Longitudinal analysis of new multiple sclerosis lesions with magnetization transfer and diffusion tensor imaging.

OBJECTIVE: The potential of magnetization transfer imaging (MTI) and diffusion tensor imaging (DTI) for the detection and evolution of new multiple sclerosis (MS) lesions was analyzed. METHODS: Nineteen patients with MS obtained conventional MRI, MTI, and DTI examinations bimonthly for 12 months and again after 24 months at 1.5 T MRI. MTI was acquired with balanced steady-state free precession (bSSFP) in 10 min (1.3 mm3 isotropic resolution) yielding both magnetization transfer ratio (MTR) and quantitative magnetization transfer (qMT) parameters (pool size ratio (F), exchange rate (kf), and relaxation times (T1/T2)). DTI provided fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). RESULTS: At the time of their appearance on MRI, the 21 newly detected MS lesions showed significantly reduced MTR/F/kf and prolonged T1/T2 parameters, as well as significantly reduced FA and increased AD/MD/RD. Significant differences were already observed for MTR 4 months and for qMT parameters 2 months prior to lesions' detection on MRI. DTI did not show any significant pre-lesional differences. Slightly reversed trends were observed for most lesions up to 8 months after their detection for qMT and less pronounced for MTR and three diffusion parameters, while appearing unchanged on MRI. CONCLUSIONS: MTI provides more information than DTI in MS lesions and detects tissue changes 2 to 4 months prior to their appearance on MRI. After lesions' detection, qMT parameter changes promise to be more sensitive than MTR for the lesions' evolutional assessment. Overall, bSSFP-based MTI adumbrates to be more sensitive than MRI and DTI for the early detection and follow-up assessment of MS lesions. CLINICAL RELEVANCE STATEMENT: When additionally acquired in routine MRI, fast bSSFP-based MTI can complement the MRI/DTI longitudinal lesion assessment by detecting MS lesions 2-4 months earlier than with MRI, which could implicate earlier clinical decisions and better follow-up/treatment assessment in MS patients. KEY POINTS: • Magnetization transfer imaging provides more information than DTI in multiple sclerosis lesions and can detect tissue changes 2 to 4 months prior to their appearance on MRI. • After lesions' detection, quantitative magnetization transfer changes are more pronounced than magnetization transfer ratio changes and therefore promise to be more sensitive for the lesions' evolutional assessment. • Balanced steady-state free precession-based magnetization transfer imaging is more sensitive than MRI and DTI for the early detection and follow-up assessment of multiple sclerosis lesions.

Dynamic MR imaging of the skeletal muscle in young and senior volunteers during synchronized minimal neuromuscular electrical stimulation.

OBJECTIVE: Neuromuscular electrical stimulation (NMES)-induced isometric contraction is feasible during MRI and can be combined with acquisition of volumetric dynamic MR data, in a synchronous and controlled way. Since NMES is a potent resource for rehabilitation, MRI synchronized with NMES presents a valuable validation tool. Our aim was to show how minimal NMES-induced muscle contraction characterization, as evaluated through phase-contrast MRI, differs between senior and young volunteers. MATERIALS AND METHODS: Simultaneous NMES of the quadriceps muscle and phase-contrast imaging were applied at 3 T to 11 senior (75 ± 3 years) and 12 young volunteers (29 ± 7 years). A current sufficient to induce muscle twitch without knee extension was applied to both groups. RESULTS: Strain vectors were extracted from the velocity fields and strain datasets were compared with non-parametric tests and descriptive statistics. Strain values were noticeably different between both groups at both current intensities and significant differences were observed for similar current level. DISCUSSION: In conclusion, NMES-synchronized MRI could be successfully applied in senior volunteers with strain results clearly different from the younger volunteers. Also, differences within the senior group were detected both in the magnitude of strain and in the position of maximum strain pixels.

Visualizing artery-specific blood flow patterns above the circle of Willis with vessel-encoded arterial spin labeling.

PURPOSE: To establish the feasibility of using vessel-encoded pseudocontinuous arterial spin labeling (VEPCASL) for noninvasive vascular territory imaging (VTI) and artery-specific dynamic angiography of a large number of arterial branches above the circle of Willis within a clinically feasible scan time. METHODS: 3D time-of-flight angiography was used to select a labeling plane and establish 7 pairs of encoding cycles. These were used for VEPCASL VTI and dynamic 2D angiography (8 min and 3 min acquisition times, respectively) in healthy volunteers, allowing the separation of signals arising from 13 arterial branches (including extracranial arteries) in postprocessing. To demonstrate the clinical potential of this approach, VEPCASL angiography was also applied in 5 patients with brain arteriovenous malformation (AVM). RESULTS: In healthy volunteers, the artery-specific filling of the vascular tree and resulting perfusion territories were well depicted. SNRs were approximately 5 times higher than those achievable with single-artery selective methods. Blood supply to the AVMs was well visualized in all cases, showing the main feeding arteries and venous drainage. CONCLUSIONS: VEPCASL is a highly efficient method for both VTI and dynamic angiography of a large number of arterial branches, providing a comprehensive picture of vascular flow patterns and the effect on downstream tissue perfusion within an acceptable scan time. Automation of labeling plane and vessel-encoding selection would improve robustness and efficiency, and further refinement could allow quantitative blood flow measurements to be obtained. This technique shows promise for visualizing the blood supply to lesions and collateral flow patterns.

Synchronous MRI of muscle motion induced by electrical stimulation.

PURPOSE: Assessing the functionality of muscle fibers is essential to monitor both pathological and physiological processes. Here, we present a new method for accurate, quantitative measurement of muscle contraction with magnetic resonance imaging (MRI) using an electrical muscle stimulator (EMS), hence allowing the direct assessment of muscle kinematics. METHODS: A commercially available EMS device was used to induce involuntary periodic muscle contraction of the vastus lateralis muscle (VL) synchronized with high-temporal-resolution cine phase contrast MRI acquisition at 3T. The proposed method was evaluated in ten male volunteers at varying levels of stimulation (10-18 mA) and maximum velocity, strain, and strain rate were calculated offline. RESULTS: Artifact-free velocity, strain and strain rate maps were produced and were consistent across the volunteers. Quantitatively, all parameters varied significantly at different levels of stimulation, in an approximately power-law dependence on the stimulation current. At 18 mA maximum contraction speeds at the beginning of the contraction were 4.28 ± 2.64 cm/s; principal strain was 0.30 ± 0.12; and positive in-plane strain rate was 0.25 ± 0.14 s-1 . CONCLUSION: MRI of EMS-controlled involuntary muscle contraction is feasible and allows offline calculation of velocity, strain and strain rate maps, which appear to depend significantly on the stimulation current used. Magn Reson Med 77:664-672, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Blockade of TNF-α rapidly inhibits pain responses in the central nervous system.

There has been a consistent gap in understanding how TNF-α neutralization affects the disease state of arthritis patients so rapidly, considering that joint inflammation in rheumatoid arthritis is a chronic condition with structural changes. We thus hypothesized that neutralization of TNF-α acts through the CNS before directly affecting joint inflammation. Through use of functional MRI (fMRI), we demonstrate that within 24 h after neutralization of TNF-α, nociceptive CNS activity in the thalamus and somatosensoric cortex, but also the activation of the limbic system, is blocked. Brain areas showing blood-oxygen level-dependent signals, a validated method to assess neuronal activity elicited by pain, were significantly reduced as early as 24 h after an infusion of a monoclonal antibody to TNF-α. In contrast, clinical and laboratory markers of inflammation, such as joint swelling and acute phase reactants, were not affected by anti-TNF-α at these early time points. Moreover, arthritic mice overexpressing human TNF-α showed an altered pain behavior and a more intensive, widespread, and prolonged brain activity upon nociceptive stimuli compared with wild-type mice. Similar to humans, these changes, as well as the rewiring of CNS activity resulting in tight clustering in the thalamus, were rapidly reversed after neutralization of TNF-α. These results suggest that neutralization of TNF-α affects nociceptive brain activity in the context of arthritis, long before it achieves anti-inflammatory effects in the joints.

Physical exercise as a cognitive rehabilitation treatment after traumatic brain injury: Intensity- and sex-dependent effects.

We investigated the effects of forced physical exercise (PE) intensity on cognitive dysfunction and histological changes associated with traumatic brain injury (TBI), in both male and female rats. Controlled cortical impact (CCI) produced similar short- and long-term memory deficits in both sexes, and these deficits were associated with reduced volume and neuronal loss in the hippocampus, but not with changes in neurogenesis. We found sex differences in the effects of intensity of forced PE on cognitive recovery: all PE intensities tested improved short-term memory in both sexes, but to a greater extent in females, while long-term memory benefits were intensity- and sex-dependent. Males benefited most from low-intensity PE, while females showed optimal results at moderate intensity. These optimal PE intensities increased the neurogenesis in both sexes. A neuroprotective effect of low-intensity PE was evident in males, but no effect was observed in females. These findings suggest an intensity- and sex-specific effect of PE post-TBI, emphasizing the need for tailored PE protocols based on sex to enhance therapeutic outcomes.

Treating Traumatic Brain Injury with Exercise: Onset Delay and Previous Training as Key Factors Determining its Efficacy.

PURPOSE: Exercise reduces cognitive deficits in traumatic brain injury (TBI), but early post-trauma exercise is often discouraged due to potential harm. The purpose was to evaluate the interaction between pre- and post-injury physical exercise on cognition, neuronal survival and inflammation. METHODS: Rats were either sham-operated and kept sedentary (Sham) or subjected to controlled cortical impact injury and then distributed into sedentary (Tbi), pre-injury exercise (Pre-Tbi), post-injury exercise with early (24 hours, Tbi-early) or late (6 days, Tbi-late) onset, and a combination of pre- and post-injury exercise with early (Pre-Tbi-early) or late (Pre-Tbi-late) onset. Object recognition memory, hippocampal volume, neuronal survival (NeuN+) in the hippocampus and perirhinal cortex, and microglial activity (Iba-1) in the hippocampus were evaluated. RESULTS: All exercise conditions, except TBI-early, attenuated the significant memory impairment at 24-hour retention caused by TBI. Additionally, Pre-TBI-early treatment led to memory improvement at 3-hour retention. Pre-TBI reduced neuronal death and microglial activation in the hippocampus. TBI-late, but not TBI-early, mitigated hippocampal volume loss, loss of mature neurons in the hippocampus, and inflammation. Combining pre-injury and early-onset exercise reduced memory deficits but did not affect neuronal death or microglial activation. Combining pre-injury and late-onset exercise had a similar memory-enhancing effect than late post-injury treatment alone, albeit with reduced effects on neuronal density and neuroinflammation. CONCLUSIONS: Pre-TBI physical exercise reduces the necessary onset delay of post-TBI exercise to obtain cognitive benefits, yet the exact mechanisms underlying this reduction require further research.

Aerobic exercise and cognitive function in chronic severe traumatic brain injury survivors: a within-subject A-B-A intervention study.

BACKGROUND: Following acute and sub-acute rehabilitation from severe traumatic brain injury (TBI), minimal to no efficacious interventions to treat ongoing cognitive deficits are available. Aerobic exercise is a non-invasive behavioral intervention with promise to treat cognitive deficits in TBI populations. METHODS: Six individuals, aged 24-62 years, with chronic (> 8 months since injury) severe (Glasgow Coma Scale of 3-8) TBI were recruited from two outpatient rehabilitation centers. In an A-B-A study design, 20-weeks of supervised aerobic exercise interventions were delivered three times per week (phase B) in addition to participants typical rehabilitation schedules (phases A). The effect of phase B was tested on a trail making test part B (primary outcome measure of executive function) as well as objective daily physical activity (PA), using both group level (linear mixed effect models) and single subject statistics. RESULTS: Five of six participants increased trail-making test part B by more than 10% pre-to-post phase B, with three of six making a clinically meaningful improvement (+ 1SD in normative scores). A significant main effect of time was seen with significant improvement in trail-making test part B pre-to-post exercise (phase B). No significant effects in other planned comparisons were found. Statistically significant increases in daily moderate-to-vigorous PA were also seen during phase B compared to phase A with three of six individuals making a significant behaviour change. CONCLUSIONS: The addition of supervised aerobic exercise to typical rehabilitation strategies in chronic survivors of severe TBI can improve executive set shifting abilities and increase voluntary daily PA levels. TRIAL REGISTRATION: Retrospective trial registration on July 11 2024 with trial number: ISRCTN17487462.

The Non-Affected Muscle Volume Compensates for the Partial Loss of Strength after Injection of Botulinum Toxin A.

Local botulinum toxin (BTX-A, Botox®) injection in overactive muscles is a standard treatment in patients with cerebral palsy. The effect is markedly reduced in children above the age of 6 to 7. One possible reason for this is the muscle volume affected by the drug. Nine patients (aged 11.5; 8.7-14.5 years) with cerebral palsy GMFCS I were treated with BTX-A for equinus gait at the gastrocnemii and soleus muscles. BTX-A was administered at one or two injection sites per muscle belly and with a maximum of 50 U per injection site. Physical examination, instrumented gait analysis, and musculoskeletal modelling were used to assess standard muscle parameters, kinematics, and kinetics during gait. Magnetic resonance imaging (MRI) was used to detect the affected muscle volume. All the measurements were carried out pre-, 6 weeks post-, and 12 weeks post-BTX-A. Between 9 and 15% of the muscle volume was affected by BTX-A. There was no effect on gait kinematics and kinetics after BTX-A injection, indicating that the overall kinetic demand placed on the plantar flexor muscles remained unchanged. BTX-A is an effective drug for inducing muscle weakness. However, in our patient cohort, the volume of the affected muscle section was limited, and the remaining non-affected parts were able to compensate for the weakened part of the muscle by taking over the kinetic demands associated with gait, thus not enabling a net functional effect in older children. We recommend distributing the drug over the whole muscle belly through multiple injection sites.

DigiHEALTH: Suite of Digital Solutions for Long-Term Healthy and Active Aging.

The population in the world is aging dramatically, and therefore, the economic and social effort required to maintain the quality of life is being increased. Assistive technologies are progressively expanding and present great opportunities; however, given the sensitivity of health issues and the vulnerability of older adults, some considerations need to be considered. This paper presents DigiHEALTH, a suite of digital solutions for long-term healthy and active aging. It is the result of a fruitful trajectory of research in healthy aging where we have understood stakeholders' needs, defined the main suite properties (that would allow scalability and interoperability with health services), and codesigned a set of digital solutions by applying a continuous reflexive cycle. At the current stage of development, the digital suite presents eight digital solutions to carry out the following: (a) minimize digital barriers for older adults (authentication system based on face recognition and digital voice assistant), (b) facilitate active and healthy living (well-being assessment module, recommendation system, and personalized nutritional system), and (c) mitigate specific impairments (heart failure decompensation, mobility assessment and correction, and orofacial gesture trainer). The suite is available online and it includes specific details in terms of technology readiness level and specific conditions for usage and acquisition. This live website will be continually updated and enriched with more digital solutions and further experiences of collaboration.

Differences and similarities on neuronal activities of people being happily and unhappily in love: a functional magnetic resonance imaging study.

BACKGROUND: Brain activity was studied in grief following frustrated love compared to romantic love, and it was hypothesized that unhappy lovers compared to happy lovers would have decreased brain activity in regions specific to emotional and reward circuits, such as frontal brain areas, anterior cingulate cortex (ACC), bilateral insula or posterior cingulate cortex (PCC). METHODS: Twelve volunteers intensely in love and 12 volunteers recently separated from their romantic partners were scanned performing 3 runs of functional magnetic resonance imaging acquisition. Subjects viewed partner pictures versus erotic pictures during the first run of the scanning process, autobiographical pictures versus neutral pictures during the second and autobiographical texts versus neutral texts during the third run. The Passionate Love Scale (PLS) and the Beck Depression Inventory (BDI) were additionally recorded. RESULTS: Decreased brain activity in unhappy lovers compared to happy lovers occurred in frontal areas, ACC and PCC and bilateral insula. Unhappy lovers also revealed clinical depressive symptoms in the BDI. CONCLUSION: Unhappy lovers compared to happy lovers exhibited clinical depressive symptoms and reduced blood oxygen level dependency changes in a brain network which has been described as being involved in major depression. This might be a cue for the close relationship between grief and depression.

MTR variations in normal adult brain structures using balanced steady-state free precession.

INTRODUCTION: Magnetization transfer (MT) is sensitive to the macromolecular environment of water protons and thereby provides information not obtainable from conventional magnetic resonance imaging (MRI). Compared to standard methods, MT-sensitized balanced steady-state free precession (bSSFP) offers high-resolution images with significantly reduced acquisition times. In this study, high-resolution magnetization transfer ratio (MTR) images from normal appearing brain structures were acquired with bSSFP. METHODS: Twelve subjects were studied on a 1.5 T scanner. MTR values were calculated from MT images acquired in 3D with 1.3 mm isotropic resolution. The complete MT data set was acquired within less than 3.5 min. Forty-one brain structures of the white matter (WM) and gray matter (GM) were identified for each subject. RESULTS: MTR values were higher for WM than GM. In general, MTR values of the WM and GM structures were in good accordance with the literature. However, MTR values showed more homogenous values within WM and GM structures than previous studies. CONCLUSIONS: MT-sensitized bSSFP provides isotropic high-resolution MTR images and hereby allows assessment of reliable MTR data in also very small brain structures in clinically feasible acquisition times and is thus a promising sequence for being widely used in the clinical routine. The present normative data can serve as a reference for the future characterization of brain pathologies.

Probiotic Properties of Bifidobacterium longum KABP042 and Pediococcus pentosaceus KABP041 Show Potential to Counteract Functional Gastrointestinal Disorders in an Observational Pilot Trial in Infants.

Functional gastrointestinal disorders (FGIDs) are a common concern during the first year of life. Recognized as gut-brain axis disorders by Rome IV criteria, FGIDs etiology is linked to altered gut-brain interaction, intestinal physiology, and microbiota. In this regard, probiotics have emerged as a promising therapy for infant FGIDs. In this study, we have investigated the probiotic potential of the strains Bifidobacterium longum KABP042 and Pediococcus pentosaceus KABP041-isolated from healthy children's feces-in the treatment of FGIDs. To this scope, genome sequences of both strains were obtained and subjected to in silico analyses. No virulence factors were detected for any strain and only the non-transferable erm(49) gene, which confers resistance to erythromycin and clindamycin, was identified in the genome of B. longum KABP042. Safety of both strains was confirmed by acute oral toxicity in rats. In vitro characterization revealed that the strains tolerate gastric and bile challenges and display a great adhesion capacity to human intestinal cells. The two strains mediate adhesion by different mechanisms and, when combined, synergically induce the expression of Caco-2 tight junction proteins. Moreover, growth inhibition experiments demonstrated the ability of the two strains alone and in combination to antagonize diverse Gram-negative and Gram-positive bacterial pathogens during sessile and planktonic growth. Pathogens' inhibition was mostly mediated by the production of organic acids, but neutralization experiments strongly suggested the presence of additional antimicrobial compounds in probiotic culture supernatants such as the bacteriocin Lantibiotic B, whose gene was detected in the genome of B. longum KABP042. Finally, an exploratory, observational, pilot study involving 36 infants diagnosed with at least one FGID (infant colic and/or functional constipation) showed the probiotic formula was well tolerated and FGID severity was significantly reduced after 14 days of treatment with the 2 strains. Overall, this work provides evidence of the probiotic and synergic properties of strains B. longum KABP042 and P. pentosaceus KABP041, and of their potential to treat pediatric FGIDs. Clinical Trial Registration: [www.ClinicalTrials.gov], [identifier NCT04944628].

Quantification and Monitoring of the Effect of Botulinum Toxin A on Paretic Calf Muscles of Children With Cerebral Palsy With MRI: A Preliminary Study.

Background: Muscles from patients with cerebral palsy (CP) are often spastic and form contractures that limit the range of motion. Injections of botulinum toxin A (BTX) into the calf muscles are an important treatment for functional equinus; however, improvement in gait function is not always achieved. BTX is also used to test muscle weakening for risk evaluation of muscle lengthening surgery. Our aim was to assess the effect of BTX over time on calf muscle properties in pediatric CP patients with MRI. Material and Methods: Six toe-walking CP patients (mean age 11.6 years) with indication for lengthening surgery were prospectively enrolled and received BTX injections into the gastrocnemius and soleus muscles. MRI scans at 3T of the lower legs and clinical examinations were performed pre-BTX, 6 weeks (6w), and 12 weeks (12w) post-BTX. A fat-suppressed 2D multi-spin-echo sequence was used to acquire T2 maps and for segmentation. Fat fraction maps were calculated from 3D multi-echo Dixon images. Diffusion tensor imaging (DTI) with a 2D echo-planar imaging (EPI) sequence yielded maps of the mean apparent diffusion coefficient (ADC) and of the fractional anisotropy (FA). Hyperintense regions of interest (ROIs) on the T2-weighted (T2w) images at 6w were segmented in treated muscles. Mean values of T2, fat fraction, ADC, and FA were calculated in hyperintense ROIs and in reference ROIs in non-treated muscles. Results: Hyperintensity on T2w scans and increased T2 (group mean ± standard deviation: 35 ± 1 ms pre-BTX, 45 ± 2 ms at 6w, and 44 ± 2 ms at 12w) were observed in all patients at the injection sites. The T2 increase was spatially limited to parts of the injected muscles. FA increased (0.30 ± 0.03 pre-BTX, 0.34 ± 0.02 at 6w, and 0.36 ± 0.03 at 12w) while ADC did not change in hyperintense ROIs, indicating a BTX-induced increase in extracellular space and a simultaneous decrease of muscle fiber diameter. Fat fraction showed a trend for increase at 12w. Mean values in reference ROIs remained unchanged. Conclusion: MRI showed limited spatial distribution of the BTX-induced effects in pediatric CP patients. It could be a promising non-invasive tool for future studies to test BTX treatment protocols.

Delayed voluntary physical exercise restores "when" and "where" object recognition memory after traumatic brain injury.

Physical exercise has been associated with improved cognition and may even reduce memory deficits after brain injuries. The aims of this work were to: 1) assess whether voluntary physical exercise can reduce the deficits associated with traumatic brain injury (TBI) in two different components of episodic-like memory based on object recognition, temporal order memory ("when"), and object location memory ("where"); and 2) determine whether changes in levels of brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex, as well as alterations in hippocampal cytokines, insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF), may influence the effects exercise has on either or both tasks. The rats were distributed into a sham group, a TBI group that remained sedentary (TBI-sed), and a TBI group that had access to a running wheel for a 25-day period from post-injury day 11 (TBI-exe). The rats were sacrificed after the "where" memory task, at post-injury day 37. Physical exercise restored the "when" and "where" memories, which had been impaired by the TBI, and increased the concentration of BDNF in the hippocampus, but not the prefrontal cortex. Neither TBI nor exercise were found to significantly affect hippocampal cytokines, IGF-1 or VEGF at this time post-injury. BDNF levels showed significant positive correlations with exercise, and with "when" (but not "where") memory. These results indicate that post-injury physical exercise restores "when" and "where" object recognition memory tasks after TBI, and that increased BDNF seems to be involved in this effect, particularly with regard to "when" memory.

Regular Consumption of Lipigo® Promotes the Reduction of Body Weight and Improves the Rebound Effect of Obese People Undergo a Comprehensive Weight Loss Program.

Obesity is a global public health problem. OBJECTIVE: To evaluate the effect of the regular consumption of the product Lipigo® on body weight and rebound effect on overweight/obese subjects undergoing a comprehensive weight loss program. METHODS: A randomized, parallel, double-blind, placebo-controlled clinical trial was conducted with male and female subjects presenting a BMI 25-39.9 kg/m2. All subjects underwent a comprehensive weight loss program (WLP) for 12 weeks, which included an individualized hypocaloric diet, physical activity recommendations, nutritional education seminars, and three times a day consumption of the product Lipigo® or Placebo. After-WLP, subjects continued the treatment for 9 months to assess rebound effect. Body weight (BW), BMI, and body composition were measured at the beginning and the end of the WLP, and in the follow-up. RESULTS: A total of 120 subjects (85% women) 49.0 ± 9.5 years old and with a BW of 81.57 ± 13.26 kg (BMI 31.19 ± 3.44 kg/m2) were randomized and 73 subjects finished the study. At the end of the WLP, there was a tendency toward reduced BW (p = 0.093), BMI (p = 0.063), and WC (p = 0.059) in the treated group. However, subjects with obesity type 1 (OB1) from the treated group significantly reduced body weight (-5.27 ± 2.75 vs. -3.08 ± 1.73 kg; p = 0.017) and BMI (-1.99 ± 1.08 vs. -1.09 ± 0.55 kg/m2; p = 0.01) compared with placebo. They also presented a minor rebound effect after 9 months with product consumption (-4.19 ± 3.61 vs. -1.44 ± 2.51 kg; p = 0.026), minor BMI (-1.61 ± 1.43 vs. -0.52 ± 0.96 kg/m2; p = 0.025) and tended to have less fat-mass (-3.44 ± 2.46 vs. -1.44 ± 3.29 kg; p = 0.080) compared with placebo. CONCLUSIONS: The regular consumption of the product Lipigo® promotes the reduction of body weight and reduces the rebound effect of obese people after 52 weeks (12 months), mainly in obesity type 1, who undergo a comprehensive weight loss program.

Relevance of host tau in tau seeding and spreading in tauopathies.

Human tau seeding and spreading occur following intracerebral inoculation of brain homogenates obtained from tauopathies in transgenic mice expressing natural or mutant tau, and in wild-type (WT) mice. The present study was geared to learning about the patterns of tau seeding, the cells involved and the characteristics of tau following intracerebral inoculation of homogenates from primary age-related tauopathy (PART: neuronal 4Rtau and 3Rtau), aging-related tau astrogliopathy (ARTAG: astrocytic 4Rtau) and globular glial tauopathy (GGT: 4Rtau with neuronal deposits and specific tau inclusions in astrocytes and oligodendrocytes). For this purpose, young and adult WT mice were inoculated unilaterally in the hippocampus or in the lateral corpus callosum with sarkosyl-insoluble fractions from PART, ARTAG and GGT cases, and were killed at variable periods of three to seven months. Brains were processed for immunohistochemistry in paraffin sections. Tau seeding occurred in the ipsilateral hippocampus and corpus callosum and spread to the septal nuclei, periventricular hypothalamus and contralateral corpus callosum, respectively. Tau deposits were mainly found in neurons, oligodendrocytes and threads; the deposits were diffuse or granular, composed of phosphorylated tau, tau with abnormal conformation and 3Rtau and 4Rtau independently of the type of tauopathy. Truncated tau at the aspartic acid 421 and ubiquitination were absent. Tau deposits had the characteristics of pre-tangles. A percentage of intracellular tau deposits co-localized with active (phosphorylated) tau kinases p38 and ERK 1/2. Present study shows that seeding and spreading of human tau into the brain of WT mice involves neurons and glial cells, mainly oligodendrocytes, thereby supporting the idea of a primary role of oligodendrogliopathy, together with neuronopathy, in the progression of tauopathies. In addition, it suggests that human tau inoculation modifies murine tau metabolism with the production and deposition of 3Rtau and 4Rtau, and by activation of specific tau kinases in affected cells.

The benefits of voluntary physical exercise after traumatic brain injury on rat's object recognition memory: A comparison of different temporal schedules.

Physical exercise can reduce the cognitive decline associated with traumatic brain injury, yet little is known about the optimal administration schedules. Here, different protocols of voluntary wheel running were evaluated for their effects on object recognition memory (ORM), neuroprotection (NeuN+ cells), microglial reactivity (Iba1 staining) and neurogenesis (DCX+ cells) after controlled cortical impact injury (CCI). CCI-lesioned rats were divided into a sedentary group and three exercise groups: early discontinued exercise (3 weeks of exercise initiated 4 days post-injury, followed by 4 weeks in a sedentary state); delayed exercise (3 weeks of exercise initiated 4 weeks post-injury), and early continuous exercise (7 weeks of exercise starting 4 days post-injury). The deficits induced by CCI in a 24 h ORM test were reversed in the delayed exercise group and reduced in the early discontinued and early continuous groups. The early discontinued protocol also reduced the loss of NeuN+ cells in the hilus, while attenuated microglial reactivity was found in the dorsal hippocampus of both the early exercising groups. Running at the end of the experiment increased the number of DCX+ cells in the early continuous and delayed groups, and an inverted U-shaped relationship was found between the mean daily exercise time and the amount of neurogenesis. Thus, exercise had benefits on memory both when it was commenced soon and later after injury, although the neural mechanisms implicated differed. Accordingly, the effects of exercise on memory and neurogenesis appear to not only depend on the specific temporal schedule but also, they may be influenced by the amount of daily exercise.

Valproate-induced metabolic changes in patients with epilepsy: assessment with H-MRS.

PURPOSE: Valproate (VPA) interferes with mitochondrial metabolism causing hyperammonemia, thereby shifting the balance reaction of glutamine (Gln)/glutamate (Glu) toward Gln. In this study we wanted to determine whether metabolic changes could be reproduced in VPA-treated patients with epilepsy and whether the results differed from those known in chronic hepatic encephalopathy (CHE). METHODS: Seven patients with epilepsy pretreated with VPA and seven healthy volunteers were investigated on a 3T-scanner. We performed proton magnetic resonance spectroscopy ((1)H-MRS) using a short echo time point-resolved spectroscopy (PRESS) in the parietal and occipital lobe, respectively. Spectral analysis was performed by LCModel, allowing a separation of Glu and Gln at 3T. Absolute values of myo-Inositol (mI), choline (Cho), creatine (Cr), N-acetyl-aspartate (NAA), glutamine (Gln), glutamate (Glu), and the sum of Gln and Glu (Glx) were calculated. RESULTS: In the parietal lobe, mI was significantly decreased in the patients' group compared to the healthy volunteers. After separation of the signals of Gln and Glu, a significant increase of Gln was observed in the parietal lobe in the patients' group. No significant differences in the occipital spectra could be observed between the groups. DISCUSSION: In VPA-treated patients the alteration of the Glu/Gln ratio differs from that in patients with CHE, where Glx is markedly increased because of an increase in Gln. The expected shift from the biochemical balance reaction of Gln/Glu induced by VPA could be reproduced for the parietal lobe. Significantly reduced mI in the parietal lobe of VPA-treated patients most likely reflects an osmolytic compensation for high Gln.

Involvement of Oligodendrocytes in Tau Seeding and Spreading in Tauopathies.

Introduction: Human tau seeding and spreading occur following intracerebral inoculation into different gray matter regions of brain homogenates obtained from tauopathies in transgenic mice expressing wild or mutant tau, and in wild-type (WT) mice. However, little is known about tau propagation following inoculation in the white matter. Objectives: The present study is geared to learning about the patterns of tau seeding and cells involved following unilateral inoculation in the corpus callosum of homogenates from sporadic Alzheimer's disease (AD), primary age-related tauopathy (PART: neuronal 4Rtau and 3Rtau), pure aging-related tau astrogliopathy (ARTAG: astroglial 4Rtau with thorn-shaped astrocytes TSAs), globular glial tauopathy (GGT: 4Rtau with neuronal tau and specific tau inclusions in astrocytes and oligodendrocytes, GAIs and GOIs, respectively), progressive supranuclear palsy (PSP: 4Rtau with neuronal inclusions, tufted astrocytes and coiled bodies), Pick's disease (PiD: 3Rtau with characteristic Pick bodies in neurons and tau containing fibrillar astrocytes), and frontotemporal lobar degeneration linked to P301L mutation (FTLD-P301L: 4Rtau familial tauopathy). Methods: Adult WT mice were inoculated unilaterally in the lateral corpus callosum with sarkosyl-insoluble fractions or with sarkosyl-soluble fractions from the mentioned tauopathies; mice were killed from 4 to 7 months after inoculation. Brains were fixed in paraformaldehyde, embedded in paraffin and processed for immunohistochemistry. Results: Tau seeding occurred in the ipsilateral corpus callosum and was also detected in the contralateral corpus callosum. Phospho-tau deposits were found in oligodendrocytes similar to coiled bodies and in threads. Moreover, tau deposits co-localized with active (phosphorylated) tau kinases p38 and ERK 1/2, suggesting active tau phosphorylation of murine tau. TSAs, GAIs, GOIs, tufted astrocytes, and tau-containing fibrillar astrocytes were not seen in any case. Tau deposits were often associated with slight myelin disruption and the presence of small PLP1-immunoreactive globules and dots in the ipsilateral corpus callosum 6 months after inoculation of sarkosyl-insoluble fractions from every tauopathy. Conclusions: Seeding and spreading of human tau in the corpus callosum of WT mice occurs in oligodendrocytes, thereby supporting the idea of a role of oligodendrogliopathy in tau seeding and spreading in the white matter in tauopathies. Slight differences in the predominance of threads or oligodendroglial deposits suggest disease differences in the capacity of tau seeding and spreading among tauopathies.