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Previous work has shown that motor skill learning stimulates and requires generation of myelinating oligodendrocytes (OLs) from their precursor cells (OLPs) in the brains of adult mice. In the present study we ask whether OL production is also required for non-motor learning and cognition, using T-maze and radial-arm-maze tasks that tax spatial working memory. We find that maze training stimulates OLP proliferation and OL production in the medial prefrontal cortex (mPFC), anterior corpus callosum (genu), dorsal thalamus and hippocampal formation of adult male mice; myelin sheath formation is also stimulated in the genu. Genetic blockade of OL differentiation and neo-myelination in Myrf conditional-knockout mice strongly impairs training-induced improvements in maze performance. We find a strong positive correlation between the performance of individual wild type mice and the scale of OLP proliferation and OL generation during training, but not with the number or intensity of c-Fos+ neurons in their mPFC, underscoring the important role played by OL lineage cells in cognitive processing.
\n \n\n \n \nIntroductionThere is growing evidence that sleep is disrupted after stroke, with worse sleep relating to poorer motor outcomes. It is also widely acknowledged that consolidation of motor learning, a critical component of poststroke recovery, is sleep-dependent. However, whether the relationship between disrupted sleep and poor outcomes after stroke is related to direct interference of sleep-dependent motor consolidation processes, is currently unknown. Therefore, the aim of the present study is to understand whether measures of motor consolidation mediate the relationship between sleep and clinical motor outcomes post stroke.Methods and analysisWe will conduct a longitudinal observational study of up to 150 participants diagnosed with stroke affecting the upper limb. Participants will be recruited and assessed within 7\u2009days of their stroke and followed up at approximately 1 and 6 months. The primary objective of the study is to determine whether sleep in the subacute phase of recovery explains the variability in upper limb motor outcomes after stroke (over and above predicted recovery potential from the Predict Recovery Potential algorithm) and whether this relationship is dependent on consolidation of motor learning. We will also test whether motor consolidation mediates the relationship between sleep and whole-body clinical motor outcomes, whether motor consolidation is associated with specific electrophysiological sleep signals and sleep alterations during subacute recovery.Ethics and disseminationThis trial has received both Health Research Authority, Health and Care Research Wales and National Research Ethics Service approval (IRAS: 304135; REC: 22/LO/0353). The results of this trial will help to enhance our understanding of the role of sleep in recovery of motor function after stroke and will be disseminated via presentations at scientific conferences, peer-reviewed publication, public engagement events, stakeholder organisations and other forms of media where appropriate.Trial registration numberClinicalTrials.gov:NCT05746260, registered on 27 February 2023.
\n \n\n \n \nBackgroundMobility limitation in older age reduces quality of life, generates substantial health- and social-care costs, and increases mortality.ObjectiveThe REtirement in ACTion (REACT) trial aimed to establish whether or not a community-based active ageing intervention could prevent decline in physical functioning in older adults already at increased risk of mobility limitation.DesignA multicentre, pragmatic, two-arm, parallel-group randomised controlled trial with parallel process and health economic evaluations.SettingUrban and semi-rural locations across three sites in England.ParticipantsPhysically frail or pre-frail older adults (aged \u2265\u200965 years; Short Physical Performance Battery score of 4\u20139). Recruitment was primarily via 35 primary care practices.InterventionsParticipants were randomly assigned to receive brief advice (three healthy ageing education sessions) or a 12-month, group-based, multimodal exercise and behavioural maintenance programme delivered in fitness and community centres. Randomisation was stratified by site and used a minimisation algorithm to balance age, sex and Short Physical Performance Battery score. Data collection and analyses were blinded.Main outcome measuresThe primary outcome was change in lower limb physical function (Short Physical Performance Battery score) at 24 months, analysed using an intention-to-treat analysis. The economic evaluation adopted the NHS and Personal Social Services perspective.ResultsBetween June 2016 and October 2017, 777 participants (mean age 77.6 years, standard deviation 6.8 years; 66% female; mean Short Physical Performance Battery score 7.37, standard deviation 1.56) were randomised to the intervention arm (n\u2009=\u2009410) or the control arm (n\u2009=\u2009367). Data collection was completed in October 2019. Primary outcome data at 24 months were provided by 628 (80.8%) participants. At the 24-month follow-up, the Short Physical Performance Battery score was significantly greater in the intervention arm (mean 8.08, standard deviation 2.87) than in the control arm (mean 7.59, standard deviation 2.61), with an adjusted mean difference of 0.49 (95% confidence interval 0.06 to 0.92). The difference in lower limb function between intervention and control participants was clinically meaningful at both 12 and 24 months. Self-reported physical activity significantly increased in the intervention arm compared with the control arm, but this change was not observed in device-based physical activity data collected during the trial. One adverse event was related to the intervention. Attrition rates were low (19% at 24 months) and adherence was high. Engagement with the REACT intervention was associated with positive changes in exercise competence, relatedness and enjoyment and perceived physical, social and mental well-being benefits. The intervention plus usual care was cost-effective compared with care alone over the 2 years of REACT; the price year was 2019. In the base-case scenario, the intervention saved \u00a3103 per participant, with a quality-adjusted life-year gain of 0.04 (95% confidence interval 0.006 to 0.074) within the 2-year trial window. Lifetime horizon modelling estimated that further cost savings and quality-adjusted life-year gains were accrued up to 15 years post randomisation.ConclusionA relatively low-resource, 1-year multimodal exercise and behavioural maintenance intervention can help older adults to retain physical functioning over a 24-month period. The results indicate that the well-established trajectory of declining physical functioning in older age is modifiable.LimitationsParticipants were not blinded to study arm allocation. However, the primary outcome was independently assessed by blinded data collectors. The secondary outcome analyses were exploratory, with no adjustment for multiple testing, and should be interpreted accordingly.Future workFollowing refinements guided by the process evaluation findings, the REACT intervention is suitable for large-scale implementation. Further research will optimise implementation of REACT at scale.Trial registrationThis trial is registered as ISRCTN45627165.FundingThis project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 10, No. 14. See the NIHR Journals Library website for further project information.
\n \n\n \n \nHealth-related behaviours have been related to brain structural features. In developing settings, such as Latin America, high social inequality has been inversely associated with several health-related behaviours affecting brain development. Understanding the relationship between health behaviours and brain structure in such settings is particularly important during adolescence when critical habits are acquired and ingrained. In this cross-sectional study, we carry out a multimodal analysis identifying a brain region associated with health-related behaviours (i.e., adiposity, fitness, sleep problems and others) and cognitive/academic performance, independent of socioeconomic status in a large sample of Chilean adolescents. Our findings suggest that the relationship between health behaviours and cognitive/academic performance involves a particular brain phenotype that could play a mediator role. These findings fill a significant gap in the literature, which has largely focused on developed countries and raise the possibility of promoting healthy behaviours in adolescence as a means to influence brain structure and thereby cognitive/academic achievement, independently of socioeconomic factors. By highlighting the potential impact on brain structure and cognitive/academic achievement, policymakers could design interventions that are more effective in reducing health disparities in developing countries.
\n \n\n \n \nBetter understanding of breathlessness perception addresses an unmet clinical need for more effective treatments for intractable dyspnoea, a prevalent symptom of multiple medical conditions. The insular-cortex is predominantly activated in brain-imaging studies of dyspnoea, but its precise role remains unclear. We measured experimentally-induced hypercapnic air-hunger in three insular-glioma patients before and after surgical resection. Tests involved one-minute increments in inspired CO2, raising end-tidal PCO2 to 7.5\u2009mmHg above baseline (38.5\u2009\u00b1\u20095.7\u2009mmHg), whilst ventilation was constrained (10.7\u2009\u00b1\u20092.3\u2009L/min). Patients rated air-hunger on a visual analogue scale (VAS). Patients had lower stimulus-response (2.8\u2009\u00b1\u20092 vs. 11\u2009\u00b1\u20094 %VAS/mmHg; p\u2009=\u20090.004), but similar threshold (40.5\u2009\u00b1\u20093.9 vs. 43.2\u2009\u00b1\u20095.1\u2009mmHg), compared to healthy individuals. Volunteered comments implicated diminished affective valence. After surgical resection; sensitivity increased in one patient, decreased in another, and other was unable to tolerate the ventilatory limit before any increase in inspired CO2.We suggest that functional insular-cortex is essential to register breathlessness unpleasantness and could be targeted with neuromodulation in chronically-breathless patients. Neurological patients with insula involvement should be monitored for blunted breathlessness to inform clinical management.
\n \n\n \n \nSymptoms in people with carpal tunnel syndrome (CTS) are traditionally attributed to neural tissue, but recent studies suggest that the subsynovial connective tissue (SSCT) may also play a role in CTS. The SSCT undergoes fibrotic thickening which is generally described as \u201cnon-inflammatory\u201d based on basic histology. This study uses immunohistochemistry to determine the presence of macrophages and T-cells within SSCT and their relationship with symptoms in people with CTS. SSCT was collected from twenty people with CTS and eight controls undergoing wrist fracture surgery. Immunohistochemical quantification of CD3+ T-cells and CD68+ macrophage densities as well as CD4+/CD8+ T-cell subpopulations were compared between groups using independent t-tests. Spearman correlations were used to identify associations between immune cell densities and CTS symptom scores. The density of CD3+ T-cells was significantly higher in SSCT of people with CTS compared to controls (CTS mean 26.7 (SD 13.7); controls 6.78 (6.3), p = 0.0005) while the density of CD68+ macrophages was lower (CTS mean 9.5 (SD 6.0); controls 17.7 (8.2), p = 0.0058). Neither CD68+ nor CD3+ cell densities correlated with symptom scores. In contrast to previous assumptions, our data show that the SSCT in the carpal tunnel in both people with CTS and controls is not devoid of immune cells. Whereas the higher density of CD68+ macrophages in control participants may be associated with their early recruitment after acute fracture, CD3+ cells within the SSCT may play a role in chronic CTS.
\n \n\n \n \nPURPOSE: Cotoretigene toliparvovec (BIIB112/AAV8-RPGR) is an investigational vector-based gene therapy designed to provide a full-length, codon-optimized, retinitis pigmentosa GTPase regulator (RPGR) protein to individuals with RPGR-associated X-linked retinitis pigmentosa (XLRP). We assessed efficacy and safety of cotoretigene toliparvovec subretinal gene therapy. DESIGN: Part 2 of the XIRIUS trial (NCT03116113) was a Phase 2/3, 12-month, randomized (1:1:1), dose-expansion study. PARTICIPANTS: Males aged \u226510 years with RPGR-associated XLRP were included. METHODS: Participants were randomized 1:1:1 to subretinal cotoretigene toliparvovec low dose (5 \u00d7 1010 vector genomes [vg]/eye), cotoretigene toliparvovec high dose (2.5 \u00d7 1011 vg/eye), or untreated control. MAIN OUTCOME MEASURES: The primary endpoint was the percentage of participants meeting microperimetry responder criteria (\u22657 dB improvement at \u22655 of 16 central loci). Secondary endpoints included change from baseline in retinal sensitivity at the central 16 loci and the entire 68 loci at 12 months and change from baseline in low-luminance visual acuity (LLVA) at 12 months; and the proportion of eyes with a \u226515 and \u226510 LLVA ETDRS letter change from baseline at month 12. RESULTS: Because of the impact of COVID-19, enrollment ended before reaching the initial target, leaving the trial underpowered. Twenty-nine participants were included (low dose n=10, high dose n=10, control n=9). At month 12, the percentage of participants meeting microperimetry responder criteria was not significantly different between cotoretigene toliparvovec (low dose, 37.5%, P=0.3181; high dose, 25.0%, P=0.5177) and control (22.2%). Mean change from baseline in microperimetry sensitivity, however, significantly improved with the low dose versus control at month 12 (P=0.0350). Significant improvement in LLVA occurred with low dose versus control at month 12 (33.3% difference [80% CI, 14.7-55.2]; P=0.0498). Three ocular-related serious adverse events occurred in the low-dose group versus 7 in the high-dose group. CONCLUSIONS: The primary microperimetry endpoint was not met. Significant improvements in LLVA and mean microperimetry and fewer serious adverse events were observed with low-dose cotoretigene toliparvovec.
\n \n\n \n \nAbstractThere is strong evidence of brain-related abnormalities in COVID-191\u201313. However, it remains unknown whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here we investigated brain changes in 785 participants of UK Biobank (aged 51\u201381 years) who were imaged twice\u00a0using magnetic resonance imaging, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans\u2014with 141 days on average separating their diagnosis and the second scan\u2014as well as 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. We identified significant longitudinal effects when comparing the two groups, including (1) a greater reduction in grey matter thickness and tissue contrast in the orbitofrontal cortex and parahippocampal gyrus; (2) greater changes in markers of tissue damage in regions that are functionally connected to the primary olfactory cortex; and (3) a greater reduction in global brain size\u00a0in the SARS-CoV-2 cases. The participants who were infected with SARS-CoV-2 also showed on average a greater cognitive decline between the two time points. Importantly, these imaging and cognitive longitudinal effects were still observed after excluding the 15 patients who had been hospitalised. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease through olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious effect can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow-up.
\n \n\n \n \nAbstractThere is strong evidence for brain-related abnormalities in COVID-191\u201313. It remains unknown however whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here, we investigated brain changes in 785 UK Biobank participants (aged 51\u201381) imaged twice, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans, with 141 days on average separating their diagnosis and second scan, and 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. We identified significant longitudinal effects when comparing the two groups, including: (i) greater reduction in grey matter thickness and tissue-contrast in the orbitofrontal cortex and parahippocampal gyrus, (ii) greater changes in markers of tissue damage in regions functionally-connected to the primary olfactory cortex, and (iii) greater reduction in global brain size. The infected participants also showed on average larger cognitive decline between the two timepoints. Importantly, these imaging and cognitive longitudinal effects were still seen after excluding the 15 cases who had been hospitalised. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease via olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious impact can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow up.
\n \n\n \n \nAbstractBackgroundThe medium-term effects of Coronavirus disease (COVID-19) on multiple organ health, exercise capacity, cognition, quality of life and mental health are poorly understood.MethodsFifty-eight COVID-19 patients post-hospital discharge and 30 comorbidity-matched controls were prospectively enrolled for multiorgan (brain, lungs, heart, liver and kidneys) magnetic resonance imaging (MRI), spirometry, six-minute walk test, cardiopulmonary exercise test (CPET), quality of life, cognitive and mental health assessments.FindingsAt 2-3 months from disease-onset, 64% of patients experienced persistent breathlessness and 55% complained of significant fatigue. On MRI, tissue signal abnormalities were seen in the lungs (60%), heart (26%), liver (10%) and kidneys (29%) of patients. COVID-19 patients also exhibited tissue changes in the thalamus, posterior thalamic radiations and sagittal stratum on brain MRI and demonstrated impaired cognitive performance, specifically in the executive and visuospatial domain relative to controls. Exercise tolerance (maximal oxygen consumption and ventilatory efficiency on CPET) and six-minute walk distance (405\u00b1118m vs 517\u00b1106m in controls, p<0.0001) were significantly reduced in patients. The extent of extra-pulmonary MRI abnormalities and exercise tolerance correlated with serum markers of ongoing inflammation and severity of acute illness. Patients were more likely to report symptoms of moderate to severe anxiety (35% versus 10%, p=0.012) and depression (39% versus 17%, p=0.036) and a significant impairment in all domains of quality of life compared to controls.InterpretationA significant proportion of COVID-19 patients discharged from hospital experience ongoing symptoms of breathlessness, fatigue, anxiety, depression and exercise limitation at 2-3 months from disease-onset. Persistent lung and extra-pulmonary organ MRI findings are common. In COVID-19 survivors, chronic inflammation may underlie multiorgan abnormalities and contribute to impaired quality of life.FundingNIHR Oxford and Oxford Health Biomedical Research Centres, British Heart Foundation Centre for Research Excellence, UKRI, Wellcome Trust, British Heart Foundation.
\n \n\n \n \nABSTRACTSARS-CoV-2 infection has been shown to damage multiple organs, including the brain. Multiorgan MRI can provide further insight on the repercussions of COVID-19 on organ health but requires a balance between richness and quality of data acquisition and total scan duration. We adapted the UK Biobank brain MRI protocol to produce high-quality images while being suitable as part of a post-COVID-19 multiorgan MRI exam. The analysis pipeline, also adapted from UK Biobank, includes new imaging-derived phenotypes (IDPs) designed to assess the effects of COVID-19. A first application of the protocol and pipeline was performed in 51 COVID-19 patients post-hospital discharge and 25 controls participating in the Oxford C-MORE study.The protocol acquires high resolution T1, T2-FLAIR, diffusion weighted images, susceptibility weighted images, and arterial spin labelling data in 17 minutes. The automated imaging pipeline derives 1575 IDPs, assessing brain anatomy (including olfactory bulb volume and intensity) and tissue perfusion, hyperintensities, diffusivity, and susceptibility. In the C-MORE data, these quantitative measures were consistent with clinical radiology reports. Our exploratory analysis tentatively revealed that recovered COVID-19 patients had a decrease in frontal grey matter volumes, an increased burden of white matter hyperintensities, and reduced mean diffusivity in the total and normal appearing white matter in the posterior thalamic radiation and sagittal stratum, relative to controls. These differences were generally more prominent in patients who received organ support. Increased T2* in the thalamus was also observed in recovered COVID-19 patients, with a more prominent increase for non-critical patients.This initial evidence of brain changes in COVID-19 survivors prompts the need for further investigations. Follow-up imaging in the C-MORE study is currently ongoing, and this protocol is now being used in large-scale studies. The pipeline is widely applicable and will contribute to new analyses to hopefully clarify the medium to long-term effects of COVID-19.HighlightsUK Biobank brain MRI protocol and pipeline was adapted for multiorgan MRI of COVID-19High-quality brain MRI data from 5 modalities are acquired in 17 minutesAnalysis pipeline derives 1575 IDPs of brain anatomy, perfusion, and microstructureEvidence of brain changes in COVID-19 survivors was found in the C-MORE studyThis MRI protocol is now being used in multiple large-scale studies on COVID-19
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