Advances in Therapeutics to Alleviate Cognitive Decline and Neuropsychiatric Symptoms of Alzheimer's Disease.

Dementia exists as a 'progressive clinical syndrome of deteriorating mental function significant enough to interfere with activities of daily living', with the most prevalent type of dementia being Alzheimer's disease (AD), accounting for about 80% of diagnosed cases. AD is associated with an increased risk of comorbidity with other clinical conditions such as hypertension, diabetes, and neuropsychiatric symptoms (NPS) including, agitation, anxiety, and depression as well as increased mortality in late life. For example, up to 70% of patients diagnosed with AD are affected by anxiety. As aging is the major risk factor for AD, this represents a huge global burden in ageing populations. Over the last 10 years, significant efforts have been made to recognize the complexity of AD and understand the aetiology and pathophysiology of the disease as well as biomarkers for early detection. Yet, earlier treatment options, including acetylcholinesterase inhibitors and glutamate receptor regulators, have been limited as they work by targeting the symptoms, with only the more recent FDA-approved drugs being designed to target amyloid-ß protein with the aim of slowing down the progression of the disease. However, these drugs may only help temporarily, cannot stop or reverse the disease, and do not act by reducing NPS associated with AD. The first-line treatment options for the management of NPS are selective serotonin reuptake inhibitors/selective noradrenaline reuptake inhibitors (SSRIs/SNRIs) targeting the monoaminergic system; however, they are not rational drug choices for the management of anxiety disorders since the GABAergic system has a prominent role in their development. Considering the overall treatment failures and side effects of currently available medication, there is an unmet clinical need for rationally designed therapies for anxiety disorders associated with AD. In this review, we summarize the current status of the therapy of AD and aim to highlight novel angles for future drug therapy in our ongoing efforts to alleviate the cognitive deficits and NPS associated with this devastating disease.

Digital adaptation of the Standing up for Myself intervention in young people and adults with intellectual disabilities: the STORM feasibility study.

Background: Stigma contributes to the negative social conditions persons with intellectual disabilities are exposed to, and it needs tackling at multiple levels. Standing Up for Myself is a psychosocial group intervention designed to enable individuals with intellectual disabilities to discuss stigmatising encounters in a safe and supportive setting and to increase their self-efficacy in managing and resisting stigma. Objectives: To adapt Standing Up for Myself to make it suitable as a digital intervention; to evaluate the feasibility and acceptability of Digital Standing Up for Myself and online administration of outcome measures in a pilot; to describe usual practice in the context of the coronavirus disease 2019 pandemic to inform future evaluation. Design: Adaptation work followed by a single-arm pilot of intervention delivery. Setting and participants: Four third and education sector organisations. Individuals with mild-to-moderate intellectual disabilities, aged 16+, members of existing groups, with access to digital platforms. Intervention: Digital Standing Up for Myself intervention. Adapted from face-to-face Standing Up for Myself intervention, delivered over four weekly sessions, plus a 1-month follow-up session. Outcomes: Acceptability and feasibility of delivering Digital Standing Up for Myself and of collecting outcome and health economic measures at baseline and 3 months post baseline. Outcomes are mental well-being, self-esteem, self-efficacy in rejecting prejudice, reactions to discrimination and sense of social power. Results: Adaptation to the intervention required changes to session duration, group size and number of videos; otherwise, the content remained largely the same. Guidance was aligned with digital delivery methods and a new group member booklet was produced. Twenty-two participants provided baseline data. The intervention was started by 21 participants (four groups), all of whom were retained at 3 months. Group facilitators reported delivering the intervention as feasible and suggested some refinements. Fidelity of the intervention was good, with over 90% of key components observed as implemented by facilitators. Both facilitators and group members reported the intervention to be acceptable. Group members reported subjective benefits, including increased confidence, pride and knowing how to deal with difficult situations. Digital collection of all outcome measures was feasible and acceptable, with data completeness ≥ 95% for all measures at both time points. Finally, a picture of usual practice has been developed as an intervention comparator for a future trial. Limitations: The pilot sample was small. It remains unclear whether participants would be willing to be randomised to a treatment as usual arm or whether they could be retained for 12 months follow-up. Conclusions: The target number of groups and participants were recruited, and retention was good. It is feasible and acceptable for group facilitators with some training and supervision to deliver Digital Standing Up for Myself. Further optimisation of the intervention is warranted. Future work: To maximise the acceptability and reach of the intervention, a future trial could offer the adapted Digital Standing Up for Myself, potentially alongside the original face-to-face version of the intervention. Study registration: This study was registered as ISRCTN16056848. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: 17/149/03) and is published in full in Public Health Research; Vol. 12, No. 1. See the NIHR Funding and Awards website for further award information.

People with intellectual disabilities (or 'learning disabilities' in United Kingdom language) are more likely to experience poor physical and mental health than the general population. Stigma (negative stereotypes, prejudice and discrimination) has been linked to lower self-esteem, quality of life, and mental and physical ill health. Efforts to empower people with intellectual disabilities themselves to challenge stigma with a view to improving well-being, health and self-esteem are lacking. In 2017, we developed Standing Up for Myself, a brief group-based programme for people with mild-to-moderate intellectual disabilities aged 16+ to address this gap. As this study got underway, face-to-face meetings were suspended due to the coronavirus disease 2019 pandemic. We used the opportunity to assess whether Standing Up for Myself could be delivered through web-based meetings. We adapted Standing Up for Myself for digital delivery, with close input from advisors with intellectual disabilities and experienced group facilitators. We then tested the digital version in charity and education settings to evaluate if Digital Standing Up for Myself could be delivered as planned and how acceptable it was to group facilitators and participants. Four groups, with a total of 22 members, signed up to try Digital Standing Up for Myself. One participant dropped out before starting Standing Up for Myself, and the other 21 continued until the end of the programme. Retention and attendance were good; participants on average attended four of the five sessions. Ninety per cent of the core programme requirements were fully delivered as detailed in the Digital Standing Up for Myself manual. Problems with technology were manageable, although facilitators found using the Standing Up for Myself Wiki platform (an online platform for storage and sharing of resources) difficult, particularly when sharing video content. Facilitators felt acceptable levels of privacy were achieved and there were no reports of undue distress. All facilitators and many group members said they would recommend Digital Standing Up for Myself to others. Group members shared how the programme benefitted them, noting increased awareness about disabilities, and for some increased confidence, pride and independence. Some had learnt how to stand up for themselves and manage difficult situations and took pride in this. Completing outcome and health cost measures via web-based meetings was acceptable and data were largely fully complete and useable.

Mental health and service use of parents with and without borderline intellectual functioning.

BACKGROUND: People with borderline intellectual functioning (BIF) encounter greater social adversities than the general population and have an increased prevalence of mental illness. However, little is known about the socio-demographic characteristics and mental health of parents with BIF. METHODS: A secondary data analysis of the Adult Psychiatric Morbidity Survey 2014 was conducted. Logistic regression models were fitted to compare differences in socio-demographic, mental health and service-use characteristics between parents and non-parents with and without BIF, and to investigate if the relationship between parent status and mental health outcomes was modified by BIF status, sex, and employment. RESULTS: Data from 6872 participants was analyzed; 69.1% were parents. BIF parents had higher odds of common mental disorder, severe mental illness, post-traumatic stress disorder, self-harm/suicide and were more likely to see their General Practitioner (GP) and to receive mental health treatment than non-BIF parents. BIF parents did not have a higher prevalence of mental health problems than BIF non-parents. Being a parent, after adjusting for BIF status and other confounders, was associated with increased odds of having a common mental disorder, visits to see a GP and treatment for mental health. Female parents had higher odds of treatment for mental health problems. CONCLUSIONS: Being a parent is associated with elevated rates of common mental disorders. There is a higher burden of mental health problems and service use in people with BIF. A greater provision of specialist support services including ascertainment is indicated for this group.

A systematic review of psychosocial interventions for people with intellectual disabilities and dementia.

OBJECTIVES: As the life expectancy of individuals with intellectual disabilities (ID) continues to increase, there is an increased risk of developing dementia. While psychosocial interventions are gaining prominence, evidence is limited for people with both dementia and ID. This review discusses the effectiveness of direct psychosocial interventions and adaptations to facilitate delivery within this population. METHODS: The review followed the PRISMA guidelines. Five electronic databases, grey literature, and reference lists of included articles were searched for relevant studies. 10 eligible studies were appraised and analysed by narrative synthesis. RESULTS: Ten distinct interventions were identified and categorised based on their purpose and delivery. All interventions were beneficial in improving a range of outcomes, though some studies were of low quality and most had small samples. Common adaptations included simplification of tasks and material, higher staff-to-client ratio, and alternative communication methods. CONCLUSION: There is emerging evidence for several psychosocial interventions for people with ID and dementia, though further research is required on effectiveness and generalisability. The adaptations discussed may guide implementation into routine care and contribute to current policies and guidelines on improving ID and dementia care.

Stakeholder views on the barriers and facilitators of psychosocial interventions to address reduction in aggressive challenging behaviour in adults with intellectual disabilities.

Background: Success of psychosocial interventions in reducing aggressive challenging behaviour is likely to be related not only to mechanistic aspects, but also to therapeutic and system factors. The study aims to examine the facilitators and barriers that influence whether psychosocial interventions for aggressive challenging behaviour in adults with intellectual disabilities lead to positive change. Methods: We conducted 42 semi-structured interviews with adults with intellectual disabilities and aggressive challenging behaviour, family/paid carers, and professionals engaged in or delivering a psychosocial intervention across the UK. Data were analysed thematically using a framework approach. Results: Stakeholders considered therapeutic and supportive relationships and personalised care as facilitating factors of psychosocial interventions to address aggressive challenging behaviour. The operational structure of community intellectual disability services and conflicting expectations of professionals and carers were the main contextual barriers that impeded the implementation of psychosocial interventions addressing aggressive challenging behaviour in adults with intellectual disabilities. Conclusions: Findings highlight the valued components that maximise positive change in adults with intellectual disabilities who display aggressive challenging behaviour. Several operational adjustments including referral criteria, roles of professionals and workforce issues need to be addressed in services to maximise the implementation of psychosocial interventions to reduce aggressive challenging behaviour in adults with intellectual disabilities.

The current study looked at what factors that lead to good outcomes from therapies that aim to reduce aggressive challenging behaviour in adults with learning disabilities. We also looked at the factors that may prevent positive change ( i.e., reduction in aggressive challenging behaviour). We interviewed 42 people including 14 adults with learning disabilities, 13 carers (6 family; 7 paid) and 13 professionals across the UK. All stakeholders agreed that supportive relationships between the person with a learning disability and their therapist, staff consistent, personalised therapy and involvement of the person with a learning disability and their carer(s) in care planning facilitate the reduction of aggressive challenging behaviour. On the other hand, differences in expectations between professionals and carers, personal reasons ( e.g. being the right timing for a person), and the way community learning disability services currently run may stop people from having the opportunity to take part in therapy are barriers to positive change such as reduction of aggressive challenging behaviour. The study findings highlight the valued components that maximise the positive change in adults with intellectual disabilities who display aggressive challenging behaviour. Several operational adjustments including referral criteria, roles of professionals and workforce issues need to be addressed in services to maximise the implementation of psychosocial interventions to reduce aggressive challenging behaviour in adults with intellectual disabilities.

Age-Dependent Sex Differences in Perineuronal Nets in an APP Mouse Model of Alzheimer's Disease Are Brain Region-Specific.

Alzheimer's disease (AD) is the most common form of dementia, which disproportionately affects women. AD symptoms include progressive memory loss associated with amyloid-ß (Aß) plaques and dismantled synaptic mechanisms. Perineuronal nets (PNNs) are important components of the extracellular matrix with a critical role in synaptic stabilisation and have been shown to be influenced by microglia, which enter an activated state during AD. This study aimed to investigate whether sex differences affected the density of PNNs alongside the labelling of microglia and Aß plaques density.We performed neurochemistry experiments using acute brain slices from both sexes of the APPNL-F/NL-F mouse model of AD, aged-matched (2-5 and 12-16 months) to wild-type mice, combined with a weighted gene co-expression network analysis (WGCNA). The lateral entorhinal cortex (LEC) and hippocampal CA1, which are vulnerable during early AD pathology, were investigated and compared to the presubiculum (PRS), a region unscathed by AD pathology. The highest density of PNNs was found in the LEC and PRS regions of aged APPNL-F/NL-F mice with a region-specific sex differences. Analysis of the CA1 region using multiplex-fluorescent images from aged APPNL-F/NL-F mice showed regions of dense Aß plaques near clusters of CD68, indicative of activated microglia and PNNs. This was consistent with the results of WGCNA performed on normalised data on microglial cells isolated from age-matched, late-stage male and female wild-type and APP knock-in mice, which revealed one microglial module that showed differential expression associated with tissue, age, genotype, and sex, which showed enrichment for fc-receptor-mediated phagocytosis. Our data are consistent with the hypothesis that sex-related differences contribute to a disrupted interaction between PNNs and microglia in specific brain regions associated with AD pathogenesis.

Complex interventions for aggressive challenging behaviour in adults with intellectual disability: A rapid realist review informed by multiple populations.

OBJECTIVES: Approximately 10% of people with intellectual disability display aggressive challenging behaviour, usually due to unmet needs. There are a variety of interventions available, yet a scarcity of understanding about what mechanisms contribute to successful interventions. We explored how complex interventions for aggressive challenging behaviour work in practice and what works for whom by developing programme theories through contexts-mechanism-outcome configurations. METHODS: This review followed modified rapid realist review methodology and RAMESES-II standards. Eligible papers reported on a range of population groups (intellectual disability, mental health, dementia, young people and adults) and settings (community and inpatient) to broaden the scope and available data for review. RESULTS: Five databases and grey literature were searched and a total of 59 studies were included. We developed three overarching domains comprising of 11 contexts-mechanism-outcome configurations; 1. Working with the person displaying aggressive challenging behaviour, 2. Relationships and team focused approaches and 3. Sustaining and embedding facilitating factors at team and systems levels. Mechanisms underlying the successful application of interventions included improving understanding, addressing unmet need, developing positive skills, enhancing carer compassion, and boosting staff self-efficacy and motivation. CONCLUSION: The review emphasises how interventions for aggressive challenging behaviour should be personalised and tailored to suit individual needs. Effective communication and trusting relationships between service users, carers, professionals, and within staff teams is essential to facilitate effective intervention delivery. Carer inclusion and service level buy-in supports the attainment of desired outcomes. Implications for policy, clinical practice and future directions are discussed. PROSPERO REGISTRATION NUMBER: CRD42020203055.

Group cognitive stimulation therapy versus usual care for people with intellectual disabilities and dementia (CST-IDD) in the UK: protocol for a mixed-methods feasibility randomised controlled trial.

INTRODUCTION: The prevalence of dementia is almost five times higher in people with intellectual disabilities compared with the general population. However, evidence-based treatments for this population are lacking, as most randomised controlled trials for dementia interventions have not included people with intellectual disabilities. Cognitive stimulation therapy (CST) has a robust evidence base in the general dementia population, consistently showing benefits to cognition, quality of life and being cost-effective. We are conducting a mixed-methods feasibility trial of group CST for people with intellectual disabilities and dementia, to determine if a future definitive randomised controlled trial is feasible. METHODS AND ANALYSIS: Fifty individuals with intellectual disabilities and dementia will be randomised to either the intervention arm (14 sessions of group CST plus treatment as usual) or the control arm (treatment as usual). Randomisation will occur after informed consent has been obtained and baseline assessments completed. Each arm will have 25 participants, with the intervention arm divided into five or more CST groups with three to five participants in each. The outcomes will be feasibility of recruitment, acceptability and adherence of the intervention, suitability of study outcome measures and feasibility of collecting resource use data. Quantitative and qualitative approaches, including semistructured interviews with group participants, carers and group facilitators, will be employed to assess these outcomes. ETHICS AND DISSEMINATION: This study has been approved by Essex REC (Ref: 21/EE/027) and the HRA ethical approval process through the Integrated Research Application System (IRAS ID: 306 756). We plan to publish the results in peer-reviewed journals and conferences as well as provide feedback to funders, sponsors and study participants. TRIAL REGISTRATION NUMBER: ISRCTN88614460.

Standing up for Myself (STORM): Adapting and piloting a web-delivered psychosocial group intervention for people with intellectual disabilities.

BACKGROUND: Our STORM intervention was developed for people (16 +) with intellectual disabilities to enhance their capacity to manage and resist stigma. The current study describes the adaptation of STORM for (synchronous) on-line delivery in the context of the Covid-19 pandemic. AIMS: To adapt the manualised face-to-face STORM group intervention for delivery via web-based meeting platforms and to conduct an initial pilot study to consider its acceptability and feasibility. METHODS AND PROCEDURES: The 5-session STORM intervention was carefully adapted for online delivery. In a pilot study with four community groups (N = 22), outcome, health economics and attendance data were collected, and fidelity of delivery assessed. Focus groups with participants, and interviews with facilitators provided data on acceptability and feasibility. OUTCOMES AND RESULTS: The intervention was adapted with minimal changes to the content required. In the pilot study, 95% of participants were retained at follow-up, 91% attended at least three of the five sessions. Outcome measure completion and fidelity were excellent, and facilitators reported implementation to be feasible. The intervention was reported to be acceptable by participants. CONCLUSIONS AND IMPLICATIONS: When provided with the necessary resources and support, people with intellectual disabilities participate actively in web-delivered group interventions.

Behavioural and cognitive-behavioural interventions for outwardly directed aggressive behaviour in people with intellectual disabilities.

BACKGROUND: Outwardly directed aggressive behaviour in people with intellectual disabilities is a significant issue that may lead to poor quality of life, social exclusion and inpatient psychiatric admissions. Cognitive and behavioural approaches have been developed to manage aggressive behaviour but the effectiveness of these interventions on reducing aggressive behaviour and other outcomes are unclear. This is the third update of this review and adds nine new studies, resulting in a total of 15 studies in this review. OBJECTIVES: To evaluate the efficacy of behavioural and cognitive-behavioural interventions on outwardly directed aggressive behaviour compared to usual care, wait-list controls or no treatment in people with intellectual disability. We also evaluated enhanced interventions compared to non-enhanced interventions. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was March 2022. We revised the search terms to include positive behaviour support (PBS). SELECTION CRITERIA: We included randomised and quasi-randomised trials of children and adults with intellectual disability of any duration, setting and any eligible comparator. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were change in 1. aggressive behaviour, 2. ability to control anger, and 3. adaptive functioning, and 4. ADVERSE EFFECTS: Our secondary outcomes were change in 5. mental state, 6. medication, 7. care needs and 8. quality of life, and 9. frequency of service utilisation and 10. user satisfaction data. We used GRADE to assess certainty of evidence for each outcome. We expressed treatment effects as mean differences (MD) or odds ratios (OR), with 95% confidence intervals (CI). Where possible, we pooled data using a fixed-effect model. MAIN RESULTS: This updated version comprises nine new studies giving 15 included studies and 921 participants. The update also adds new interventions including parent training (two studies), mindfulness-based positive behaviour support (MBPBS) (two studies), reciprocal imitation training (RIT; one study) and dialectical behavioural therapy (DBT; one study). It also adds two new studies on PBS. Most studies were based in the community (14 studies), and one was in an inpatient forensic service. Eleven studies involved adults only. The remaining studies involved children (one study), children and adolescents (one study), adolescents (one study), and adolescents and adults (one study). One study included boys with fragile X syndrome. Six studies were conducted in the UK, seven in the USA, one in Canada and one in Germany. Only five studies described sources of funding. Four studies compared anger management based on cognitive behaviour therapy to a wait-list or no treatment control group (n = 263); two studies compared PBS with treatment as usual (TAU) (n = 308); two studies compared carer training on mindfulness and PBS with PBS only (n = 128); two studies involving parent training on behavioural approaches compared to wait-list control or TAU (n = 99); one study of mindfulness to a wait-list control (n = 34); one study of adapted dialectal behavioural therapy compared to wait-list control (n = 21); one study of RIT compared to an active control (n = 20) and one study of modified relaxation compared to an active control group (n = 12). There was moderate-certainty evidence that anger management may improve severity of aggressive behaviour post-treatment (MD -3.50, 95% CI -6.21 to -0.79; P = 0.01; 1 study, 158 participants); very low-certainty evidence that it might improve self-reported ability to control anger (MD -8.38, 95% CI -14.05 to -2.71; P = 0.004, I2 = 2%; 3 studies, 212 participants), adaptive functioning (MD -21.73, 95% CI -36.44 to -7.02; P = 0.004; 1 study, 28 participants) and psychiatric symptoms (MD -0.48, 95% CI -0.79 to -0.17; P = 0.002; 1 study, 28 participants) post-treatment; and very low-certainty evidence that it does not improve quality of life post-treatment (MD -5.60, 95% CI -18.11 to 6.91; P = 0.38; 1 study, 129 participants) or reduce service utilisation and costs at 10 months (MD 102.99 British pounds, 95% CI -117.16 to 323.14; P = 0.36; 1 study, 133 participants). There was moderate-certainty evidence that PBS may reduce aggressive behaviour post-treatment (MD -7.78, 95% CI -15.23 to -0.32; P = 0.04, I2 = 0%; 2 studies, 275 participants) and low-certainty evidence that it probably does not reduce aggressive behaviour at 12 months (MD -5.20, 95% CI -13.27 to 2.87; P = 0.21; 1 study, 225 participants). There was low-certainty evidence that PBS does not improve mental state post-treatment (OR 1.44, 95% CI 0.83 to 2.49; P = 1.21; 1 study, 214 participants) and very low-certainty evidence that it might not reduce service utilisation at 12 months (MD -448.00 British pounds, 95% CI -1660.83 to 764.83; P = 0.47; 1 study, 225 participants). There was very low-certainty evidence that mindfulness may reduce incidents of physical aggression (MD -2.80, 95% CI -4.37 to -1.23; P < 0.001; 1 study; 34 participants) and low-certainty evidence that MBPBS may reduce incidents of aggression post-treatment (MD -10.27, 95% CI -14.86 to -5.67; P < 0.001, I2 = 87%; 2 studies, 128 participants). Reasons for downgrading the certainty of evidence were risk of bias (particularly selection and performance bias); imprecision (results from single, often small studies, wide CIs, and CIs crossing the null effect); and inconsistency (statistical heterogeneity). AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that cognitive-behavioural approaches such as anger management and PBS may reduce outwardly directed aggressive behaviour in the short term but there is less certainty about the evidence in the medium and long term, particularly in relation to other outcomes such as quality of life. There is some evidence to suggest that combining more than one intervention may have cumulative benefits. Most studies were small and there is a need for larger, robust randomised controlled trials, particularly for interventions where the certainty of evidence is very low. More trials are needed that focus on children and whether psychological interventions lead to reductions in the use of psychotropic medications.

Presubiculum principal cells are preserved from degeneration in knock-in APP/TAU mouse models of Alzheimer's disease.

The presubiculum (PRS) is an integral component of the perforant pathway that has recently been recognised as a relatively unscathed region in clinical Alzheimer's disease (AD), despite neighbouring components of the perforant pathway, CA1 and the entorhinal cortex, responsible for formation of episodic memory and storage, showing severe hallmarks of AD including, amyloid-beta (Aß) plaques, tau tangles and marked gliosis. However, the question remains whether this anatomical resilience translates into functional resilience of the PRS neurons. Using neuroanatomy combined with whole-cell electrophysiological recordings, we investigated whether the unique spatial profile of the PRS was replicable in two knock-in mouse models of AD, APPNL-F/NL-F, and APPNL-F/MAPTHTAU and whether the intrinsic properties and morphological integrity of the PRS principal neurons was maintained compared to the lateral entorhinal cortex (LEC) and hippocampal CA1 principal cells. Our data revealed an age-dependent Aß and tau pathology with neuroinflammation in the LEC and CA1, but a presence of fleece-like Aß deposits with an absence of tau tangles and cellular markers of gliosis in the PRS of the mouse models at 11-16 and 18-22 months. These observations were consistent in human post-mortem AD tissue. This spatial profile also correlated with functional resilience of strong burst firing PRS pyramidal cells that showed unaltered sub- and suprathreshold intrinsic biophysical membrane properties and gross morphology in the AD models that were similar to the properties of pyramidal cells recorded in age-matched wild-type mice (11-14 months). This was in contrast to the LEC and CA1 principal cells which showed altered subthreshold intrinsic properties such as a higher input resistance, longer membrane time constants and hyperexcitability in response to suprathreshold stimulation that correlated with atrophied dendrites in both AD models. In conclusion, our data show for the first time that the unique anatomical profile of the PRS constitutes a diffuse AD pathology that is correlated with the preservation of principal pyramidal cell intrinsic biophysical and morphological properties despite alteration of LEC and CA1 pyramidal cells in two distinct genetic models of AD. Understanding the underlying mechanisms of this resilience could be beneficial in preventing the spread of disease pathology before cognitive deficits are precipitated in AD.

The fate of interneurons, GABAA receptor sub-types and perineuronal nets in Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurological disease, which is associated with gradual memory loss and correlated with synaptic hyperactivity and abnormal oscillatory rhythmic brain activity that precedes phenotypic alterations and is partly responsible for the spread of the disease pathology. Synaptic hyperactivity is thought to be because of alteration in the homeostasis of phasic and tonic synaptic inhibition, which is orchestrated by the GABAA inhibitory system, encompassing subclasses of interneurons and GABAA receptors, which play a vital role in cognitive functions, including learning and memory. Furthermore, the extracellular matrix, the perineuronal nets (PNNs) which often go unnoticed in considerations of AD pathology, encapsulate the inhibitory cells and neurites in critical brain regions and have recently come under the light for their crucial role in synaptic stabilisation and excitatory-inhibitory balance and when disrupted, serve as a potential trigger for AD-associated synaptic imbalance. Therefore, in this review, we summarise the current understanding of the selective vulnerability of distinct interneuron subtypes, their synaptic and extrasynaptic GABAA R subtypes as well as the changes in PNNs in AD, detailing their contribution to the mechanisms of disease development. We aim to highlight how seemingly unique malfunction in each component of the interneuronal GABA inhibitory system can be tied together to result in critical circuit dysfunction, leading to the irreversible symptomatic damage observed in AD.

'Standing up for Myself' (STORM): Development and qualitative evaluation of a psychosocial group intervention designed to increase the capacity of people with intellectual disabilities to manage and resist stigma.

BACKGROUND: People with intellectual disabilities are at risk of experiencing stigma and require the skills and confidence to deal with stigma in their daily lives. METHOD: Development and piloting of a 5-session manualised psychosocial group intervention designed to increase the capacity of people with intellectual disabilities aged 16+ to manage and resist stigma. Ten pre-existing groups (N = 67) in third sector and education settings participated. Interviews with participants (n = 26), facilitators (n = 9) and significant others (n = 7) 2-4 months after the intervention assessed perceived impact. RESULTS: Perceived benefits of the intervention for participants included increased understanding, improved connections with others, drive for advocacy, increased activity and self-efficacy, and opportunity to process difficult events and emotions. Differential impact depending on individuals' pre-existing self-advocacy skills was noted. CONCLUSIONS: This early-stage study indicates that further evaluation is merited to examine feasibility and outcomes of the STORM intervention.

Analysing trends of psychiatric disorders, treatment and service use across time in adults with borderline intellectual impairment: A cross-sectional study of private households.

While there is evidence that mental health problems are more prevalent in people with borderline intellectual functioning (BIF) compared to the general population, it is not known to what extent this has varied or changed over time and whether there have been changes in access to services. This paper compares the prevalence rates of psychiatric disorders and monitors trends in treatment and services in this population compared to the general population. We conducted secondary analysis on the Adult Psychiatric Morbidity Surveys carried out in England in 2000, 2007 and 2014. The total sample analysed included 21,796 participants, with 12.8% of individuals identified with BIF (n = 2786). Regression models were used to examine trends in psychiatric disorders, treatment and service use across the three datasets. People with BIF had significantly higher odds of developing mood and anxiety disorders, psychosis, drug dependence and suicidal behaviour than the general population, increasing at each subsequent timepoint. They received significantly more pharmacological treatments than the general population but have had increasingly more access to general practitioners, community care and daycare services over time. This study shows increasing prevalence rates of several mental disorders in people with BIF. Access to day-care, community care and healthcare services has increased over time for this group but not formal psychiatric care. These changes over time underline some of the problems this population faces, emphasizing a need to recognize that this is a population often overlooked in research and clinical practice.

Estimation of the minimal clinically important difference on the Aberrant Behaviour Checklist-Irritability (ABC-I) for people with intellectual disabilities who display aggressive challenging behaviour: A triangulated approach.

BACKGROUND: The minimal clinically important difference (MCID) is relevant in the estimation of improvement in a patient outcome. AIM: To determine the MCID on the Aberrant Behaviour Checklist-Irritability (ABC-I), widely used to measure the effects of intervention for aggressive challenging behaviour in people with intellectual disabilities. METHOD AND PROCEDURES: We utilised distribution and anchor based methods to estimate the ABC-I MCID. We extracted data from 15 randomised controlled trials (RCTs) for meta-analysis. We conducted three online workshops with family carers and professionals to consider meaningful change in case vignettes of increasing severity of aggressive challenging behaviour. OUTCOMES AND RESULTS: We did not find overlap in the range of values between the two approaches. The meta-analysis indicated a range of MCID on the ABC-I (0.05, 4.94) whilst the anchor-based estimation indicated a larger change (6.6, 16.6). CONCLUSIONS AND IMPLICATIONS: The MCID is essential in interpreting the results from intervention studies. The present work was undertaken as part of a wider programme on the development and testing of a psychosocial intervention for aggressive challenging behaviour, and it is of interest to researchers in justifying how they choose and determine the MCID on the outcome of interest.

Alzheimer's Disease Enhanced Tonic Inhibition is Correlated With Upregulated Astrocyte GABA Transporter-3/4 in a Knock-In APP Mouse Model.

Cognitive decline is a major symptom in Alzheimer's disease (AD), which is strongly associated with synaptic excitatory-inhibitory imbalance. Here, we investigated whether astrocyte-specific GABA transporter 3/4 (GAT3/4) is altered in APP knock-in mouse model of AD and whether this is correlated with changes in principal cell excitability. Using the APP NL-F/NL-F knock-in mouse model of AD, aged-matched to wild-type mice, we performed in vitro electrophysiological whole-cell recordings combined with immunohistochemistry in the CA1 and dentate gyrus (DG) regions of the hippocampus. We observed a higher expression of GAD67, an enzyme that catalyses GABA production, and GAT3/4 in reactive astrocytes labelled with GFAP, which correlated with an enhanced tonic inhibition in the CA1 and DG of 12-16 month-old APP NL-F/NL-F mice compared to the age-matched wild-type animals. Comparative neuroanatomy experiments performed using post-mortem brain tissue from human AD patients, age-matched to healthy controls, mirrored the results obtained using mice tissue. Blocking GAT3/4 associated tonic inhibition recorded in CA1 and DG principal cells resulted in an increased membrane input resistance, enhanced firing frequency and synaptic excitation in both wild-type and APP NL-F/NL-F mice. These effects exacerbated synaptic hyperactivity reported previously in the APP NL-F/NL-F mice model. Our data suggest that an alteration in astrocyte GABA homeostasis is correlated with increased tonic inhibition in the hippocampus, which probably plays an important compensatory role in restoring AD-associated synaptic hyperactivity. Therefore, reducing tonic inhibition through GAT3/4 may not be a good therapeutic strategy for AD.

Individual cognitive stimulation therapy (iCST) for people with intellectual disability and dementia: a feasibility randomised controlled trial.

OBJECTIVES: To examine the feasibility, acceptability and fidelity of individual Cognitive Stimulation Therapy (iCST) in people with intellectual disability (ID) and dementia. METHOD: We aimed to recruit forty dyads (carer and individual with dementia and ID) who were randomised to iCST or a waiting list control group. Both groups received treatment as usual. Family and paid carers delivered the manualised intervention (40 sessions over 20 weeks). Recruitment and retention of participants, intervention adherence, fidelity and acceptability were assessed. Outcome measures of cognition, adaptive functioning, quality of life (QoL) and carer outcomes were collected at baseline, midpoint (11 weeks) and at 21 weeks. Qualitative interviews were conducted with six carers about their experience of iCST. RESULTS: Forty dyads were recruited over 10 months from 12 National Health Service trusts. One dyad dropped out and 87.5% and 97.5% completed the midpoint and end-point assessments respectively. Assessment of fidelity indicated that the correct session structure was not followed; 70% completed at least 20 sessions and there was a high level of satisfaction with iCST. QoL was significantly higher in the iCST arm at 21 weeks (adjusted mean difference: 3.11; 95% CI: 0.64 to 5.58). There were no differences in the other outcome measures. CONCLUSION: The intervention was feasible and acceptable. A full-scale trial is warranted but some modifications are needed, including improved training and supervision for carers to improve fidelity.

The experiences of family caregivers of people with severe mental illness in the Middle East: A systematic review and meta-synthesis of qualitative data.

BACKGROUND: There is a wealth of literature exploring the experiences of family caregivers of people with severe mental illness (SMI) in western countries, however, this topic has been neglected in the Middle East, despite families being the main source of caregiving in this context. The purpose of this review was to conduct a systematic review and qualitative meta-synthesis to explore the experiences of family caregivers living in countries in the Middle East caring for a relative with severe mental illness. METHODS: A systematic review and meta-synthesis were conducted, to comprehensively gain a thorough and detailed overview of what is known about family caregivers' experiences from published qualitative research in the Middle East geographical area from inception to May 2021. The review protocol was pre-registered with PROSPERO (Ref: CRD42020165519). RESULTS: The review identified twelve qualitative studies that explored caregivers' experiences of caring for relatives with SMI in Middle East countries. Family caregivers' experiences were captured under seven overarching themes. The participants across all studies reported negative consequences of providing care, increased burden and emotional distress. Many experienced issues with family/marital relationships and stigmatizing attitudes and behaviours from their communities. Caregivers expressed the need for increased support which was perceived to have a critical role in improving family caregivers' experiences. CONCLUSIONS: The meta-synthesis revealed many challenges and issues that affect caregivers of people with SMI in the Middle East. Family caregivers experienced distress and burden, and reported significant impact on their psychological well-being. Their experiences highlight the urgent need to provide more support for family caregivers in Middle East countries.

Effects of the COVID-19 pandemic on mental healthcare and services: results of a UK survey of front-line staff working with people with intellectual disability and/or autism.

AIMS AND METHOD: Mental health services have changed the way they operate during the COVID-19 pandemic. We investigated the challenges and innovations reported by staff working in services for people with intellectual disability and/or autism in National Health Service (NHS) and non-NHS sectors, and in in-patient and community settings. RESULTS: Data were drawn from 648 staff who participated in a UK-wide online survey. Issues around infection risk and mitigation were more important to those working in the NHS and in-patient settings. Community staff were more likely to express concern about the practicalities of a rapid shift to remote working and engaging patients remotely. Qualitative data revealed support for maintaining remote staff working and remote service provision post-pandemic. CLINICAL IMPLICATIONS: Given the current emphasis on community support for people with intellectual disability and/or autism, the focus of research and clinical practice should be the development of accessible and effective models of remote service provision.

A qualitative exploration of stigma experience and inclusion among adults with mild to moderate intellectual disability in an Indonesian context.

BACKGROUND: People with intellectual disability are among the most stigmatised groups in society. There is a paucity of studies reporting on how stigma is experienced in low- and middle-income countries. This study aims to explore the experience of stigma among adults with mild/moderate intellectual disability and the extent of their inclusion in Indonesian society. METHOD: Fifteen adults with mild/moderate intellectual disability were purposively recruited from three service providers and were interviewed using a semi-structured interview schedule. The data were analysed using thematic analysis. RESULTS: The findings suggest that adults with intellectual disability experience stigma in multiple settings (family, school, community), have limited access to social activities, and internalised the experienced stigma. CONCLUSION: This study adds to the international understanding of stigma experienced by adults with mild/moderate intellectual disability in daily life and their inclusion in society in a middle-income country.