Andre Strydom’s research while affiliated with King's College London and other places

Individuals with Down syndrome (DS) are at high risk of Alzheimer's disease (AD), displaying AD pathology similar to the general population. This study evaluated AD‐related blood biomarkers in DS within the AT(N) framework through a systematic review and meta‐analysis of studies published between 2017 and October 2024. The meta‐analysis focused on plasma amyloid beta (Aβ)42, Aβ40, total tau (t‐tau), phosphorylated tau (p‐tau)181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) levels, comparing 2109 DS individuals and 1006 euploid controls. Plasma Aβ42, Aβ40, NfL, and GFAP levels were significantly elevated in DS compared to euploid controls, while the Aβ42/40 ratio was reduced. In DS‐AD individuals, Aβ42 and t‐tau levels were elevated, with p‐tau181, NfL, and GFAP consistently high across clinical subgroups. Notably, Aβ40 and the Aβ42/40 ratio changed significantly in preclinical AD, while t‐tau increased in clinical AD. Incorporating inflammation (I) markers highlights neuroinflammation's role in DS‐AD progression, supporting the blood‐based AT(N)I framework for early AD detection and monitoring in DS. Highlights We reviewed 58 studies on Down syndrome (DS) blood biomarkers and a meta‐analysis of 18 using single molecule array. Plasma amyloid beta (Aβ)42, Aβ40, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) levels were elevated in DS compared to controls. DS‐Alzheimer's disease (AD) individuals showed higher Aβ42, total tau (t‐tau), phosphorylated tau (p‐tau)181, NfL, and GFAP levels. Plasma p‐tau181, NfL, and GFAP were elevated across all clinical subgroups. Aβ40 and Aβ42/40 ratio changed in preclinical AD; t‐tau rose in clinical AD.

INTRODUCTION The Cambridge Cognitive Examination modified for use in people with Down syndrome (CAMCOG‐DS) is a sensitive cognitive test for Alzheimer's disease (AD)–related decline in people with DS, but needs updates for sensitivity, cultural adaptability, and additional memory/executive function items. This study aimed to develop and validate the CAMCOG‐DS‐II. METHODS In this multi‐language, multi‐site study, the psychometric properties of the CAMCOG‐DS‐II were evaluated against previously validated measures in 223 participants (mean age: 40.18 years) with DS across seven countries. RESULTS The CAMCOG‐DS‐II had a high completion rate, minimal floor/ceiling effects (compared to the modified Cued Recall Test, the CANTAB Paired Associates Learning, and the Purdue Pegboard), strong validity and reliability, and performance was unaffected by language across sites. It differentiated between those with/without AD and distinguished clinically rated cognitively stable and prodromal individuals. CONCLUSION The CAMCOG‐DS‐II is a sensitive measure of cognitive performance in people with DS at risk of AD. Its cross‐language and site reliability support its potential use in AD–DS clinical trials. Highlights Developed and validated the Cambridge Cognitive Examination modified for use in people with Down syndrome (CAMCOG‐DS‐II) for Alzheimer's disease in Down syndrome. CAMCOG‐DS‐II shows increased sensitivity to Alzheimer's disease–related decline in Down syndrome. Improved applicability across an international and culturally diverse population. Differentiates Alzheimer's disease status: cognitively stable, prodromal, and clinical.

People with Down syndrome (DS) are prone to develop Alzheimer’s disease (AD). Behavioral and psychological symptoms of dementia (BPSD) are core features, but have not been comprehensively evaluated in DS. In a European multidisciplinary study, the novel Behavioral and Psychological Symptoms of Dementia in Down Syndrome (BPSD-DS) scale was developed to identify frequency and severity of behavioral changes taking account of life-long characteristic behavior. 83 behavioral items in 12 clinically defined sections were evaluated. The central aim was to identify items that change in relation to the dementia status, and thus may differentiate between diagnostic groups. Structured interviews were conducted with informants of persons with DS without dementia (DS, n = 149), with questionable dementia (DS+Q, n = 65), and with diagnosed dementia (DS+AD, n = 67). First exploratory data suggest promising interrater, test-retest, and internal consistency reliability measures. Concerning item relevance, group comparisons revealed pronounced increases in frequency and severity in items of anxiety, sleep disturbances, agitation & stereotypical behavior, aggression, apathy, depressive symptoms, and eating/drinking behavior. The proportion of individuals presenting an increase was highest in DS+AD, intermediate in DS+Q, and lowest in DS. Interestingly, among DS+Q individuals, a substantial proportion already presented increased anxiety, sleep disturbances, apathy, and depressive symptoms, suggesting that these changes occur early in the course of AD. Future efforts should optimize the scale based on current results and clinical experiences, and further study applicability, reliability, and validity. Future application of the scale in daily care may aid caregivers to understand changes, and contribute to timely interventions and adaptation of caregiving.

Background Aggressive challenging behaviour is prevalent in adults with an intellectual disability and is associated with over-medication, physical ill-health and psychiatric hospitalisation. We urgently need interventions that can moderate this behaviour and improve quality of life in this population. We report on the development and modelling of a 7-module tailored manualised psychological intervention to support adults who display aggressive challenging behaviour in community settings (hence referred to as the PETAL therapy). Method The PETAL therapy was designed following an extensive review of existing management provisions and was co-produced with carers with lived experience and self-advocates with an intellectual disability. A logic model was developed to illustrate the theoretical approach behind the development of the PETAL intervention. A single arm multi-site modelling study was conducted in England to test the delivery and acceptability of the PETAL intervention. Seventeen NHS healthcare professionals were trained during a two-day training programme and were regularly supervised to deliver the therapy in up to 14 weeks. Following completion, we conducted qualitative interviews with stakeholders and explored the intervention’s fidelity and acceptability. Results We held seven co-production meetings and developed the PETAL therapy, consisting of the following modules: Getting to know the person, understanding aggressive challenging behaviour, communication, emotions, a calm environment, carer wellbeing and healthy habits. We then recruited ten dyads or triads (person with a learning disability and 1–2 carers) to participate in a modelling study to test delivery aspects and measure fidelity. Nineteen stakeholders were interviewed, and the findings were analysed deductively using Normalisation Process Theory and its four domains: coherence, cognitive participation, collective action and reflexive monitoring. Conclusion The PETAL therapy was possible to deliver in community services with high fidelity and was acceptable. The PETAL manual and training programme have been reviewed and refined and a cluster randomised controlled trial is underway.

Down syndrome (DS) or trisomy 21 (T21) is present in a significant number of children and adults around the world and is associated with cognitive and medical challenges. Through research, the T21 Research Society (T21RS), established in 2014, unites a worldwide community dedicated to understanding the impact of T21 on biological systems and improving the quality of life of people with DS across the lifespan. T21RS hosts an international conference every two years to support collaboration, dissemination, and information sharing for this goal. In 2022, T21RS hosted an international conference in Long Beach, California, from June 9 to 12. The conference, attended by 483 people including scientists, families, self-advocates, and industry representatives from 17 countries, was a dynamic and interactive meeting that shared discoveries from international research teams. This summary highlights the scientific discoveries shared at the 4th T21RS meeting with the Imagine, Discover, Inspire theme.

Blood‐based biomarkers continue to be explored for disease detection, monitoring of progression, and therapeutic outcomes as the diagnostic determination of Alzheimer's Disease in Down Syndrome (DS‐AD) remains challenging in clinical settings. This perspective highlights the current status of this effort. Overall, amyloid (A), tau (T), and neurodegeneration (AT[N]) blood‐based biomarkers have been shown to increase with disease pathology for individuals with DS. Phosphorylated tau biomarkers (p‐tau217, p‐tau181) have been consistently shown to track disease progression for DS‐AD and are likely good candidates for use in clinical settings. Biomarkers of inflammation (glial fibrillary acidic protein) also show promise; however, additional work is needed. Findings from stability work of blood‐based biomarkers conducted among non‐DS also support the potential longitudinal utility of biomarkers such as neurofilament light chain and p‐tau181 in DS. Gaps in our knowledge are highlighted, and a potential role for sex differences in biomarker outcomes is noted, along with recommendations for determining the appropriate context of use when translating biomarkers into clinical applications. Highlights An overview of blood‐based biomarkers for Alzheimer's disease (AD) was provided for consideration of their utility among individuals with Down syndrome when looking toward potential clinical applications. Longitudinal stability of many blood biomarkers and improvement in detection sensitivity make blood such as plasma a viable source for exploring AD pathology. Variability in reviewed findings regarding the application of blood biomarkers highlights the importance of understanding and defining the appropriate context of use, particularly when translating them into clinical practice.

Objective Intellectual disability liaison nurses in general hospitals could enhance access to high-quality, adapted healthcare and improve outcomes. We aimed to explore associations between the input of intellectual disability liaison nurses and the quality of care in people with intellectual disability who are admitted to hospital. Design Retrospective analysis of a national dataset of mortality reviews. Setting General hospitals in England. Participants 4742 adults with intellectual disability who died in hospital between 2016 and 2021 and whose deaths were reviewed as part of the Learning from Lives and Deaths mortality review programme. Outcome measures We used logistic regression to compare the sociodemographic and clinical characteristics of those who did, and did not, receive input from an intellectual disability liaison nurse. We explored associations between liaison nurse input, care processes and overall quality of care. Results One-third of people with intellectual disability who died in hospital in England between 2016 and 2021 had input from an intellectual disability liaison nurse. Intellectual disability liaison nurse input was not evenly distributed across England and was more common in those who died of cancer. Having an intellectual disability liaison nurse involved in an individual’s care was associated with increased likelihood of reasonable adjustments being made to care (adjusted OR (aOR) 1.95, 95% CI 1.63 to 2.32) and of best practice being identified (aOR 1.37, 95% CI 1.17 to 1.60) but was not associated with a rating of overall quality of care received (aOR 0.94, 95% CI 0.78 to 1.12). Conclusions Intellectual disability liaison nurses see only a minority of people with intellectual disability who are admitted to hospital in England. Increasing the availability of intellectual disability liaison nurses could improve care for this disadvantaged group.

Constipation is common in people with intellectual disability, with case reports of associated deaths. Risk factors include lifestyle factors, health conditions, and certain medications. We aimed to explore constipation in a sample of people with intellectual disability who died in 2021. We described prevalence of constipation, causes of death and the risk of secondary constipation from prescribed medications. Medications were scored based on the risk of constipation indicated in the drug profile. Forty-eight percent of the sample had constipation. Half of the sample were prescribed at least two medications that are commonly associated with side effects of constipation. There were high rates of antipsychotic (30%) and laxative (40%) drug prescription. Five people with a history of constipation died of causes of death associated with constipation. Our findings highlight the risk of secondary constipation due to prescribed medication and the seriousness of the condition in people with intellectual disability.

Alzheimer’s disease (AD) is characterized by extracellular amyloid plaques containing amyloid-β (Aβ) peptides, intraneuronal neurofibrillary tangles, extracellular neuropil threads, and dystrophic neurites surrounding plaques composed of hyperphosphorylated tau protein (pTau). Aβ can also deposit in blood vessel walls leading to cerebral amyloid angiopathy (CAA). While amyloid plaques in AD brains are constant, CAA varies among cases. The study focuses on differences observed between rare and poorly studied patient groups with APP duplications (APPdup) and Down syndrome (DS) reported to have higher frequencies of elevated CAA levels in comparison to sporadic AD (sAD), most of APP mutations, and controls. We compared Aβ and tau pathologies in postmortem brain tissues across cases and Aβ peptides using mass spectrometry (MS). We further characterized the spatial distribution of Aβ peptides with MS-brain imaging. While intraparenchymal Aβ deposits were numerous in sAD, DS with AD (DS-AD) and AD with APP mutations, these were less abundant in APPdup. On the contrary, Aβ deposits in the blood vessels were abundant in APPdup and DS-AD while only APPdup cases displayed high Aβ deposits in capillaries. Investigation of Aβ peptide profiles showed a specific increase in Aβx-37, Aβx-38 and Aβx-40 but not Aβx-42 in APPdup cases and to a lower extent in DS-AD cases. Interestingly, N-truncated Aβ2-x peptides were particularly increased in APPdup compared to all other groups. This result was confirmed by MS-imaging of leptomeningeal and parenchymal vessels from an APPdup case, suggesting that CAA is associated with accumulation of shorter Aβ peptides truncated both at N- and C-termini in blood vessels. Altogether, this study identified striking differences in the localization and composition of Aβ deposits between AD cases, particularly APPdup and DS-AD, both carrying three genomic copies of the APP gene. Detection of specific Aβ peptides in CSF or plasma of these patients could improve the diagnosis of CAA and their inclusion in anti-amyloid immunotherapy treatments.