The mental and physical health profiles of older adults who endorse elevated autistic traits

Objective The mental and physical health profile of autistic people has been studied in adolescence and adulthood, with elevated rates of most conditions being reported. However, this has been little studied taking a dimensional approach to autistic traits, and in older age. Methods A total of 20,220 adults aged 50-81 years from the PROTECT study reported whether they experienced persistent socio-communicative traits characteristic of autism. Approximately 1%, 276 individuals, were identified as endorsing elevated autistic traits in childhood and currently, henceforth the ‘Autism Spectrum Trait’ (AST) group. An age and gender matched comparison group was formed of 10,495 individuals who did not endorse any autistic behavioral traits, henceforth the ‘Control Older Adults’ (COA) group. Differences between AST and COA groups were explored in self-reported psychiatric diagnoses, self-reported symptoms of current depression and anxiety, and self-reported physical health diagnoses. Associations were also examined between autistic traits and health across the whole sample. Results The AST group reported significantly elevated rates of psychiatric diagnoses compared to COAs. Additionally, the AST group showed significantly higher self-reported symptoms of current depression and anxiety than COAs. However, few differences were observed in individual physical health conditions, and no differences in total co-occurring physical diagnoses between groups. Similar associations between autistic traits and health were also found taking a dimensional approach across the whole sample. Discussion These findings suggest that older adults with elevated autistic traits may be at greater risk of poorer mental, but not physical, health in later life. Future studies should incorporate polygenic scores to elucidate the possible genetic links between propensity to autism/high autistic traits and to psychiatric conditions, and to explore whether those with elevated autistic traits experience particular barriers to mental health care

The mental and physical health of older adults with a genetic predisposition for autism

Autism commonly aggregates in families, with twin studies stimating heritability to be around 80%. Subclinical autism-like characteristics have also been found at elevated rates in relatives of autistic probands. Physical and psychiatric conditions have been reported at elevated rates in autistic children and adults, and also in their relatives. However, to date there has been no exploration of how ageing may affect this pattern. This study examined cross-sectional data from the ongoing online PROTECT study. A total of 20,220 adults aged 50 years and older reported whether they have an autistic first-degree relative. In total, 739 older adults reported having an autistic first-degree relative (AFDR group) and 11,666 were identified as having no family history of any neurodevelopmental disorder (NFD group). The AFDR group demonstrated significantly higher frequencies of self-reported psychiatric diagnoses and a greater total number of co-occurring psychiatric diagnoses than the NFD group. Furthermore, the AFDR group reported elevated current self-report symptoms of depression, anxiety, traumatic experience, and post-traumatic stress than the NFD group. By contrast, few differences between AFDR and NFD groups were observed in physical health conditions, and no differences were observed in the total number of co-occurring physical health diagnoses. These findings suggest that adults who have an autistic first-degree relative may be at greater risk of poor mental, but not physical, health in later life. Older adults with autistic relatives may benefit from close monitoring to mitigate this susceptibility and to provide timely intervention

Traumatic life experiences and post-traumatic stress symptoms in middle-aged and older adults with and without autistic traits

Objectives Research with younger adults has begun to explore associations between autism/autistic traits and vulnerability to Post Traumatic Stress Disorder (PTSD). Large scale studies and/or examination of age-effects have not been conducted. Methods Adults aged 50 years+ from the PROTECT study (n = 20,220) completed items about current and childhood socio-communicative difficulties characteristic of autism. Approximately 1% (n = 251) endorsed high autistic traits, henceforth the Autism Spectrum Traits (AST) group. Differences between the AST and an age—and sex-matched “Comparison Older Adults” (COA; n = 9179) group were explored for lifetime traumatic experiences and current symptoms of PTSD, depression, and anxiety. Results Almost 30% of the AST group, compared to less than 8% of the COA, reported severe trauma in childhood/adulthood, including emotional, physical or sexual abuse. Elevated current PTSD symptoms were reported by AST compared to COA. An interaction was observed between autistic traits and trauma severity; the effect of level of trauma on PTSD symptoms was significantly greater for AST versus COA participants. This interaction remained significant when controlling for current depression and anxiety symptoms. Conclusions The findings suggest that high autistic traits may increase the likelihood of experiencing trauma across the lifespan, and the impact of severe trauma on PTSD symptoms. Older adults with high (vs. low) autistic traits may be at greater risk of experiencing PTSD symptoms in latter life. Future research should test whether the pattern of results is similar for diagnosed autistic adults

Effect of Nitrogen on Properties of Na2O-CaO-SrO-ZnO-SiO2 Glasses

Glasses in the Na2O-CaO-SrO-ZnO-SiO2 system have previously been investigated for suitability as a reagent in Al-free glass polyalkenoate cements (GPCs). These materials have many properties that offer potential in orthopedics. However, their applicability has been limited, to date, because of their poor strength. This study was undertaken with the aim of increasing the mechanical properties of a series of these Zn-based GPC glasses by doping with nitrogen to give overall compositions of: 10Na2O-10CaO-20SrO-20ZnO-(40-3x)SiO2-xSi3N4 (x is the no. of moles of Si3N4). The density, glass-transition temperature, hardness, and elastic modulus of each glass were found to increase fairly linearly with nitrogen content. Indentation fracture resistance also increases with nitrogen content according to a power law relationship. These increases are consistent with the incorporation of N into the glass structure in threefold coordination with silicon resulting in extra cross-linking of the glass network. This was confirmed using 29Si MAS-NMR which showed that an increasing number of Q2 units and some Q3 units with extra bridging anions are formed as nitrogen content increases at the expense of Q1 units. A small proportion of Zn ions are found to be in tetrahedral coordination in the base oxide glass and the proportion of these increases with the presence of nitrogen

Mechanical properties, structure, bioactivity and cytotoxicity of bioactive Na-Ca-Si-PO-(N) glasses

peer-reviewedBioactive glasses are able to bond to bone through formation of carbonated hydroxyapatite in body fluids. However, because of their poor strength their use is restricted to non-load-bearing applications. The effects of nitrogen addition on the physical and mechanical properties and structure of bioactive oxynitride glasses in the system Na–Ca–Si–P–O–N have been studied. Glasses with compositions (mol.%): 29Na2O–13.5CaO–2.5P2O5–(55 −3x)SiO2–xSi3N4 (x is the no. of moles of Si3N4) were synthesised with up to 1.5 at% P and 4.1 at% N. A novel 3-step process was used for addition of P and N and this proved successful in minimising weight losses and producing homogeneous glasses with such high SiO2 contents. The substitution of 4.12 at% N for oxygen results in linear increases in density (1.6%), glass transition temperature (6%), hardness (18%) and Young’s modulus (74%). Vickers Indentation Fracture (VIF) resistance (Kifr) was calculated from various relationships depending on the load, indent diagonal, crack lengths and Young’s modulus to hardness (E/H) ratio. Firstly, Meyer’s index n is calculated from the slope of the logarithmic plot of load versus indent diagonal. Then by comparing the experimental slopes of the logarithmic plots of crack lengths versus load it is concluded that the cracking mode is Radial Median type. The substitution of 4.12 at% N for oxygen results in an increase in Kifr of 40%. These increases in properties are consistent with the incorporation of N into the glass structure in three-fold coordination with silicon which results in extra cross-linking of the glass network. The structure of these bioactive oxynitride glasses was investigated by solid state nuclear magnetic resonance (MAS NMR) of 31P and 29Si. The structure reveals that all the N atoms are bonded to Si atoms with the formation of SiO3N, SiO2N2 and Q4 structural units with extra bridging anions at the expense of Q3 units. The bioactivity of the glasses has been evaluated by soaking them in simulated body fluid (SBF) and results confirm that all these oxynitride glasses are bioactive. Cytotoxicity tests based on different concentrations of these bioactive glass powders in a cell growth environment have also shown that they are not cytotoxic

Identification and characterisation of mutations associated with von Willebrand disease in a Turkish patient cohort

Several cohort studies have investigated the molecular basis of von Willebrand disease (VWD); however, these have mostly focused on European and North American populations. This study aimed to investigate mutation spectrum in 26 index cases (IC) from Turkey diagnosed with all three VWD types, the majority (73%) with parents who were knowingly related. IC were screened for mutations using multiplex ligation-dependent probe amplification and analysis of all von Willebrand factor gene (VWF) exons and exon/intron boundaries. Selected missense mutations were expressed in vitro. Candidate VWF mutations were identified in 25 of 26 IC and included propeptide missense mutations in four IC (two resulting in type 1 and two in recessive 2A), all influencing VWF expression in vitro. Four missense mutations, a nonsense mutation and a small in-frame insertion resulting in type 2A were also identified. Of 15 type 3 VWD IC, 13 were homozygous and two compound heterozygous for 14 candidate mutations predicted to result in lack of expression and two propeptide missense changes. Identification of intronic breakpoints of an exon 17–18 deletion suggested that the mutation resulted from non-homologous end joining. This study provides further insight into the pathogenesis of VWD in a population with a high degree of consanguineous partnerships

Characterization of large in-frame von Willebrand factor deletions highlights differing pathogenic mechanisms

Copy number variation (CNV) is known to cause all von Willebrand disease (VWD) types, although the associated pathogenic mechanisms involved have not been extensively studied. Notably, in-frame CNV provides a unique opportunity to investigate how specific von Willebrand factor (VWF) domains influence the processing and packaging of the protein. Using multiplex ligation-dependent probe amplification, this study determined the extent to which CNV contributed to VWD in the Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease cohort, highlighting in-frame deletions of exons 3, 4-5, 32-34, and 33-34. Heterozygous in vitro recombinant VWF expression demonstrated that, although deletion of exons 3, 32-34, and 33-34 all resulted in significant reductions in total VWF (P < .0001, P < .001, and P < .01, respectively), only deletion of exons 3 and 32-34 had a significant impact on VWF secretion (P < .0001). High-resolution microscopy of heterozygous and homozygous deletions confirmed these observations, indicating that deletion of exons 3 and 32-34 severely impaired pseudo-Weibel-Palade body (WPB) formation, whereas deletion of exons 33-34 did not, with this variant still exhibiting pseudo-WPB formation similar to wild-type VWF. In-frame deletions in VWD, therefore, contribute to pathogenesis via moderate or severe defects in VWF biosynthesis and secretion

Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge

BACKGROUND: Microglia are increasingly understood to play an important role in the pathogenesis of Alzheimer's disease. The rs75932628 (p.R47H) TREM2 variant is a well-established risk factor for Alzheimer's disease. TREM2 is a microglial cell surface receptor. In this multi-modal/multi-tracer PET/MRI study we investigated the effect of TREM2 p.R47H carrier status on microglial activation, tau and amyloid deposition, brain structure and cognitive profile. METHODS: We compared TREM2 p.R47H carriers (n = 8; median age = 62.3) and participants with mild cognitive impairment (n = 8; median age = 70.7). Participants underwent two [18F]DPA-714 PET/MRI scans to assess TSPO signal, indicative of microglial activation, before and after receiving the seasonal influenza vaccination, which was used as an immune stimulant. Participants also underwent [18F]florbetapir and [18F]AV1451 PET scans to assess amyloid and tau burden, respectively. Regional tau and TSPO signal were calculated for regions of interest linked to Braak stage. An additional comparison imaging healthy control group (n = 8; median age = 45.5) had a single [18F]DPA-714 PET/MRI. An expanded group of participants underwent neuropsychological testing, to determine if TREM2 status influenced clinical phenotype. RESULTS: Compared to participants with mild cognitive impairment, TREM2 carriers had lower TSPO signal in Braak II (P = 0.04) and Braak III (P = 0.046) regions, despite having a similar burden of tau and amyloid. There were trends to suggest reduced microglial activation following influenza vaccine in TREM2 carriers. Tau deposition in the Braak VI region was higher in TREM2 carriers (P = 0.04). Furthermore, compared to healthy controls TREM2 carriers had smaller caudate (P = 0.02), total brain (P = 0.049) and white matter volumes (P = 0.02); and neuropsychological assessment revealed worse ADAS-Cog13 (P = 0.03) and Delayed Matching to Sample (P = 0.007) scores. CONCLUSIONS: TREM2 p.R47H carriers had reduced levels of microglial activation in brain regions affected early in the Alzheimer's disease course and differences in brain structure and cognition. Changes in microglial response may underlie the increased Alzheimer's disease risk in TREM2 p.R47H carriers. Future therapeutic agents in Alzheimer's disease should aim to enhance protective microglial actions

Antistaphylococcal activity of DNA-interactive pyrrolobenzodiazepine (PBD) dimers and PBD-biaryl conjugates

Objectives: pyrrolobenzodiazepine (PBD) dimers, tethered through inert propyldioxy or pentyldioxy linkers, possess potent bactericidal activity against a range of Gram-positive bacteria by virtue of their capacity to cross-link duplex DNA in sequence-selective fashion. Here we attempt to improve the antibacterial activity and cytotoxicity profile of PBD-containing conjugates by extension of dimer linkers and replacement of one PBD unit with phenyl-substituted or benzo-fused heterocycles that facilitate non-covalent interactions with duplex DNA.Methods: DNase I footprinting was used to identify high-affinity DNA binding sites. A staphylococcal gene microarray was used to assess epidemic methicillin-resistant Staphylococcus aureus 16 phenotypes induced by PBD conjugates. Molecular dynamics simulations were employed to investigate the accommodation of compounds within the DNA helix.Results: increasing the length of the linker in PBD dimers led to a progressive reduction in antibacterial activity, but not in their cytotoxic capacity. Complex patterns of DNA binding were noted for extended PBD dimers. Modelling of DNA strand cross-linking by PBD dimers indicated distortion of the helix. A majority (26 of 43) of PBD-biaryl conjugates possessed potent antibacterial activity with little or no helical distortion and a more favourable cytotoxicity profile. Bactericidal activity of PBD-biaryl conjugates was determined by inability to excise covalently bound drug molecules from bacterial duplex DNA.Conclusions: PBD-biaryl conjugates have a superior antibacterial profile compared with PBD dimers such as ELB-21. We have identified six PBD-biaryl conjugates as potential drug development candidate