Neurons derived from individual early Alzheimer's disease patients reflect their clinical vulnerability.

Establishing preclinical models of Alzheimer's disease that predict clinical outcomes remains a critically important, yet to date not fully realized, goal. Models derived from human cells offer considerable advantages over non-human models, including the potential to reflect some of the inter-individual differences that are apparent in patients. Here we report an approach using induced pluripotent stem cell-derived cortical neurons from people with early symptomatic Alzheimer's disease where we sought a match between individual disease characteristics in the cells with analogous characteristics in the people from whom they were derived. We show that the response to amyloid-ß burden in life, as measured by cognitive decline and brain activity levels, varies between individuals and this vulnerability rating correlates with the individual cellular vulnerability to extrinsic amyloid-ß in vitro as measured by synapse loss and function. Our findings indicate that patient-induced pluripotent stem cell-derived cortical neurons not only present key aspects of Alzheimer's disease pathology but also reflect key aspects of the clinical phenotypes of the same patients. Cellular models that reflect an individual's in-life clinical vulnerability thus represent a tractable method of Alzheimer's disease modelling using clinical data in combination with cellular phenotypes.

Quantitative super-resolution imaging of pathological aggregates reveals distinct toxicity profiles in different synucleinopathies.

Protein aggregation is a hallmark of major neurodegenerative disorders. Increasing data suggest that smaller aggregates cause higher toxic response than filamentous aggregates (fibrils). However, the size of small aggregates has challenged their detection within biologically relevant environments. Here, we report approaches to quantitatively super-resolve aggregates in live cells and ex vivo brain tissues. We show that Amytracker 630 (AT630), a commercial aggregate-activated fluorophore, has outstanding photophysical properties that enable super-resolution imaging of α-synuclein, tau, and amyloid-ß aggregates, achieving ∼4 nm precision. Applying AT630 to AppNL-G-F mouse brain tissues or aggregates extracted from a Parkinson's disease donor, we demonstrate excellent agreement with antibodies specific for amyloid-ß or α-synuclein, respectively, confirming the specificity of AT630. Subsequently, we use AT630 to reveal a linear relationship between α-synuclein aggregate size and cellular toxicity and discovered that aggregates smaller than 450 ± 60 nm (aggregate450nm) readily penetrated the plasma membrane. We determine aggregate450nm concentrations in six Parkinson's disease and dementia with Lewy bodies donor samples and show that aggregates in different synucleinopathies demonstrate distinct potency in toxicity. We further show that cell-penetrating aggregates are surrounded by proteasomes, which assemble into foci to gradually process aggregates. Our results suggest that the plasma membrane effectively filters out fibrils but is vulnerable to penetration by aggregates of 450 ± 60 nm. Together, our findings present an exciting strategy to determine specificity of aggregate toxicity within heterogeneous samples. Our approach to quantitatively measure these toxic aggregates in biological environments opens possibilities to molecular examinations of disease mechanisms under physiological conditions.

Increasing Uptake of COVID-19 Vaccination and Reducing Health Inequalities in Patients on Renal Replacement Therapy-Experience from a Single Tertiary Centre.

BACKGROUND: COVID-19 vaccination has changed the landscape of the COVID-19 pandemic; however, decreased uptake due to vaccine hesitancy has been observed, particularly in patients from minority ethnic backgrounds and socially deprived areas. These patient characteristics are common in patients on Renal Replacement Therapy (RRT), a population at extremely high risk of developing serious illness from COVID-19 and who would thus benefit the most from the vaccination programme. We designed a bespoke COVID-19 vaccination programme for our RRT population with the aim of decreasing health inequalities and increasing vaccination uptake. METHODS: Key interventions included addressing vaccine hesitancy by deploying the respective clinical teams as trusted messengers, prompt eligible patient identification and notification, the deployment of resources to optimise vaccine administration in a manner convenient to patients, and the timely collection and analysis of local safety and efficacy data. First, COVID-19 vaccination data in relation to ethnicity and social deprivation in our RRT population, measured by the multiple deprivation index, were analysed and compared to uptake data in the total regional adult clinically extremely vulnerable (CEV) population in Greater Manchester (GM). Univariate logistic regression analysis was used to explore the factors associated with not receiving a vaccine. RESULTS: Out of 1156 RRT patients included in this analysis, 96.7% received the first dose of the vaccination compared to 93% in the cohort of CEV patients in the GM. Age, gender, ethnicity, and a lower index of multiple deprivation were not identified as significant risk factors for poor first dose vaccine uptake in our cohort. Vaccine uptake in Asian and Black RRT patients was 94.9% and 92.3%, respectively, compared to 93% and 76.2% for the same ethnic groups in the reference CEV GM. Vaccine uptake was 96.1% for RRT patients in the lowest quartile of the multiple deprivation index, compared to 90.5% in the GM reference population. CONCLUSION: Bespoke COVID-19 vaccination programmes based on local clinical teams as trusted messengers can improve negative attitudes towards vaccination and reduce health inequalities.

A Potential Mechanism for Targeting Aggregates With Proteasomes and Disaggregases in Liquid Droplets.

Insoluble protein deposits are hallmarks of neurodegenerative disorders and common forms of dementia. The aberrant aggregation of misfolded proteins involves a complex cascade of events that occur over time, from the cellular to the clinical phase of neurodegeneration. Declining neuronal health through increased cell stress and loss of protein homeostasis (proteostasis) functions correlate with the accumulation of aggregates. On the cellular level, increasing evidence supports that misfolded proteins may undergo liquid-liquid phase separation (LLPS), which is emerging as an important process to drive protein aggregation. Studying the reverse process of aggregate disassembly and degradation has only recently gained momentum, following reports of enzymes with distinct aggregate-disassembly activities. In this review, we will discuss how the ubiquitin-proteasome system and disaggregation machineries such as VCP/p97 and HSP70 system may disassemble and/or degrade protein aggregates. In addition to their canonically associated functions, these enzymes appear to share a common feature: reversibly assembling into liquid droplets in an LLPS-driven manner. We review the role of LLPS in enhancing the disassembly of aggregates through locally increasing the concentration of these enzymes and their co-proteins together within droplet structures. We propose that such activity may be achieved through the concerted actions of disaggregase machineries, the ubiquitin-proteasome system and their co-proteins, all of which are condensed within transient aggregate-associated droplets (TAADs), ultimately resulting in aggregate clearance. We further speculate that sustained engagement of these enzymatic activities within TAADs will be detrimental to normal cellular functions, where these activities are required. The possibility of facilitating endogenous disaggregation and degradation activities within TAADs potentially represents a novel target for therapeutic intervention to restore protein homeostasis at the early stages of neurodegeneration.

The role of a clinical nurse specialist in managing patients with trigeminal neuralgia.

BACKGROUND AND AIMS: Patients with trigeminal neuralgia (TN) can be overwhelmed with information they are given when first seen in a specialist secondary care clinic. The purpose of this study is to evaluate the extent to which a telephone service provided by the clinical nurse specialist (CNS) with independent prescribing rights improves patient management and satisfaction and reduces costs. METHODS: All patients with a diagnosis of TN who used the CNS telephone service in 2015 were contacted by two medical students (independent observers) using a semi-structured questionnaire. Patients who could not be contacted were sent the same questionnaire and asked to return it by post. RESULTS: Fifty-two patients were identified and 34 replied to a telephone call and 10 to a questionnaire, response rate 85%. Overall, 61% of patients rated their care outstanding or excellent. Four patients could not remember their consultation, others had used it on multiple occasions. Reasons for the consultation were pain management 50%, changeover of drugs 25%, advice about drug schedules 17%, and dealing with side effects 8%. The number of general practitioner (GP) consultations decreased as a result of this service. Patients suggested that the service should be available more than once a week. CONCLUSION: The CNS telephone service cut down on the number of outpatient appointments needed and reduced travel costs. Patients were appreciative that the CNS was in contact with GPs and this ensured prescriptions were filled in a timely manner and strengthen links with practices.

An Overview of Vesicobullous Conditions Affecting the Oral Mucosa.

Vesicobullous diseases are characterised by the presence of vesicles or bullae at varying locations in the mucosa. The most common occurring in the oral cavity are mucous membrane pemphigoid (MMP) and pemphigus vulgaris (PV). Both are autoimmune diseases with a peak age onset of over 60 years and females are more commonly affected than men. This paper reviews the structure of the oral mucosa, with specific reference to the basement membrane zone, as well as bullous conditions affecting the mucosa, including PV and pemphigoid, their aetiology, clinical presentation, and management.

Long-term effects of flooding on mortality in England and Wales, 1994-2005: controlled interrupted time-series analysis.

BACKGROUND: Limited evidence suggests that being flooded may increase mortality and morbidity among affected householders not just at the time of the flood but for months afterwards. The objective of this study is to explore the methods for quantifying such long-term health effects of flooding by analysis of routine mortality registrations in England and Wales. METHODS: Mortality data, geo-referenced by postcode of residence, were linked to a national database of flood events for 1994 to 2005. The ratio of mortality in the post-flood year to that in the pre-flood year within flooded postcodes was compared with that in non-flooded boundary areas (within 5 km of a flood). Further analyses compared the observed number of flood-area deaths in the year after flooding with the number expected from analysis of mortality trends stratified by region, age-group, sex, deprivation group and urban-rural status. RESULTS: Among the 319 recorded floods, there were 771 deaths in the year before flooding and 693 deaths in the year after (post-/pre-flood ratio of 0.90, 95% CI 0.82, 1.00). This ratio did not vary substantially by age, sex, population density or deprivation. A similar post-flood 'deficit' of deaths was suggested by the analyses based on observed/expected deaths. CONCLUSIONS: The observed post-flood 'deficit' of deaths is counter-intuitive and difficult to interpret because of the possible influence of population displacement caused by flooding. The bias that might arise from such displacement remains unquantified but has important implications for future studies that use place of residence as a marker of exposure.