Glymphatic inhibition exacerbates tau propagation in an Alzheimer's disease model.

BACKGROUND: The aggregation and spread of misfolded amyloid structured proteins, such as tau and α-synuclein, are key pathological features associated with neurodegenerative disorders, including Alzheimer's and Parkinson's disease. These proteins possess a prion-like property, enabling their transmission from cell to cell leading to propagation throughout the central and peripheral nervous systems. While the mechanisms underlying their intracellular spread are still being elucidated, targeting the extracellular space has emerged as a potential therapeutic approach. The glymphatic system, a brain-wide pathway responsible for clearing extracellular metabolic waste from the central nervous system, has gained attention as a promising target for removing these toxic proteins. METHODS: In this study, we investigated the impact of long-term modulation of glymphatic function on tau aggregation and spread by chronically treating a mouse model of tau propagation with a pharmacological inhibitor of AQP4, TGN-020. Thy1-hTau.P301S mice were intracerebrally inoculated with tau into the hippocampus and overlying cortex, and subsequently treated with TGN-020 (3 doses/week, 50 mg/kg TGN-020, i.p.) for 10-weeks. During this time, animal memory was studied using cognitive behavioural tasks, and structural MR images were acquired of the brain in vivo prior to brain extraction for immunohistochemical characterisation. RESULTS: Our findings demonstrate increased tau aggregation in the brain and transhemispheric propagation in the hippocampus following the inhibition of glymphatic clearance. Moreover, disruption of the glymphatic system aggravated recognition memory in tau inoculated mice and exacerbated regional changes in brain volume detected in the model. When initiation of drug treatment was delayed for several weeks post-inoculation, the alterations were attenuated. CONCLUSIONS: These results indicate that by modulating AQP4 function and, consequently, glymphatic clearance, it is possible to modify the propagation and pathological impact of tau in the brain, particularly during the initial stages of the disease. These findings highlight the critical role of the glymphatic system in preserving healthy brain homeostasis and offer valuable insights into the therapeutic implications of targeting this system for managing neurodegenerative diseases characterized by protein aggregation and spread.

GBS vaccines in the UK: a round table discussion.

Background: Group B streptococcus (GBS) remains a leading cause of infant sepsis, meningitis and death despite intrapartum antibiotic prophylaxis. A vaccine is urgently required, and two candidates are in advanced clinical trials. For successful GBS vaccine implementation, especially if a vaccine is licensed based on an immunological threshold, there must be cross-sector engagement, effective advocacy, robust plans for phase IV studies and equitable access. Meeting: A round-table discussion, held at St George's University of London, reviewed the current position of GBS vaccines in the UK context, focusing on phase IV plans, convening a diverse group of stakeholders from across the UK, with a role in GBS vaccine licensure, advocacy, implementation or effectiveness evaluation.Presentations outlined the latest UK epidemiology, noting the rising infant invasive GBS (iGBS) infection rates from 1996 to 2021 for both early and late onset disease, with the highest disease rates in Black infants (1.1/1000 livebirths vs white infants (0.81/1000 livebirths). Potential coverage of the candidate vaccines was high (>95%). Regulatory input suggested that EU regulators would consider waiving the need for a pre-licensure efficacy study if a putative correlate of protection could be adequately justified. Phase IV study methodologies for a GBS vaccine were considered, largely based on previous UK maternal vaccine assessments, such as a nationwide cohort study design using a vaccine register and a maternal services dataset. Other strategies were also discussed such as a cluster or stepped-wedge randomised trial to evaluate implementation outcomes. Opportunities for advocacy, education and engagement with additional key partners were discussed and identified. Conclusions: With an approved GBS vaccine a near possibility, planning of phase IV studies and identification of critical barriers to implementation are urgently needed. Cross-sector engagement is essential and will facilitate a successful pathway.

Lithographically defined encoded magnetic heterostructures for the targeted screening of kidney cancer.

Renal cell carcinoma (RCC) is the 7th commonest cancer in the UK and the most lethal urological malignancy; 50% of all RCC patients will die from the condition. However, if identified early enough, small RCCs are usually cured by surgery or percutaneous procedures, with 95% 10 year survival. This study describes a newly developed non-invasive urine-based assay for the early detection of RCC. Our approach uses encoded magnetically controllable heterostructures as a substrate for immunoassays. These heterostructures have molecular recognition abilities and embedded patterned codes for a rapid identification of RCC biomarkers. The magnetic heterostructures developed for this study have a magnetic configuration designed for a remote multi axial control of their orientation by external magnetic fields, this control facilitates the code readout when the heterostructures are in liquid. Furthermore, the optical encoding of each set of heterostructures provides a multiplexed analyte capture platform, as different sets of heterostructures, specific to different biomarkers can be mixed together in a patient sample. Our results show a precise magnetic control of the heterostructures with an efficient code readout during liquid immunoassays. The use of functionalised magnetic heterostructures as a substrate for immunoassay is validated for urine specimen spiked with recombinant RCC biomarkers. Initial results of the newly proposed screening method on urine samples from RCC patients, and controls with no renal disorders are presented in this study. Comprehensive optimisation cycles are in progress to validate the robustness of this technology as a novel, non-invasive screening method for RCC.

Appearances of diffuse excessive high signal intensity (DEHSI) on MR imaging following preterm birth.

BACKGROUND: Diffuse damage to the periventricular white matter has recently been suggested to be a cause of the cognitive deficits seen following preterm birth. It is unclear whether this form of injury can be visualised on MR imaging, but one group has described diffuse excessive high signal intensity (DEHSI) as a possible form of diffuse white matter injury. This finding is dependent on window imaging and the subjective assessment of the reviewer, but little data have been published on the degree of subjectivity on its appearance among raters. OBJECTIVE: To assess the subjectivity of DEHSI on conventional and ultrafast T2-weighted MR imaging following preterm birth. MATERIALS AND METHODS: An observational study of 40 preterm infants who had MR imaging of the brain around term-equivalent age, including conventional fast spin-echo (FSE) and ultrafast single-shot fast spin-echo (SSFSE) T2-weighted sequences in the axial plane. Images were anonymised and scored twice by four observers for the presence of DEHSI. Inter- and intra-observer agreement were calculated. RESULTS: Sixty-five percent of conventional and 100% of the ultrafast images were of diagnostic quality. DEHSI was noted in between 0% and 69.2% of conventional images and 27.5-90% of the ultrafast images. Inter- and intra-observer agreement ranged from none to moderate. CONCLUSION: The visual appearances of DEHSI on conventional FSE and ultrafast SSFSE T2-W images are highly subjective, limiting its clinical application.

Cerebellar volume and cerebellar metabolic characteristics in adults with dyslexia.

Developmental dyslexia is associated with problems in a range of linguistic and non-linguistic skills. Some of those problems have been attributed to dysfunction of the cerebellum and its associated neural systems. Two studies of cerebellar structure were undertaken by our group. In Study 1, white and grey matter volumes in the cerebellum were investigated in 10 dyslexic and 11 control adult male, right-handed participants using whole-brain volumetric MRI (3D-T1-weighted data sets with a spatial resolution of 0.8 x 0.8 x 0.8 mm(3)). The key finding was that the dyslexic group had a larger volume of white matter in both cerebellar hemispheres, differences that remained significant even when adjusting for total cerebellar volume. In Study 2, with the same participants, long-echo-time proton spectroscopy was used to investigate the ratios of the metabolites choline (Cho), N-acetylaspartate (NAA), and creatine (Cr) in the cerebellar hemispheres and vermis. Two significant differences were found: The dyslexic group had a lower ratio of NAA/Cho in the right cerebellar hemisphere together with a higher ratio of Cho/Cr in the left cerebellar hemisphere. Although it is difficult to interpret the volumetric and spectroscopic results unambiguously, taken together they suggest two possible interpretations: excessive connectivity or abnormal myelination.

MRI assessment of basal ganglia iron deposition in Parkinson's disease.

PURPOSE: To estimate the levels of basal ganglia iron levels in Parkinson's disease (PD) using the PRIME MR sequence at 3.0 Tesla, in relation to patients' motor symptom severity. MATERIALS AND METHODS: Seventy patients with PD and 10 healthy controls underwent assessment of movement and MR imaging. Mean R2' relaxation rates were recorded in the substantia nigra, frontal white matter and in the rostral, mid, and caudal putamen. RESULTS: R2' relaxation rates were significantly higher in patients with PD than in healthy controls. R2' in the most affected substantia nigra correlated with PD patients' motor symptom severity, but not with disease duration. Neuroradiological observation revealed a rostral to caudal "gradient" of putaminal hypointensity. This was substantiated by the finding that the mid and caudal putamen showed significantly higher R2' relaxation rates, consistent with higher iron levels in PD relative to the healthy controls. CONCLUSION: MRI at 3.0 Tesla suggests that substantia nigra iron levels are increased and linked to the severity of motor symptoms experienced in PD. Findings consistent with increased iron levels in the PD putamen are shown, in a region-specific rostral to caudal gradient.