Inhibiting Hippo pathway kinases releases WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice.

The localization, number, and function of postsynaptic AMPA-type glutamate receptors (AMPARs) are crucial for synaptic plasticity, a cellular correlate for learning and memory. The Hippo pathway member WWC1 is an important component of AMPAR-containing protein complexes. However, the availability of WWC1 is constrained by its interaction with the Hippo pathway kinases LATS1 and LATS2 (LATS1/2). Here, we explored the biochemical regulation of this interaction and found that it is pharmacologically targetable in vivo. In primary hippocampal neurons, phosphorylation of LATS1/2 by the upstream kinases MST1 and MST2 (MST1/2) enhanced the interaction between WWC1 and LATS1/2, which sequestered WWC1. Pharmacologically inhibiting MST1/2 in male mice and in human brain-derived organoids promoted the dissociation of WWC1 from LATS1/2, leading to an increase in WWC1 in AMPAR-containing complexes. MST1/2 inhibition enhanced synaptic transmission in mouse hippocampal brain slices and improved cognition in healthy male mice and in male mouse models of Alzheimer's disease and aging. Thus, compounds that disrupt the interaction between WWC1 and LATS1/2 might be explored for development as cognitive enhancers.

Self-Reported Late-Life Hypertension Is Associated with a Healthy Cognitive Status and Reduced Alzheimer's Disease Pathology Burden.

Background: While mid-life hypertension represents a risk factor for the development of Alzheimer's disease (AD), the risk after the age of 65 is less certain. Establishing relationships between late life hypertension and the pathological changes of AD could be crucial in understanding the relevance of blood pressure as a risk factor for this disorder. Objective: We investigated associations between self-reported late-life hypertension, cognitive status and AD pathology at death. The impact of antihypertensive medication was also examined. Methods: Using the Cornell Medical Index questionnaire, we ascertained whether participants had ever reported hypertension. We also noted use of antihypertensive medication. The donated brains of 108 individuals were assessed for AD pathology using consensus guidelines. Statistical analysis aimed to elucidate relationships between hypertension and AD pathology. Results: We found no associations between self-reported hypertension and cognitive impairment at death. However, those with hypertension were significantly more likely to exhibit lower levels of AD pathology as measured by Thal phase, Braak stage, CERAD score, and NIA-AA criteria-even after controlling for sex, level of education and presence of APOEɛ4 allele(s). No significant associations could be found when examining use of antihypertensive medications. Conclusions: Our findings suggest that late-life hypertension is associated with less severe AD pathology. We postulate that AD pathology may be promoted by reduced cerebral blood flow.

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration.

High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. Here we show that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1ß release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in male mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1ß release, contributing to an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of male and female postmortem human brains demonstrate that SA is hyperactivated in Alzheimer's disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer's disease, providing mechanistic insight into the biology of neuroinflammation.

Homozygous HLA-DQB1*06:02 combined with T-cell receptor alpha polymorphism results in narcolepsy onset - A familial case report.

Narcolepsy is a life-long neurological disorder with well-established genetic risk factors. Human leukocyte antigen-DQB1*06:02 remains the strongest genetic predeterminant; however, polymorphisms in genes encoding the T-cell receptor alpha chain are also strongly linked. This case report shows the inheritance pathway of these genetic markers contributing to narcolepsy onset in a 17-year-old female.

Virtual reality in simulation-based emergency skills training: A systematic review with a narrative synthesis.

Objective: An important role is predicted for virtual reality (VR) in the future of medical education. We performed a systematic review of the literature with a narrative synthesis, to examine the current evidence for VR in simulation-based emergency skills training. We broadly define emergency skills as any clinical skill used in the emergency care of patients across all clinical settings. Methods: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. The data sources accessed during this study included: PubMed, CINAHL, EMBASE, AMED, EMCARE, HMIC, BNI, PsychINFO, Medline, CENTRAL, SCOPUS, Web of Science, BIOSIS Citation Index, ERIC, ACM Digital Library, IEEE Xplore, and ProQuest Dissertations and Thesis Global. Cochrane's Rob 2 and ROBVIS tools were used during study quality assessment. No ethical review was required for this work. Results: Thirty-four articles published between 14th March 1998 and 1st March 2022 were included in this review. Studies were predominantly conducted in the USA and Europe and focussed on a variety of healthcare disciplines including medical, nursing, and allied health. VR education was delivered using head-mounted displays, Cave Automatic Virtual Environment systems, and bespoke setups. These systems delivered education in a variety of areas (emergency medicine, equipment training, obstetrics, and basic/advanced life support). Subjective potential advantages of this technology included realism, replayability, and time-effectiveness. Reports of adverse events were low in frequency across the included studies. Whilst clear educational benefit was generally noted, this was not reflected in changes to patient-based outcomes. Conclusion: There may be educational benefit to using VR in the context of simulation-based emergency skills training including knowledge gain and retention, skill performance, acceptability, usability, and validity. Currently, there is insufficient evidence to demonstrate clear cost-effectiveness, or direct improvement of patient or institutional outcomes, at this stage.

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration.

High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. We demonstrate that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1ß release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1ß release, initiating an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D (GSDMD)-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of postmortem brains demonstrate that SA is hyperactivated in Alzheimer's disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer's disease, providing new mechanistic insight into the biology of neuroinflammation.

Education mediating the associations between early life factors and frailty: a cross-sectional study of the UK Biobank.

OBJECTIVES: Exposures in utero and during infancy may impact the development of diseases later in life. They may be linked with development of frailty, although the mechanism is unclear. This study aims to determine the associations between early life risk factors and development of frailty among middle-aged and older adults as well as potential pathways via education, for any observed association. DESIGN: A cross-sectional study. SETTINGS: This study used data from UK Biobank, a large population-based cohort. PARTICIPANTS: 502 489 individuals aged 37-73 years were included in the analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: Early life factors in this study included being breast fed as a baby, maternal smoking, birth weight, the presence of perinatal diseases, birth month and birth place (in or outside the UK). We developed a frailty index comprising 49 deficits. We used generalised structural equation modelling to examine the associations between early life factors and development of frailty and whether any observed association was mediated via educational attainment. RESULTS: A history of breast feeding and normal birth weight were associated with a lower frailty index while maternal smoking, the occurrence of perinatal diseases and birth month with a longer day length were associated with a higher frailty index. Educational level mediated the relationship between these early life factors and frailty index. CONCLUSIONS: This study highlights that biological and social risk occurring at different stages of life are related to the variations in frailty index in later life and suggests opportunities for prevention across the life course.

Low copy numbers of complement C4 and C4A deficiency are risk factors for myositis, its subgroups and autoantibodies.

BACKGROUND: Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterised by myositis-related autoantibodies plus infiltration of leucocytes into muscles and/or the skin, leading to the destruction of blood vessels and muscle fibres, chronic weakness and fatigue. While complement-mediated destruction of capillary endothelia is implicated in paediatric and adult dermatomyositis, the complex diversity of complement C4 in IIM pathology was unknown. METHODS: We elucidated the gene copy number (GCN) variations of total C4, C4A and C4B, long and short genes in 1644 Caucasian patients with IIM, plus 3526 matched healthy controls using real-time PCR or Southern blot analyses. Plasma complement levels were determined by single radial immunodiffusion. RESULTS: The large study populations helped establish the distribution patterns of various C4 GCN groups. Low GCNs of C4T (C4T=2+3) and C4A deficiency (C4A=0+1) were strongly correlated with increased risk of IIM with OR equalled to 2.58 (2.28-2.91), p=5.0×10-53 for C4T, and 2.82 (2.48-3.21), p=7.0×10-57 for C4A deficiency. Contingency and regression analyses showed that among patients with C4A deficiency, the presence of HLA-DR3 became insignificant as a risk factor in IIM except for inclusion body myositis (IBM), by which 98.2% had HLA-DR3 with an OR of 11.02 (1.44-84.4). Intragroup analyses of patients with IIM for C4 protein levels and IIM-related autoantibodies showed that those with anti-Jo-1 or with anti-PM/Scl had significantly lower C4 plasma concentrations than those without these autoantibodies. CONCLUSIONS: C4A deficiency is relevant in dermatomyositis, HLA-DRB1*03 is important in IBM and both C4A deficiency and HLA-DRB1*03 contribute interactively to risk of polymyositis.

Associations between chronotype and employment status in a longitudinal study of an elderly population.

Individuals with an 'evening' chronotype tend to sleep and wake later than people described to be 'morning' type if given a free choice. Since early awakening times, due to school and occupation, may be more challenging for those with evening chronotype, they are expected to be at greater risk of adverse health, occupational and educational outcomes. Our objectives are to investigate associations between chronotype and occupational, educational and health outcomes in a longitudinal cohort. We use sleep, sociodemographic and health data from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, 1982 through 2010. The relationship between employment and longitudinal midsleep trajectories were estimated using linear mixed models. Associations between employment status and Cornell Medical Index, Beck Depression Inventory scores, cortisol concentrations at different times of the day stratified by chronotype were estimated using regression. The relationship between chronotype, occupational success, education, and cognition were also examined using regression methods. In older adults, compared to non-employed participants, employed participants get up 0.45 hours earlier. Evening-type employed individuals had earlier midsleep time compared to their non-employed counterparts and had abnormal longitudinal trajectories with an increasing trend as they aged. Employed individuals with evening chronotype had a higher risk of depression than employed morning-types. Moreover, employed individuals with evening chronotype had a higher cortisol concentration at 14:00 h than non-employed individuals. In addition, memory score was lower in individuals with morning chronotype, however processing speed was higher in individuals with morning chronotype compared to evening. Morning-types had a higher age when they finished full time education. Relative to evening-types, those with morning chronotype were 6.5% more likely to be in a job classed as professional or intermediate. Our findings suggest that evening-types are at a disadvantage with regards to occupational, educational and health outcomes in older adults due to their vulnerability to circadian and sleep disruption.

The effect of season of birth on brain epigenome-wide DNA methylation of older adults.

Perinatal light exposure predisposes towards health and behaviour in adulthood. Season of birth is associated with psychiatric, allergic, cardiovascular and metabolic problems. It has been proposed that early-life environmental light disrupts the development of biological rhythms which, in turn, influence later-life health. However, the mechanisms linking perinatal seasonal light to later-life biological rhythm and health in humans are unknown. In this study, we investigated the association between season of birth and epigenome-wide DNA methylation of two postmortem human brain regions (16 hypothalamus, 14 temporal cortex). We did not find statistically significant differences at the whole epigenome level, either because we lacked statistical power or that no association exists. However, when we examined 24 CpG sites that had the highest significance or differential methylation, we identified regions which may be associated with circadian rhythm entrainment, cholinergic neurotransmission and neural development. Amongst methylation of the core clock genes, we identified that hypothalamus Neuronal PAS Domain Protein 2 (NPAS2) gene has hypermethylated regions in long photoperiod-born individuals. In addition, we found nominal associations between season of birth and genes linked to chronotype and narcolepsy. Season of birth-related brain DNA methylation profile was different than a previously reported blood methylation profile, suggesting a tissue-specific mechanism of perinatal light programming. Overall, we are the first to analyse the relationship between season of birth and human brain DNA methylation. Further studies with larger sample sizes are required to confirm an imprinting effect of perinatal light on the circadian clock.

Systematic review of associations between HLA and renal function.

INTRODUCTION: Kidney dysfunction is a highly significant disease, both in the United Kingdom and globally. Many previous studies have reported associations between human leukocyte antigens (HLA) and renal function; this systematic review attempts to identify, summarize and appraise all published studies of these associations. METHODS: A literature search was performed using Medline, Embase and Cochrane Central Register of Controlled Trials to identify papers whose keywords included each of the following concepts: HLA, renal failure and genetic association. A total of 245 papers were identified and assessed for eligibility; 35 of these were included in the final study. RESULTS: A total of 95 HLA types and 14 three-locus haplotypes were reported to be associated with either increased or decreased renal function. A number of these findings were replicated by independent studies that reported 16 types were protective against renal dysfunction and 15 types were associated with reduced renal function. A total of 20 HLA types were associated with both increased risk of renal disease and decreased risk by independent studies. DISCUSSION: There is very little consensus on which HLA types have a protective or deleterious effect on renal function. Ethnicity may play a role, with HLA types possibly having different effects among different populations, and it is possible that the different primary diseases that lead to ESRD may have different HLA associations. Some of the studies may contain type I and type II errors caused by insufficient sample sizes, cohort selection and statistical methods. Although we have compiled a comprehensive list of published associations between renal function and HLA, in many cases, it is unclear which associations are reliable. Further studies are required to confirm or refute these findings.

Telephone Interview for Cognitive Status Scores Associate with Cognitive Impairment and Alzheimer's Disease Pathology at Death.

BACKGROUND: Early diagnosis of Alzheimer's disease (AD) provides an opportunity for early intervention. Cognitive testing has proven to be a reliable way to identify individuals who may be at risk of AD. The Telephone Assessment for Cognitive Screening (TICS) is proficient in screening for cognitive impairment. However, its ability to identify those at risk of developing AD pathology is unknown. OBJECTIVE: We aim to investigate associations between TICS scores, collected over a period of 13 years, and the cognitive status of participants at death. We also examine relationships between TICS scores and neuropathological indices of AD (CERAD score, Thal phase, and Braak stage). METHODS: Between 2004 and 2017, participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age underwent cognitive assessment using TICS. Scores from four time points were available for analysis. Cognitive impairment and AD pathology at death was evaluated in 101 participants. RESULTS: TICS scores at time points 2, 3, and 4 were significantly lower in those cognitively impaired at death compared to those considered cognitively normal. There were significant negative correlations between TICS scores and CERAD score and Braak stage at time points 2 and 4. No correlations between Thal phase and TICS were found. CONCLUSION: Findings indicate that TICS could be used not only to screen for cognitive impairment, but also to identify individuals at risk of developing AD pathology, many years before any overt symptoms occur. Once identified, 'at risk' individuals could be targeted for early interventions which could attenuate the progression of the disease.

Superior Frontal Gyrus TOMM40-APOE Locus DNA Methylation in Alzheimer's Disease.

BACKGROUND: The APOE ɛ4 allele is the strongest known genetic risk factor for sporadic Alzheimer's disease (AD). The neighboring TOMM40 gene has also been implicated in AD due to its close proximity to APOE. OBJECTIVE: Here we tested whether methylation of the TOMM40-APOE locus may influence ApoE protein levels and AD pathology. METHODS: DNA methylation levels across the TOMM40-APOE locus and ApoE levels were measured in superior frontal gyrus tissues of 62 human brains genotyped for APOE and scored for AD neuropathology. RESULTS: Methylation levels within the TOMM40 CpG island in the promoter or APOE CpG island in Exon 4 did not differ between APOE ɛ4 carriers versus non-carriers. However, APOE ɛ4 carriers had significantly higher methylation the APOE promoter compared with non-carriers. Although DNA methylation at TOMM40, APOE promoter region, or APOE did not differ between AD pathological groups, there was a negative association between TOMM40 methylation and CERAD scores. ApoE protein concentrations did not significantly different between APOE ɛ4 carriers and non-carriers, or between AD pathological groups. Finally, there was no correlation between ApoE protein concentrations and DNA methylation levels. CONCLUSION: APOE gene methylation may not be affected by genotype, relate to AD pathology or ApoE protein levels in the superior frontal gyrus, though, DNA methylation at the ApoE promoter differed between genotype. DNA methylation at TOMM40 associated with amyloid-ß plaques and longitudinal fluid intelligence. In sum, these results suggest a complicated regulation of the TOMM40-APOE locus in the brain in controlling ApoE protein levels and AD neuropathology.

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.

Analysis of human total antibody repertoires in TIF1γ autoantibody positive dermatomyositis.

We investigate the accumulated microbial and autoantigen antibody repertoire in adult-onset dermatomyositis patients sero-positive for TIF1γ (TRIM33) autoantibodies. We use an untargeted high-throughput approach which combines immunoglobulin disease-specific epitope-enrichment and identification of microbial and human antigens. We observe antibodies recognizing a wider repertoire of microbial antigens in dermatomyositis. Antibodies recognizing viruses and Poxviridae family species are significantly enriched. The identified autoantibodies recognise a large portion of the human proteome, including interferon regulated proteins; these proteins cluster in specific biological processes. In addition to TRIM33, we identify autoantibodies against eleven further TRIM proteins, including TRIM21. Some of these TRIM proteins share epitope homology with specific viral species including poxviruses. Our data suggest antibody accumulation in dermatomyositis against an expanded diversity of microbial and human proteins and evidence of non-random targeting of specific signalling pathways. Our findings indicate that molecular mimicry and epitope spreading events may play a role in dermatomyositis pathogenesis.

Associations between human leukocyte antigens and renal function.

Human leukocyte antigens (HLA) have been associated with renal function, but previous studies report contradictory findings with little consensus on the exact nature or impact of this observation. This study included 401,307 white British subjects aged 39-73 when they were recruited by UK Biobank. Subjects' HLA types were imputed using HLA*IMP:02 software. Regression analysis was used to compare 362 imputed HLA types with estimated glomerular filtration rate (eGFR) as a primary outcome and clinical indications as secondary outcome measures. 22 imputed HLA types were associated with increased eGFR (and therefore increased renal function). Decreased eGFR (decreased renal function) was associated with 11 imputed HLA types, seven of which were also associated with increased risk of end-stage renal disease and/or chronic kidney disease. Many of these HLA types are commonly inherited together in established haplotypes, for example: HLA-A*01:01, B*08:01, C*07:01, DRB1*03:01, DQB1*02:01. This haplotype has a population frequency of 9.5% in England and each allele was associated with decreased renal function. 33 imputed HLA types were associated with kidney function in white British subjects. Linkage disequilibrium in HLA heritance suggests that this is not random and particularly affects carriers of established haplotypes. This could have important applications for the diagnosis and treatment of renal disease and global population health.

Early life factors and COVID-19 infection in England: A prospective analysis of UK Biobank participants.

This study aims to examine whether maternal smoking, birth weight, birth month and breastfeeding are associated with COVID-19 infection and hospitalisation. Maternal smoking was positively associated with COVID-19 infection. Breastfeeding was negatively associated with COVID-19 infection. The odds of being hospitalised due to COVID-19 were higher among those who had lower birthweight and mothers who were smoking during pregnancy.

Mid to late-life scores of depression in the cognitively healthy are associated with cognitive status and Alzheimer's disease pathology at death.

OBJECTIVES: Early diagnosis of Alzheimer's disease (AD) is essential for early interventions. Symptoms of depression could represent a prodromal stage of AD. Very early mood alterations may help to stratify those at highest risk of late-life AD. We aim to investigate associations between baseline/longitudinal scores for depression, presence of cognitive impairment and/or AD pathology at death. METHODS/DESIGN: Between 1991 and 2015, participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age underwent 10 waves of assessment using the Geriatric Depression Scale (GDS). AD pathology at death was evaluated in 106 eligible cases. Analyses aimed to examine associations between GDS scores, cognitive status and AD pathology (as measured by Braak stage, Thal phase and CERAD). RESULTS: Baseline GDS scores were significantly higher for those cognitively impaired at death than those cognitively normal. Significantly higher baseline GDS scores were found for those with greater Consortium to Establish a Registry for Alzheimer's Disease (CERAD) scores than those with lower CERAD scores. Similarly, significantly higher baseline GDS scores were found for those with a greater Braak stage than those with lower tau burden. These correlations remained after controlling for age at death, education and APOE ε4, but were less robust. Mean longitudinal GDS scores associated with cognition but not pathology. CONCLUSIONS: GDS scores collected approximately 20 years before death were associated with cognitive status and AD pathology at death. We postulate that early AD-related pathological change produces raised GDS scores due to an overlapping neural basis with depression, and that this may be considered as an early diagnostic marker for AD.

Influence of APOE genotype in primary age-related tauopathy.

The term "Primary age-related tauopathy" (PART) was coined in 2014 to describe the common neuropathological observation of neurofibrillary tangles without associated beta-amyloid (Aß) pathology. It is possible for PART pathology to be present in both cognitively normal and cognitively impaired individuals. Genetically, Apolipoprotein E (APOE) ε4 has been shown to occur less commonly in PART than in Alzheimer's disease (AD). Here, we investigate the relationships between PART, AD and those pathologically normal for age, with an emphasis on APOE and cognition, using 152 selected participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age and the Manchester arm of the Brains for Dementia Research cohort. APOE genotype differed between PART and AD with APOE ε2 more common in the former and APOE ε4 more common in the latter. Individuals with definite PART were less likely to be cognitively impaired than those with AD and those with pathology considered pathologically normal for age. We postulate that the lack of Aß in definite PART cases may be due either to an increased frequency of APOE ε2 or decreased frequency of APOE ε4 as their resulting protein isoforms have differing binding properties in relation to Aß. Similarly, an increased frequency of APOE ε2 or decreased frequency of APOE ε4 may lead to decreased levels of cognitive impairment, which raises questions regarding the impact of Aß pathology on overall cognition in elderly subjects. We suggest that it may be possible to use the increased frequency of APOE ε2 in definite PART to assist neuropathological diagnosis.