJ em relação aos controles. Outros metabólitos e suas razões não apresentaram alterações significantes. Conclusão: No tálamo do nosso grupo de 21 pacientes com EMJ foi observada redução de MI e da relação MI/Cr. Não foi observada diferença nos outros metabólitos ou suas relações.

Effect of age, diet, and tissue type on PCr response to creatine supplementation.

Creatine/phosphorylcreatine (PCr) responses to creatine supplementation may be modulated by age, diet, and tissue, but studies assessing this possibility are lacking. Therefore we aimed to determine whether PCr responses vary as a function of age, diet, and tissue. Fifteen children, 17 omnivorous and 14 vegetarian adults, and 18 elderly individuals ("elderly") participated in this study. Participants were given placebo and subsequently creatine (0.3 g·kg-1·day-1) for 7 days in a single-blind fashion. PCr was measured through phosphorus magnetic resonance spectroscopy (31P-MRS) in muscle and brain. Creatine supplementation increased muscle PCr in children (P < 0.0003) and elderly (P < 0.001), whereas the increase in omnivores did not reach statistically significant difference (P = 0.3348). Elderly had greater PCr increases than children and omnivores (P < 0.0001 for both), whereas children experienced greater PCr increases than omnivores (P = 0.0022). In relation to diet, vegetarians (P < 0.0001), but not omnivores, had significant increases in muscle PCr content. Brain PCr content was not affected by creatine supplementation in any group, and delta changes in brain PCr (-0.7 to +3.9%) were inferior to those in muscle PCr content (+10.3 to +27.6%; P < 0.0001 for all comparisons). PCr responses to a standardized creatine protocol (0.3 g·kg-1·day-1 for 7 days) may be affected by age, diet, and tissue. Whereas creatine supplementation was able to increase muscle PCr in all groups, although to different extents, brain PCr was shown to be unresponsive overall. These findings demonstrate the need to tailor creatine protocols to optimize creatine/PCr accumulation both in muscle and in brain, enabling a better appreciation of the pleiotropic properties of creatine.NEW & NOTEWORTHY A standardized creatine supplementation protocol (0.3 g·kg-1·day-1 for 7 days) effectively increased muscle, but not brain, phosphorylcreatine. Older participants responded better than younger participants whereas vegetarians responded better than omnivores. Responses to supplementation are thus dependent on age, tissue, and diet. This suggests that a single "universal" protocol, originally designed for increasing muscle creatine in young individuals, may lead to heterogeneous muscle responses in different populations or even no responses in tissues other than skeletal muscle.

Does brain creatine content rely on exogenous creatine in healthy youth? A proof-of-principle study.

It has been hypothesized that dietary creatine could influence cognitive performance by increasing brain creatine in developing individuals. This double-blind, randomized, placebo-controlled, proof-of-principle study aimed to investigate the effects of creatine supplementation on cognitive function and brain creatine content in healthy youth. The sample comprised 67 healthy participants aged 10 to 12 years. The participants were given creatine or placebo supplementation for 7 days. At baseline and after the intervention, participants undertook a battery of cognitive tests. In a random subsample of participants, brain creatine content was also assessed in the regions of left dorsolateral prefrontal cortex, left hippocampus, and occipital lobe by proton magnetic resonance spectroscopy (1H-MRS) technique. The scores obtained from verbal learning and executive functions tests did not significantly differ between groups at baseline or after the intervention (all p > 0.05). Creatine content was not significantly different between groups in left dorsolateral prefrontal cortex, left hippocampus, and occipital lobe (all p > 0.05). In conclusion, a 7-day creatine supplementation protocol did not elicit improvements in brain creatine content or cognitive performance in healthy youth, suggesting that this population mainly relies on brain creatine synthesis rather than exogenous creatine intake to maintain brain creatine homeostasis.