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The Wellcome Centre for Integrative Neuroimaging (WIN) has won an award in this year’s University of Oxford Vice-Chancellor’s Public Engagement with Research Awards. These celebrate excellence in public engagement across the University.
AAV-mediated inhibition of ULK1 promotes axonal regeneration in the central nervous system in vitro and in vivo
<jats:title>Abstract</jats:title><jats:p>Axonal damage is an early step in traumatic and neurodegenerative disorders of the central nervous system (CNS). Damaged axons are not able to regenerate sufficiently in the adult mammalian CNS, leading to permanent neurological deficits. Recently, we showed that inhibition of the autophagic protein ULK1 promotes neuroprotection in different models of neurodegeneration. Moreover, we demonstrated previously that axonal protection improves regeneration of lesioned axons. However, whether axonal protection mediated by ULK1 inhibition could also improve axonal regeneration is unknown. Here, we used an adeno-associated viral (AAV) vector to express a dominant-negative form of ULK1 (AAV.ULK1.DN) and investigated its effects on axonal regeneration in the CNS. We show that AAV.ULK1.DN fosters axonal regeneration and enhances neurite outgrowth in vitro. In addition, AAV.ULK1.DN increases neuronal survival and enhances axonal regeneration after optic nerve lesion, and promotes long-term axonal protection after spinal cord injury (SCI) in vivo. Interestingly, AAV.ULK1.DN also increases serotonergic and dopaminergic axon sprouting after SCI. Mechanistically, AAV.ULK1.DN leads to increased ERK1 activation and reduced expression of RhoA and ROCK2. Our findings outline ULK1 as a key regulator of axonal degeneration and regeneration, and define ULK1 as a promising target to promote neuroprotection and regeneration in the CNS.</jats:p>
Deep brain stimulation of the pedunculopontine nucleus is a promising surgical procedure for the treatment of Parkinsonian gait and balance dysfunction. It has, however, produced mixed clinical results that are poorly understood. We used tractography with the aim to rationalise this heterogeneity. A cohort of eight patients with postural instability and gait disturbance (Parkinson's disease subtype) underwent pre-operative structural and diffusion MRI, then progressed to deep brain stimulation targeting the pedunculopontine nucleus. Pre-operative and follow-up assessments were carried out using the Gait and Falls Questionnaire, and Freezing of Gait Questionnaire. Probabilistic diffusion tensor tractography was carried out between the stimulating electrodes and both cortical and cerebellar regions of a priori interest. Cortical surface reconstructions were carried out to measure cortical thickness in relevant areas. Structural connectivity between stimulating electrode and precentral gyrus (r = 0.81, p = 0.01), Brodmann areas 1 (r = 0.78, p = 0.02) and 2 (r = 0.76, p = 0.03) were correlated with clinical improvement. A negative correlation was also observed for the superior cerebellar peduncle (r = -0.76, p = 0.03). Lower cortical thickness of the left parietal lobe and bilateral premotor cortices were associated with greater pre-operative severity of symptoms. Both motor and sensory structural connectivity of the stimulated surgical target characterises the clinical benefit, or lack thereof, from surgery. In what is a challenging region of brainstem to effectively target, these results provide insights into how this can be better achieved. The mechanisms of action are likely to have both motor and sensory components, commensurate with the probable nature of the underlying dysfunction.
<jats:sec><jats:title>Introduction</jats:title><jats:p>Chiari 1 malformation (CM1) is a structural abnormality of the hindbrain characterised by the descent of the cerebellar tonsils through the foramen magnum. The management of patients with CM1 remains contentious since there are currently no UK or international guidelines for clinicians. We therefore propose a collaborative, prospective, multicentre study on the investigation, management and outcome of CM1 in the UK: the <jats:italic>UK Chiari 1 Study</jats:italic> (UKC1S). Our primary objective is to determine the health-related quality of life (HRQoL) in patients with a new diagnosis of CM1 managed either conservatively or surgically at 12 months of follow-up. We also aim to: (A) determine HRQoL 12 months following surgery; (B) measure complications 12 months following surgery; (C) determine the natural history of patients with CM1 treated conservatively without surgery; (D) determine the radiological correlates of presenting symptoms, signs and outcomes; and (E) determine the scope and variation within UK practice in referral patterns, patient pathways, investigations and surgical decisions.</jats:p></jats:sec><jats:sec><jats:title>Methods and analysis</jats:title><jats:p>The UKC1S will be a prospective, multicentre and observational study that will follow the British Neurosurgical Trainee Research Collaborative model of collaborative research. Patients will be recruited after attending their first neurosurgical outpatient clinic appointment. Follow-up data will be collected from all patients at 12 months from baseline regardless of whether they are treated surgically or not. A further 12-month postoperative follow-up timepoint will be added for patients treated with decompressive surgery. The study is expected to last three years.</jats:p></jats:sec><jats:sec><jats:title>Ethics and dissemination</jats:title><jats:p>The UKC1S received a favourable ethical opinion from the East Midlands Leicester South Research Ethics Committee (REC reference: 20/EM/0053; IRAS 269739) and the Health Research Authority. The results of the study will be published in peer-reviewed medical journals, presented at scientific conferences, shared with collaborating sites and shared with participant patients if they so wish.</jats:p></jats:sec>
<jats:title>Abstract</jats:title> <jats:p>Female sex, age and carriage of the apolipoprotein E e4 allele are the greatest risk factors for sporadic Alzheimer’s disease. The hippocampus has a selective vulnerability to atrophy in ageing that may be accelerated in Alzheimer’s disease, including in those with increased genetic risk of the disease, years before onset. Within the hippocampal complex, subfields represent cytoarchitectonic and connectivity based divisions. Variation in global hippocampal and subfield volume associated with sex, age and apolipoprotein E e4 status has the potential to provide a sensitive biomarker of future vulnerability to Alzheimer’s disease. Here, we examined non-linear age, sex and apolipoprotein E effects, and their interactions, on hippocampal and subfield volumes across several decades spanning mid-life to old age in 36 653 healthy ageing individuals. FMRIB Software Library derived estimates of total hippocampal volume and Freesurfer derived estimates hippocampal subfield volume were estimated. A model-free, sliding-window approach was implemented that does not assume a linear relationship between age and subfield volume. The annualized percentage of subfield volume change was calculated to investigate associations with age, sex and apolipoprotein E e4 homozygosity. Hippocampal volume showed a marked reduction in apolipoprotein E e4/e4 female carriers after age 65. Volume was lower in homozygous e4 individuals in specific subfields including the presubiculum, subiculum head, cornu ammonis 1 body, cornu ammonis 3 head and cornu ammonis 4. Nearby brain structures in medial temporal and subcortical regions did not show the same age, sex and apolipoprotein E interactions, suggesting selective vulnerability of the hippocampus and its subfields. The findings demonstrate that in healthy ageing, two factors—female sex and apolipoprotein E e4 status—confer selective vulnerability of specific hippocampal subfields to volume loss.</jats:p>
Wearable pulse oximeters in the prompt detection of hypoxaemia and during movement: a diagnostic accuracy study (Preprint)
<sec> <title>BACKGROUND</title> <p>Commercially available wearable (ambulatory) pulse oximeters have been recommended as a method for managing patients at risk of physiological deterioration, such as active patients with COVID-19 disease receiving care in hospital isolation rooms, however, their reliability is unclear to use in the hospital setting.</p> </sec> <sec> <title>OBJECTIVE</title> <p>We report the performance of wearable pulse oximeters in a simulated clinical setting when challenged by motion and low levels of arterial blood oxygen (SaO2).</p> </sec> <sec> <title>METHODS</title> <p>The performance of one wrist-worn (Wavelet) and three finger-worn (CheckMeTM O2+, AP-20 and WristOx2® 3150) wearable, wireless transmission-mode, pulse oximeters was evaluated. Seven motion tasks were performed: At rest, Sit-to-Stand, Tapping, Rubbing, Drinking, Turning Pages, and Using a Tablet. Hypoxia exposure followed, in which inspired gases were adjusted to achieve decreasing SaO2 levels at 100%, 95%, 90%, 87%, 85%, 83% and 80%. Peripheral oxygen saturation (SpO2) estimates were compared with simultaneous SaO2 samples to calculate the root mean squared error (RMSE). Area under the receiver-operating characteristic curve was used to analyse the detection of hypoxaemia, SaO2 < 90%.</p> </sec> <sec> <title>RESULTS</title> <p>SpO2 estimates matching 215 SaO2 samples in both study phases, from 33 participants, were analysed. Tapping, rubbing, turning pages and using a tablet degraded SpO2 estimation (RMSE > 4% for a least one device). All finger-worn pulse oximeters detected hypoxaemia, with an overall sensitivity ≥ 0.87 and specificity ≥ 0.80, comparable to that of the Philips MX450.</p> </sec> <sec> <title>CONCLUSIONS</title> <p>The SpO2 accuracy of wearable finger-worn pulse oximeters was within that required by the International Organization for Standardization guidelines. Performance was degraded by motion, but all were capable of detecting hypoxaemia. Our findings support the use of wearable, wireless transmission-mode, pulse oximeters to detect the onset of clinical deterioration in hospital settings.</p> </sec> <sec> <title>CLINICALTRIAL</title> <p>ISRCTN61535692; http://www.isrctn.com/ISRCTN61535692</p> </sec> <sec> <title>INTERNATIONAL REGISTERED REPORT</title> <p>RR2-10.1136/bmjopen-2019-034404</p> </sec>
Psilocin acutely disrupts sleep and affects local but not global sleep homeostasis in laboratory mice
<jats:title>Abstract</jats:title><jats:p>Serotonergic psychedelic drugs, such as psilocin (4-hydroxy-N,N-dimethyltryptamine), profoundly alter the quality of consciousness through mechanisms which are incompletely understood. Growing evidence suggests that a single psychedelic experience can positively impact long-term psychological well-being, with relevance for the treatment of psychiatric disorders, including depression. A prominent factor associated with psychiatric disorders is disturbed sleep, and the sleep-wake cycle is implicated in the regulation of neuronal firing and activity homeostasis. It remains unknown to what extent psychedelic agents directly affect sleep, in terms of both acute arousal and homeostatic sleep regulation. Here, chronic <jats:italic>in vivo</jats:italic> electrophysiological recordings were obtained in mice to track sleep-wake architecture and cortical activity after psilocin injection. Administration of psilocin led to delayed REM sleep onset and reduced NREM sleep maintenance for up to approximately 3 hours after dosing, and the acute EEG response was associated primarily with an enhanced oscillation around 4 Hz. No long-term changes in sleep-wake quantity were found. When combined with sleep deprivation, psilocin did not alter the dynamics of homeostatic sleep rebound during the subsequent recovery period, as reflected in both sleep amount and EEG slow wave activity. However, psilocin decreased the recovery rate of sleep slow wave activity following sleep deprivation in the local field potentials of electrodes targeting medial prefrontal and surrounding cortex. It is concluded that psilocin affects both global vigilance state control and local sleep homeostasis, an effect which may be relevant for its antidepressant efficacy.</jats:p>
Background/Aim: To provide a comprehensive multimodal retinal imaging characterisation of patients with North Carolina macular dystrophy (NCMD). Methods: Clinical evaluation and retinal imaging in six families. Results: Twenty-one subjects showed phenotypic characteristics of NCMD. Small drusen-like deposits were found in all affected individuals, either tightly grouped in the macula, or surrounding atrophic or fibrotic macular alterations. These small subretinal lesions showed an increased fundus autofluorescence and were associated with only mild irregularities on optical coherence tomography imaging. Similar drusen-like deposits were regularly seen in the peripheral fundus, predominantly temporally and often with a radial distribution. Two patients showed a bilateral chorioretinal atrophy and two had a macular neovascularisation (MNV). Findings from follow-up examinations were available from 11 patients. The retinal phenotype remained overall stable, except for two patients: one patient with atrophy showed a distinct growth of the atrophic lesions on longitudinal AF imaging over a review period of 14 years. One patient with MNV showed a unilateral decline of best-corrected visual acuity. Genetic testing identified the single nucleotide variant chr6:100040987G>C upstream of the PRDM13 gene in all family members with NCMD phenotype. Conclusion: Patients with NCMD show a characteristic retinal phenotype and distribution of drusen that differ from drusen in patients with age-related macular degeneration. Although the prognosis of this developmental condition is overall better than for other macular diseases with drusen, patients may be at risk of developing MNV or enlargement of pre-existing atrophy.
There is at present some confusion about the relative value of clinical trials performed to investigate efficacy vs. those designed to investigate effectiveness. This is particularly challenging when studies performed as experiments for regulators by companies are used to shape and inform clinical practice, especially if studies conducted under more real life conditions fail to support predicted benefits. We review the field in relation to the new antipsychotics, in particular. Other indications, including mood disorders, which are also briefly touched upon, have so far received less definitive attention, but are likely to encounter the same difficulties. We conclude that, where the results of efficacy trials are positive and an effectiveness trial is negative, one should not necessarily prefer the effectiveness trial. it may simply have failed. Where efficacy trials and effectiveness trials point to similar conclusions, then the findings are mutually supportive. © 2009 wydanie polskie, Instytut Psychiatrii i Neurologii.