Updating the study protocol: Insight 46 - a longitudinal neuroscience sub-study of the MRC National Survey of Health and Development - phases 2 and 3.

BACKGROUND: Although age is the biggest known risk factor for dementia, there remains uncertainty about other factors over the life course that contribute to a person's risk for cognitive decline later in life. Furthermore, the pathological processes leading to dementia are not fully understood. The main goals of Insight 46-a multi-phase longitudinal observational study-are to collect detailed cognitive, neurological, physical, cardiovascular, and sensory data; to combine those data with genetic and life-course information collected from the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort); and thereby contribute to a better understanding of healthy ageing and dementia. METHODS/DESIGN: Phase 1 of Insight 46 (2015-2018) involved the recruitment of 502 members of the NSHD (median age = 70.7 years; 49% female) and has been described in detail by Lane and Parker et al. 2017. The present paper describes phase 2 (2018-2021) and phase 3 (2021-ongoing). Of the 502 phase 1 study members who were invited to a phase 2 research visit, 413 were willing to return for a clinic visit in London and 29 participated in a remote research assessment due to COVID-19 restrictions. Phase 3 aims to recruit 250 study members who previously participated in both phases 1 and 2 of Insight 46 (providing a third data time point) and 500 additional members of the NSHD who have not previously participated in Insight 46. DISCUSSION: The NSHD is the oldest and longest continuously running British birth cohort. Members of the NSHD are now at a critical point in their lives for us to investigate successful ageing and key age-related brain morbidities. Data collected from Insight 46 have the potential to greatly contribute to and impact the field of healthy ageing and dementia by combining unique life course data with longitudinal multiparametric clinical, imaging, and biomarker measurements. Further protocol enhancements are planned, including in-home sleep measurements and the engagement of participants through remote online cognitive testing. Data collected are and will continue to be made available to the scientific community.

Prone position plexopathy: an avoidable complication of prone positioning for COVID-19 pneumonitis?

Prone positioning is a mainstay of management for those presenting to the intensive care unit with moderate-to-severe acute respiratory distress syndrome due to COVID-19. While this is a necessary and life-saving intervention in selected patients, careful positioning and meticulous care are required to prevent compression and traction of the brachial plexus, and resultant brachial plexopathy. We describe two patients who developed a brachial plexus injury while undergoing prone positioning for management of COVID-19 pneumonitis. Both patients were diabetic and underwent prolonged periods in the prone position during which the plexopathy affected arm was abducted for 19 and 55 hours, respectively. We discuss strategies to reduce the risk of this rare but potentially disabling complication of prone positioning.

HTLV-1 encephalitis.

A 53-year-old woman developed subacute onset of upper limb weakness, sensory loss and cerebellar dysfunction. She was known to have human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy. MR scan of the brain showed extensive T2 hyperintensity within the deep and subcortical white matter, with punctate contrast enhancement. Cerebrospinal fluid (CSF) was lymphocytic with very high levels of HTLV-1 provirus in both CSF and peripheral blood lymphocytes. We diagnosed HTLV-1 encephalomyelitis and started high-dose methylprednisolone followed by a slow corticosteroid taper. She recovered well and regained functional independence in the upper limbs. Neurological manifestations of HTLV-1 infection extend beyond classical 'tropical spastic paraparesis' and are under-recognised. We review the literature on HTLV-1 encephalitis and discuss its diagnosis and management.

Associations Between Amyloid and Tau Pathology, and Connectome Alterations, in Alzheimer's Disease and Mild Cognitive Impairment.

BACKGROUND: The roles of amyloid-ß and tau in the degenerative process of Alzheimer's disease (AD) remain uncertain. [18F]AV-45 and [18F]AV-1451 PET quantify amyloid-ß and tau pathology, respectively, while diffusion tractography enables detection of their microstructural consequences. OBJECTIVE: Examine the impact of amyloid-ß and tau pathology on the structural connectome and cognition, in mild cognitive impairment (MCI) and AD. METHODS: Combined [18F]AV-45 and [18F]AV-1451 PET, diffusion tractography, and cognitive assessment in 28 controls, 32 MCI, and 26 AD patients. RESULTS: Hippocampal connectivity was reduced to the thalami, right lateral orbitofrontal, and right amygdala in MCI; alongside the insula, posterior cingulate, right entorhinal, and numerous cortical regions in AD (all p < 0.05). Hippocampal strength inversely correlated with [18F]AV-1451 SUVr in MCI (r = -0.55, p = 0.049) and AD (r = -0.57, p = 0.046), while reductions in hippocampal connectivity to ipsilateral brain regions correlated with increased [18F]AV-45 SUVr in those same regions in MCI (r = -0.33, p = 0.003) and AD (r = -0.31, p = 0.006). Cognitive scores correlated with connectivity of the right temporal pole in MCI (r = -0.60, p = 0.035) and left hippocampus in AD (r = 0.69, p = 0.024). Clinical Dementia Rating Scale scores correlated with [18F]AV-1451 SUVr in multiple areas reflecting Braak stages I-IV, including the right (r = 0.65, p = 0.004) entorhinal cortex in MCI; and Braak stages III-VI, including the right (r = 0.062, p = 0.009) parahippocampal gyrus in AD. CONCLUSION: Reductions in hippocampal connectivity predominate in the AD connectome, correlating with hippocampal tau in MCI and AD, and with amyloid-ß in the target regions of those connections. Cognitive scores correlate with microstructural changes and reflect the accumulation of tau pathology.

Neuroendoscopic surgery in children: does age at intervention influence safety and efficacy? A single-center experience.

OBJECTIVE The aim of this study was to review the safety of pediatric intraventricular endoscopy across separate age groups and to determine whether intraventricular endoscopy is associated with an increased risk of complications or reduced efficacy in infants younger than 1 year. METHODS In this retrospective cohort study, 286 pediatric patients younger than 17 years underwent intraventricular endoscopy at Great Ormond Street Hospital between December 2005 and December 2014. The primary diagnosis, procedure, and complications were recorded. RESULTS Neuroendoscopic surgery was performed in 286 pediatric patients (51 neonates 0-6 months [Group 1]; 37 infants 6-12 months [Group 2]; 75 patients 1-5 years [Group 3]; 54 patients 5-10 years [Group 4]; and 69 patients ≥ 10 years [Group 5]; male/female ratio 173:113). The most common procedures included endoscopic third ventriculostomy (ETV) in 159 patients and endoscopic fenestration of intracranial cysts in 64 patients. A total of 348 consecutive neuroendoscopic procedures were undertaken. Nine different complications were identified, of which postoperative seizures (1.7%), CSF leak (3.1%), CSF infection (2.4%), and intracranial hemorrhage (1.7%) were the most common. Specifically, no significant difference in complication rate (11.9%) or infection rate (2.4%) was observed among age groups (p = 0.40 and p = 0.91, respectively). In addition, there were no perioperative deaths; 30-day mortality was 1.1%. After neuroendoscopy for CSF diversion (n = 227), a significantly higher rate of shunt insertion was observed in the youngest group (Group 1, 63.0%) when compared with older groups (Group 2, 46.4%; Group 3, 26.3%; Group 4, 38.6%; and Group 5, 30.8%; p = 0.03). Similarly, for patients who underwent ETV as their initial neuroendoscopic procedure or in combination with additional surgical interventions (n = 171), a significantly higher rate of shunt insertion was also observed within young infants (Group 1, 67.9%; Group 2, 47.6%; Group 3, 19.6%; Group 4, 27.3%; and Group 5, 23.3%; p = 0.003). CONCLUSIONS Intraventricular endoscopy is a safe neurosurgical intervention in pediatric patients of all ages, although it might be associated with increased shunt rates after endoscopic surgery, specifically ETV, in younger infants.

Brain endothelial miR-146a negatively modulates T-cell adhesion through repressing multiple targets to inhibit NF-κB activation.

Pro-inflammatory cytokine-induced activation of nuclear factor, NF-κB has an important role in leukocyte adhesion to, and subsequent migration across, brain endothelial cells (BECs), which is crucial for the development of neuroinflammatory disorders such as multiple sclerosis (MS). In contrast, microRNA-146a (miR-146a) has emerged as an anti-inflammatory molecule by inhibiting NF-κB activity in various cell types, but its effect in BECs during neuroinflammation remains to be evaluated. Here, we show that miR-146a was upregulated in microvessels of MS-active lesions and the spinal cord of mice with experimental autoimmune encephalomyelitis. In vitro, TNFα and IFNγ treatment of human cerebral microvascular endothelial cells (hCMEC/D3) led to upregulation of miR-146a. Brain endothelial overexpression of miR-146a diminished, whereas knockdown of miR-146a augmented cytokine-stimulated adhesion of T cells to hCMEC/D3 cells, nuclear translocation of NF-κB, and expression of adhesion molecules in hCMEC/D3 cells. Furthermore, brain endothelial miR-146a modulates NF-κB activity upon cytokine activation through targeting two novel signaling transducers, RhoA and nuclear factor of activated T cells 5, as well as molecules previously identified, IL-1 receptor-associated kinase 1, and TNF receptor-associated factor 6. We propose brain endothelial miR-146a as an endogenous NF-κB inhibitor in BECs associated with decreased leukocyte adhesion during neuroinflammation.

MicroRNA-155 negatively affects blood-brain barrier function during neuroinflammation.

Blood-brain barrier (BBB) dysfunction is a hallmark of neurological conditions such as multiple sclerosis (MS) and stroke. However, the molecular mechanisms underlying neurovascular dysfunction during BBB breakdown remain elusive. MicroRNAs (miRNAs) have recently emerged as key regulators of pathogenic responses, although their role in central nervous system (CNS) microvascular disorders is largely unknown. We have identified miR-155 as a critical miRNA in neuroinflammation at the BBB. miR-155 is expressed at the neurovascular unit of individuals with MS and of mice with experimental autoimmune encephalomyelitis (EAE). In mice, loss of miR-155 reduced CNS extravasation of systemic tracers, both in EAE and in an acute systemic inflammation model induced by lipopolysaccharide. In cultured human brain endothelium, miR-155 was strongly and rapidly upregulated by inflammatory cytokines. miR-155 up-regulation mimicked cytokine-induced alterations in junctional organization and permeability, whereas inhibition of endogenous miR-155 partially prevented a cytokine-induced increase in permeability. Furthermore, miR-155 modulated brain endothelial barrier function by targeting not only cell-cell complex molecules such as annexin-2 and claudin-1, but also focal adhesion components such as DOCK-1 and syntenin-1. We propose that brain endothelial miR-155 is a negative regulator of BBB function that may constitute a novel therapeutic target for CNS neuroinflammatory disorders.

Encouraging regeneration in the central nervous system: is there a role for olfactory ensheathing cells?

The olfactory system holds a privileged position within the adult mammalian central nervous system; olfactory neurons undergo continual replacement and regeneration of synaptic contacts following injury, a feature shared by only a select few neuronal systems. The olfactory ensheathing cell, a glial cell found only in this system, is thought to play a central role in this regenerative process and has hence been the focus of numerous studies into promoting CNS regeneration following injury, in particular of the spinal cord. In trials, olfactory ensheathing cells have achieved some of the most promising results yet in promoting CNS regeneration, including a degree of functional recovery in humans following CNS injury. Comparatively, numerous other strategies, both those involving cellular transplantation and those examining neutralisation of inhibitory factors of the CNS, have achieved limited success. A combinational strategy, with olfactory ensheathing cells at its centre, is arguably the best way forward in encouraging effective recovery following CNS injury. This review examines the inhibitory environment of the CNS and the research to date on overcoming its effects on the regrowth of injured axons. The efficacy of therapies involving olfactory ensheathing cells, and the place of these therapies among the many other strategies being developed is examined.