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.

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.

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.

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.

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].

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.

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.

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.

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.

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.

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.

Diagnostic challenges and future perspectives in fracture-related infection.

Fracture-related infection (FRI) is one of the most challenging complications in orthopaedic trauma surgery. It has severe consequences for patients and an important socio-economic impact. FRI has distinct properties and needs to be addressed interdisciplinary. Since criteria for the diagnosis of FRI are not standardized, an expert panel recently proposed a definition for FRI. In this review the current diagnostic modalities and an interdisciplinary diagnostic algorithm based on this recently published definition, are presented and future diagnostic techniques discussed. Since to date, there is no single universal diagnostic test available that gives the clinician the definitive diagnosis of FRI, it is mandatory to follow a standardized diagnostic algorithm to correctly diagnose FRI.

Initial evaluation of image performance of a 3-D x-ray system: phantom-based comparison of 3-D tomography with conventional computed tomography.

Phantom-based initial performance assessment of a prototype three-dimensional (3-D) x-ray system and comparison of 3-D tomography with computed tomography (CT) were proposed. A 3-D image quality phantom was scanned with a prototype version of 3-D cone-beam CT imaging implemented on a twin robotic x-ray system using three trajectories (163 deg = table, 188 deg = upright, and 200 deg = side), six tube voltages (60, 70, 81, 90, 100, and 121 kV), and four detector doses (0.348, 0.696, 1.740, and [Formula: see text]). CT was obtained with a clinical protocol. Spatial resolution (line pairs/cm) and soft-tissue-contrast resolution were assessed by two independent readers. Radiation dose was assessed. Descriptive and analysis of variance (ANOVA) ([Formula: see text]) were performed. With 3-D tomography, a maximum of 16 lp/cm was visible and best soft-tissue-contrast resolution was 2 mm at 30 Hounsfield units (HU) for 160 projections. With CT, 10 lp/cm was visible and soft-tissue-contrast resolution was 4 mm at 20 HU. The upright trajectory yielded significantly better spatial resolution and soft tissue contrast, and the side trajectory yielded significantly higher soft tissue contrast than the table trajectory ([Formula: see text]). Radiation dose was higher in 3-D tomography (45 to 704 mGycm) than CT (44 mGycm). Three-dimensional tomography renders overall equal or higher spatial resolution and comparable soft tissue contrast to CT for medium- and high-dose protocols in the side and upright trajectories, but with higher radiation doses.

Aging-related tau astrogliopathy (ARTAG): not only tau phosphorylation in astrocytes.

Aging-related tau astrogliopathy (ARTAG) is defined by the presence of two types of tau-bearing astrocytes: thorn-shaped astrocytes (TSAs) and granular/fuzzy astrocytes in the brain of old-aged individuals. The present study is focused on TSAs in rare forms of ARTAG with no neuronal tau pathology or restricted to entorhinal and transentorhinal cortices, to avoid bias from associated tauopathies. TSAs show 4Rtau phosphorylation at several specific sites and abnormal tau conformation, but they lack ubiquitin and they are not immunostained with tau-C3 antibodies which recognize truncated tau at Asp421. Astrocytes in ARTAG have atrophic processes, reduced glial fibrillary acidic protein (GFAP) and increased superoxide dismutase 2 (SOD2) immunoreactivity. Gel electrophoresis and western blotting of sarkosyl-insoluble fractions reveal a pattern of phospho-tau in ARTAG characterized by two bands of 68 and 64 kDa, and several middle bands between 35 and 50 kDa which differ from what is seen in AD. Phosphoproteomics of dissected vulnerable regions identifies an increase of phosphorylation marks in a large number of proteins in ARTAG compared with controls. GFAP, aquaporin 4, several serine-threonine kinases, microtubule associated proteins and other neuronal proteins are among the differentially phosphorylated proteins in ARTAG thus suggesting a hyper-phosphorylation background that affects several molecules, including many kinases and proteins from several cell compartments and various cell types. Finally, present results show for the first time that tau seeding is produced in neurons of the hippocampal complex, astrocytes, oligodendroglia and along fibers of the corpus callosum, fimbria and fornix following inoculation into the hippocampus of wild type mice of sarkosyl-insoluble fractions enriched in hyper-phosphorylated tau from selected ARTAG cases. These findings show astrocytes as crucial players of tau seeding in tauopathies.

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.

Posttraining Epinephrine Reverses Memory Deficits Produced by Traumatic Brain Injury in Rats.

The aim of this research is to evaluate whether posttraining systemic epinephrine is able to improve object recognition memory in rats with memory deficits produced by traumatic brain injury. Forty-nine two-month-old naïve male Wistar rats were submitted to surgical procedures to induce traumatic brain injury (TBI) or were sham-operated. Rats were trained in an object recognition task and, immediately after training, received an intraperitoneal injection of distilled water (Sham-Veh and TBI-Veh group) or 0.01 mg/kg epinephrine (TBI-Epi group) or no injection (TBI-0 and Sham-0 groups). Retention was tested 3 h and 24 h after acquisition. The results showed that brain injury produced severe memory deficits and that posttraining administration of epinephrine was able to reverse them. Systemic administration of distilled water also had an enhancing effect, but of a lower magnitude. These data indicate that posttraining epinephrine and, to a lesser extent, vehicle injection reduce memory deficits associated with TBI, probably through induction of a low-to-moderate emotional arousal.

Traumatic brain injury in late adolescent rats: effects on adulthood memory and anxiety.

The consequences of traumatic brain injury (TBI) sustained during late adolescence (7 weeks old) on spontaneous object recognition memory and on anxiety-like behaviors in the elevated plus maze were tested in rats during adulthood. Testing took place at 2 different postinjury times, in separate groups: 3 and 6 weeks, when animals were 10 and 13 weeks old, respectively. The rats were either submitted to controlled cortical impact injury, an experimental model of focal TBI with contusion, or were sham-operated. TBI animals failed to remember the familiar object and had a significantly lower performance than sham-operated animals, indicating memory disruption, when the retention delay was 24 hr, but not when it was 3 hr. TBI did not have any significant effect on the main anxiety-related behaviors, but it reduced time in the central platform of the elevated plus maze. The effects of TBI on memory and on anxiety-like behaviors were similar at the 2 postinjury times. In both TBI and sham-operated groups, animals tested 6 weeks after surgery had lower anxiety-related indices than those tested at 3 weeks, an effect that might be indicative of reduced anxiety levels with increasing age. In summary, focal TBI with contusion sustained during late adolescence led to object recognition memory deficits in a 24-hr test during adulthood but did not have a major impact on anxiety-like behaviors. Memory deficits persisted for at least 6 weeks after injury, indicating that spontaneous modifications of these functional disturbances did not take place along this time span.