Exploring semantic verbal fluency patterns and their relationship to age and Alzheimer's disease in adults with Down syndrome.

INTRODUCTION: Adults with Down syndrome (DS) are at ultra-high risk of developing Alzheimer's disease (AD), characterized by poor episodic memory and semantic fluency in the preclinical phase in the general population. We explored semantic fluency performance in DS and its relationship to age, AD, and blood biomarkers. METHODS: A total of 302 adults with DS at baseline and 87 at follow-up from the London Down Syndrome Consortium cohort completed neuropsychological assessments. Blood biomarkers were measured with the single molecule array technique in a subset of 94 participants. RESULTS: Poorer verbal fluency performance was observed as age increases. Number of correct words declined in those with AD compared to those without over 2 years and was negatively correlated with neurofilament light (r = -0.37, P = .001) and glial fibrillary acidic protein (r = -0.31, P = .012). DISCUSSION: Semantic fluency may be useful as an early indicator of cognitive decline and provide additional information on AD-related change, showing associations with biomarkers in DS.

Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain.

A population of more than six million people worldwide at high risk of Alzheimer's disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of ß-amyloid-(Aß)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aß deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome 21 gene BACE2, but prevented by combined chemical ß and γ-secretase inhibition. We found that T21 organoids secrete increased proportions of Aß-preventing (Aß1-19) and Aß-degradation products (Aß1-20 and Aß1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1 inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ~30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.

Optimal age and outcome measures for Alzheimer's disease prevention trials in people with Down syndrome.

INTRODUCTION: People with Down syndrome (DS) typically develop Alzheimer's disease (AD) neuropathology before age 40, but a lack of outcome measures and longitudinal data have impeded their inclusion in randomized controlled trials (RCTs). METHODS: Cohort study. Event-based and dose-response Emax models were fitted to longitudinal cognitive data, to stage AD and determine the earliest ages of decline. Results informed sample size estimations for hypothetical RCTs of disease-modifying treatments that reduced decline by 35% or 75%. RESULTS: Seventy-five percent of participants progressed or remained stable in the AD staging model; effect sizes varied by age group and tests. Varied treatment effects could be detected with 50-200 people per arm when using sensitive cognitive outcome measures and targeting recruitment to ages 36 to 45 years. DISCUSSION: Efficient RCTs of AD preventative treatments can be conducted in the DS population using sensitive outcome measures to monitor early decline. Dose-response models could help tailor future RCTs.

Cognitive markers of preclinical and prodromal Alzheimer's disease in Down syndrome.

INTRODUCTION: Down syndrome (DS) is associated with an almost universal development of Alzheimer's disease. Individuals with DS are therefore an important population for randomized controlled trials to prevent or delay cognitive decline, though it is essential to understand the time course of early cognitive changes. METHODS: We conducted the largest cognitive study to date with 312 adults with DS to assess age-related and Alzheimer's disease-related cognitive changes during progression from preclinical to prodromal dementia, and prodromal to clinical dementia. RESULTS: Changes in memory and attention measures were most sensitive to early decline. Resulting sample size calculations for randomized controlled trials to detect significant treatment effects to delay decline were modest. DISCUSSION: Our findings address uncertainties around the development of randomized controlled trials to delay cognitive decline in DS. Such trials are essential to reduce the high burden of dementia in people with DS and could serve as proof-of-principle trials for some drug targets.

Transfer of cognitive training across magnitude dimensions achieved with concurrent brain stimulation of the parietal lobe.

Improvement in performance following cognitive training is known to be further enhanced when coupled with brain stimulation. Here we ask whether training-induced changes can be maintained long term and, crucially, whether they can extend to other related but untrained skills. We trained overall 40 human participants on a simple and well established paradigm assessing the ability to discriminate numerosity--or the number of items in a set--which is thought to rely on an "approximate number sense" (ANS) associated with parietal lobes. We coupled training with parietal stimulation in the form of transcranial random noise stimulation (tRNS), a noninvasive technique that modulates neural activity. This yielded significantly better and longer lasting improvement (up to 16 weeks post-training) of the precision of the ANS compared with cognitive training in absence of stimulation, stimulation in absence of cognitive training, and cognitive training coupled to stimulation to a control site (motor areas). Critically, only ANS improvement induced by parietal tRNS + Training transferred to proficiency in other parietal lobe-based quantity judgment, i.e., time and space discrimination, but not to quantity-unrelated tasks measuring attention, executive functions, and visual pattern recognition. These results indicate that coupling intensive cognitive training with tRNS to critical brain regions resulted not only in the greatest and longer lasting improvement of numerosity discrimination, but importantly in this enhancement being transferable when trained and untrained abilities are carefully chosen to share common cognitive and neuronal components.

The Association between Physical Activity and CAMDEX-DS Changes Prior to the Onset of Alzheimer's Disease in Down Syndrome.

BACKGROUND: People with Down syndrome are at ultra-high risk of developing Alzheimer's dementia. At present, there are no preventative or curative treatments. Evidence from sporadic Alzheimer's disease literature suggests that lifestyle factors including physical activity may help maintain cognitive and functional skills and reduce dementia risk. Our study aimed to explore the association between regular exercise undertaken by participants with Down syndrome and changes in dementia-related domains of cognition and function. This was to consider whether physical activity may be a protective measure to delay cognitive decline and dementia in Down syndrome. METHODS: Demographic, lifestyle, and health information was collected at baseline and at a two year follow up from 214 adults with Down syndrome without dementia, who also underwent assessment using the Cambridge Examination for Mental Disorders of Older People with Down Syndrome and Others with Intellectual Disabilities (CAMDEX-DS) and genetic analysis. Logistic regression models were used to examine the potential associations between decline in CAMDEX-DS domains and exercise whilst controlling for key variables. RESULTS: At baseline, engaging in moderate intensity exercise was associated with a 47% reduced risk of everyday skills decline and engaging in high intensity exercise was associated with a 62% reduced risk of decline in personality and behaviour. At follow-up, high levels of exercise were associated with an 87% reduced risk of decline in personality and behaviour. Moderate intensity exercise at baseline was associated with a 62% reduction in risk of decline during the follow-up period in memory and orientation. DISCUSSION: Based on our data it appears that regular moderate and high intensity exercise could reduce the risk of clinically detectable decline in a Down syndrome population with possible long-term benefits. People with Down syndrome may engage in less physical activity than their peers, and barriers remain which can prevent people with Down syndrome engaging in exercise. Our work highlights how important it is that people with Down syndrome are supported to be physically active, and to promote exercise as part of a healthy ageing plan. Clinical trials in this area would be justified to determine if engaging in exercise can lead to realistic improvements in maintaining functioning and delaying dementia onset in Down syndrome and to help develop guidance in this area.

Diagnostic and prognostic performance and longitudinal changes in plasma neurofilament light chain concentrations in adults with Down syndrome: a cohort study.

BACKGROUND: Adults with Down syndrome are at an ultra-high risk of Alzheimer's disease, but diagnosis of Alzheimer's disease in this population is challenging. We aimed to validate the clinical utility of plasma neurofilament light chain (NfL) for the diagnosis of symptomatic Alzheimer's disease in Down syndrome, assess its prognostic value, and establish longitudinal changes in adults with Down syndrome. METHODS: We did a multicentre cohort study, including adults with Down syndrome (≥18 years), recruited from six hospitals and university medical centres in France, Germany, Spain, the UK, and the USA, who had been assessed, followed up, and provided at least two plasma samples. Participants were classified by local clinicians, who were masked to biomarker data, as asymptomatic (ie, no clinical suspicion of Alzheimer's disease), prodromal Alzheimer's disease, or Alzheimer's disease dementia. We classified individuals who progressed along the Alzheimer's disease continuum during follow-up as progressors. Plasma samples were analysed retrospectively; NfL concentrations were measured centrally using commercial kits for biomarker detection. We used ANOVA to evaluate differences in baseline NfL concentrations, Cox regression to study their prognostic value, and linear mixed models to estimate longitudinal changes. To account for potential confounders, we included age, sex, and intellectual disability as covariates in the analyses. FINDINGS: Between Aug 2, 2010, and July 16, 2019, we analysed 608 samples from 236 people with Down syndrome: 165 (70%) were asymptomatic, 32 (14%) had prodromal Alzheimer's disease, and 29 (12%) had Alzheimer's disease dementia; ten [4%] participants were excluded because their classification was uncertain. Mean follow-up was 3·6 years (SD 1·6, range 0·6-9·2). Baseline plasma NfL concentrations showed an area under the receiver operating characteristic curve of 0·83 (95% CI 0·76-0·91) in the prodromal group and 0·94 (0·90-0·97) in the dementia group for differentiating from participants who were asymptomatic. An increase of 1 pg/mL in baseline NfL concentrations was associated with a 1·04-fold risk of clinical progression (95% CI 1·01-1·07; p=0·0034). Plasma NfL concentrations showed an annual increase of 3·0% (95% CI 0·4-5·8) per year in the asymptomatic non-progressors group, 11·5% (4·9-18·5) per year in the asymptomatic progressors group, and 16·0% (8·4-24·0) per year in the prodromal Alzheimer's disease progressors group. In participants with Alzheimer's disease dementia, NfL concentrations increased by a mean of 24·3% (15·3-34·1). INTERPRETATION: Plasma NfL concentrations have excellent diagnostic and prognostic performance for symptomatic Alzheimer's disease in Down syndrome. The longitudinal trajectory of plasma NfL supports its use as a theragnostic marker in clinical trials. FUNDING: AC Immune, La Caixa Foundation, Instituto de Salud Carlos III, National Institute on Aging, Wellcome Trust, Jérôme Lejeune Foundation, Medical Research Council, National Institute for Health Research, EU Joint Programme-Neurodegenerative Disease Research, Alzheimer's society, Deutsche Forschungsgemeinschaft, Stiftung für die Erforschung von Verhaltens und Umwelteinflüssen auf die menschliche Gesundheit, and NHS National Institute of Health Research Applied Research Collaborations East of England, UK.

Differential Associations of Apolipoprotein E ε4 Genotype With Attentional Abilities Across the Life Span of Individuals With Down Syndrome.

Importance: Risk of Alzheimer disease (AD) is particularly high for individuals with Down syndrome (DS). The ε4 allele of the apolipoprotein E gene (APOE ε4) is associated with an additional risk for AD. In typical development, there is evidence that the APOE ε4 genotype is associated with an early cognitive advantage. Here we investigate associations of APOE ε4 with attention across the life span of individuals with DS. Objective: To investigate associations between APOE ε4 and attentional abilities in young children and in adults with DS. Design, Settings, and Participants: In this cross-sectional study, data were collected from 80 young children with DS (8-62 months of age) and 240 adults with DS (16-71 years of age) during the period from 2013 to 2018 at a research center to examine the association between APOE status (ε4 carrier vs ε4 noncarrier) and attentional abilities. Exposure: APOE status (ε4 carrier vs ε4 noncarrier). Main Outcomes and Measures: For the children, attentional ability was assessed using an eye-tracking paradigm, the gap-overlap task; the size of the gap effect was the primary outcome. For the adults, attentional ability was assessed using the CANTAB simple reaction time task; the standard deviation of response time latencies was the primary outcome. Cross-sectional developmental trajectories were constructed linking attentional ability with age in ε4 carriers and ε4 noncarriers for children and adults separately. Results: The child sample comprised 23 ε4 carriers and 57 ε4 noncarriers. The adult sample comprised 61 ε4 carriers and 179 ε4 noncarriers. For the children, a significant difference between trajectory intercepts (ηp2 = 0.14) indicated that ε4 carriers (B = 100.24 [95% CI, 18.52-181.96]) exhibited an attentional advantage over ε4 noncarriers (B = 314.78 [95% CI, 252.17-377.39]). There was an interaction between APOE status and age (ηp2 = 0.10); while the gap effect decreased with age for ε4 noncarriers (B = -4.58 [95% CI, -6.67 to -2.48]), reflecting the development of the attention system, there was no change across age in ε4 carriers (B = 0.77 [95% CI, -1.57 to 3.12]). For the adults, there was no main effect of ε4 carrier status, but there was an interaction between APOE status and age (B = 0.02 [95% CI, 0.004-0.07]), so that ε4 carriers had poorer attentional ability than ε4 noncarriers at older ages. Conclusions and Relevance: APOE ε4 is associated with an attentional advantage early in development and a disadvantage later in life for individuals with DS, similar to the pattern reported in typical development. Understanding the differential role of APOE across the life span is an important step toward future interventions.

Health comorbidities and cognitive abilities across the lifespan in Down syndrome.

BACKGROUND: Down syndrome (DS) is associated with variable intellectual disability and multiple health and psychiatric comorbidities. The impact of such comorbidities on cognitive outcomes is unknown. We aimed to describe patterns of physical health and psychiatric comorbidity prevalence, and receptive language ability, in DS across the lifespan, and determine relationships with cognitive outcomes. METHODS: Detailed medical histories were collected and cognitive abilities measured using standardised tests for 602 individuals with DS from England and Wales (age range 3 months to 73 years). Differences in prevalence rates between age groups and between males and females were determined using chi-squared or Fisher's exact tests. In adults, rates for psychiatric comorbidities were compared to expected population rates using standardised morbidity ratios (SMRs). Adapted ANCOVA functions were constructed to explore age and sex associations with receptive language ability across the lifespan, and regression analyses were performed to determine whether the presence of health comorbidities or physical phenotypes predicted cognitive abilities. RESULTS: Multiple comorbidities showed prevalence differences across the lifespan, though there were few sex differences. In adults, SMRs were increased in males and decreased in females with DS for schizophrenia, bipolar disorder, and anxiety. Further, SMRs were increased in both males and females with DS for dementia, autism, ADHD, and depression, with differences more pronounced in females for dementia and autism, and in males for depression. Across the lifespan, receptive language abilities increasingly deviated from age-typical levels, and males scored poorer than females. Only autism and epilepsy were associated with poorer cognitive ability in those aged 16-35 years, with no relationships for physical health comorbidities, including congenital heart defects. CONCLUSIONS: Our results indicate the prevalence of multiple comorbidities varies across the lifespan in DS, and in adults, rates for psychiatric comorbidities show different patterns for males and females relative to expected population rates. Further, most health comorbidities are not associated with poorer cognitive outcomes in DS, apart from autism and epilepsy. It is essential for clinicians to consider such differences to provide appropriate care and treatment for those with DS and to provide prognostic information relating to cognitive outcomes in those with comorbidities.

Validating the Cognitive Scale for Down Syndrome (CS-DS) to Detect Longitudinal Cognitive Decline in Adults With Down Syndrome.

Down syndrome (DS) is associated with intellectual disability and an ultra-high risk of developing dementia. Informant ratings are invaluable to assess abilities and related changes in adults with DS, particularly for those with more severe intellectual disabilities and/or cognitive decline. We previously developed the informant rated Cognitive Scale for Down Syndrome (CS-DS) to measure everyday cognitive abilities across memory, executive function, and language domains in adults with DS, finding CS-DS scores are a valid measure of general abilities, and are significantly lower for those with noticeable cognitive decline compared to those without decline. To further test the validity of the CS-DS in detecting changes associated with cognitive decline we collected longitudinal data across two time points, approximately 1.5-2 years apart, for 48 adults with DS aged 36 years and over. CS-DS total scores (78.83 ± 23.85 vs. 73.83 ± 25.35, p = 0.042) and executive function scores (46.40 ± 13.59 vs. 43.54 ± 13.60, p = 0.048) significantly decreased between the two time points, with scores in the memory domain trending towards a significant decrease (22.19 ± 8.03 vs. 20.81 ± 8.63, p = 0.064). Adults with noticeable cognitive decline at follow-up showed a trend to significantly greater change in total scores (7.81 ± 16.41 vs. 3.59 ± 16.79, p = 0.067) and significantly greater change in executive function scores (5.13 ± 9.22 vs. 1.72 ± 9.97, p = 0.028) compared to those without decline. Change in total scores showed significant correlations with change in scores from other informant measures of everyday adaptive abilities and symptoms associated with dementia, and participant assessment of general cognitive abilities (all p < 0.005), while change in memory scores (R 2 = 0.28, p = 0.001) better predicted change in participant cognitive assessment scores than change in executive function (R 2 = 0.15, p = 0.016) or language (R 2 = 0.15, p = 0.018) scores. These results suggest informants may better detect changes in the executive function domain, while change in informant rated memory scores best predicts change in assessed cognitive ability. Alternatively, memory domain scores may be sensitive to changes across both early and late cognitive decline, whereas executive function domain scores are more sensitive to changes associated with later noticeable cognitive decline. Our results provide further support for the validity of the CS-DS to assess everyday cognitive abilities and to detect associated longitudinal changes in individuals with DS.

Plasma biomarkers for amyloid, tau, and cytokines in Down syndrome and sporadic Alzheimer's disease.

BACKGROUND: Down syndrome (DS), caused by chromosome 21 trisomy, is associated with an ultra-high risk of dementia due to Alzheimer's disease (AD), driven by amyloid precursor protein (APP) gene triplication. Understanding relevant molecular differences between those with DS, those with sporadic AD (sAD) without DS, and controls will aid in understanding AD development in DS. We explored group differences in plasma concentrations of amyloid-ß peptides and tau (as their accumulation is a characteristic feature of AD) and cytokines (as the inflammatory response has been implicated in AD development, and immune dysfunction is common in DS). METHODS: We used ultrasensitive assays to compare plasma concentrations of the amyloid-ß peptides Aß40 and Aß42, total tau (t-tau), and the cytokines IL1ß, IL10, IL6, and TNFα between adults with DS (n = 31), adults with sAD (n = 27), and controls age-matched to the group with DS (n = 27), and explored relationships between molecular concentrations and with age within each group. In the group with DS, we also explored relationships with neurofilament light (NfL) concentration, due to its potential use as a biomarker for AD in DS. RESULTS: Aß40, Aß42, and IL1ß concentrations were higher in DS, with a higher Aß42/Aß40 ratio in controls. The group with DS showed moderate positive associations between concentrations of t-tau and both Aß42 and IL1ß. Only NfL concentration in the group with DS showed a significant positive association with age. CONCLUSIONS: Concentrations of Aß40 and Aß42 were much higher in adults with DS than in other groups, reflecting APP gene triplication, while no difference in the Aß42/Aß40 ratio between those with DS and sAD may indicate similar processing and deposition of Aß40 and Aß42 in these groups. Higher concentrations of IL1ß in DS may reflect an increased vulnerability to infections and/or an increased prevalence of autoimmune disorders, while the positive association between IL1ß and t-tau in DS may indicate IL1ß is associated with neurodegeneration. Finally, NfL concentration may be the most suitable biomarker for dementia progression in DS. The identification of such a biomarker is important to improve the detection of dementia and monitor its progression, and for designing clinical intervention studies.

Association of Dementia With Mortality Among Adults With Down Syndrome Older Than 35 Years.

Importance: This work quantifies the fatal burden of dementia associated with Alzheimer disease in individuals with Down syndrome (DS). Objective: To explore the association of dementia associated with Alzheimer disease with mortality and examine factors associated with dementia in adults with DS. Design, Settings and Participants: Prospective longitudinal study in a community setting in England. Data collection began March 29, 2012. Cases were censored on December 13, 2017. The potential sample consisted of all adults 36 years and older from the London Down Syndrome Consortium cohort with 2 data times and dementia status recorded (N = 300); 6 withdrew from study, 28 were lost to follow-up, and 55 had a single data collection point at time of analysis. The final sample consisted of 211 participants, with 503.92 person-years' follow-up. Exposures: Dementia status, age, sex, APOE genotype, level of intellectual disability, health variables, and living situation. Main Outcomes and Measures: Crude mortality rates, time to death, and time to dementia diagnosis with proportional hazards of predictors. Results: Of the 211 participants, 96 were women (45.5%) and 66 (31.3%) had a clinical dementia diagnosis. Twenty-seven participants (11 female; mean age at death, 56.74 years) died during the study period. Seventy percent had dementia. Crude mortality rates for individuals with dementia (1191.85 deaths per 10 000 person-years; 95% CI, 1168.49-1215.21) were 5 times higher than for those without (232.22 deaths per 10 000 person-years; 95% CI, 227.67-236.77). For those with dementia, APOE ε4 carriers had a 7-fold increased risk of death (hazard ratio [HR], 6.91; 95% CI, 1.756-27.195). For those without dementia, epilepsy with onset after age 36 years was associated with mortality (HR, 9.66; 95% CI, 1.59-58.56). APOE ε4 carriers (HR, 4.91; 95% CI, 2.53-9.56), adults with early-onset epilepsy (HR, 3.61; 95% CI, 1.12-11.60), multiple health comorbidities (HR, 1.956; 95% CI, 1.087-3.519), and those living with family (HR, 2.14; 95% CI, 1.08-4.20) received significantly earlier dementia diagnoses. Conclusions and Relevance: Dementia was associated with mortality in 70% of older adults with DS. APOE ε4 carriers and/or people with multiple comorbid health conditions were at increased risk of dementia and death, highlighting the need for good health care. For those who died without a dementia diagnosis, late-onset epilepsy was the only significant factor associated with death, raising questions about potentially undiagnosed dementia cases in this group.

Aging related cognitive changes associated with Alzheimer's disease in Down syndrome.

OBJECTIVE: Individuals with Down syndrome (DS) have an extremely high genetic risk for Alzheimer's disease (AD), however, the course of cognitive decline associated with progression to dementia is ill-defined. Data-driven methods can estimate long-term trends from cross-sectional data while adjusting for variability in baseline ability, which complicates dementia assessment in those with DS. METHODS: We applied an event-based model to cognitive test data and informant-rated questionnaire data from 283 adults with DS (the largest study of cognitive functioning in DS to date) to estimate the sequence of cognitive decline and individuals' disease stage. RESULTS: Decline in tests of memory, sustained attention/motor coordination, and verbal fluency occurred early, demonstrating that AD in DS follows a similar pattern of change to other forms of AD. Later decline was found for informant measures. Using the resulting staging model, we showed that adults with a clinical diagnosis of dementia and those with APOE 3:4 or 4:4 genotype were significantly more likely to be staged later, suggesting that the model is valid. INTERPRETATION: Our results identify tests of memory and sustained attention may be particularly useful measures to track decline in the preclinical/prodromal stages of AD in DS whereas informant-measures may be useful in later stages (i.e. during conversion into dementia, or postdiagnosis). These results have implications for the selection of outcome measures of treatment trials to delay or prevent cognitive decline due to AD in DS. As clinical diagnoses are generally made late into AD progression, early assessment is essential.

Cognitive decline and dementia in Down syndrome.

PURPOSE OF REVIEW: Alzheimer's disease is most likely universal in older individuals with Down syndrome, due to having three copies of the amyloid precursor protein gene, resulting in amyloid-beta plaque deposition. Down syndrome is an important population in which to consider clinical trials of treatments to prevent or delay the development of dementia. However, assessment of subtler cognitive changes is challenging due to the presence of intellectual disability. RECENT FINDINGS: Recent research confirmed that older adults with Down syndrome often present with cognitive decline: more than 80% may experience dementia by age 65 years. Efforts have been made to improve and validate neuropsychological assessment and to describe the relationship with comorbidities such as epilepsy and haemorrhagic stroke. There have also been advances in biomarkers such as neuroimaging using amyloid PET. SUMMARY: Clinical trials of treatments, particularly in the presymptomatic phase of Alzheimer's disease, are important to consider in individuals with Down syndrome given their high dementia burden, and may also serve as proof of concept for other forms of Alzheimer's disease. However, further work is required to improve outcome measures and better understand the biomarkers of progression of disorder and their relationship with symptom development during the presymptomatic period.

The LonDownS adult cognitive assessment to study cognitive abilities and decline in Down syndrome.

BACKGROUND: Down syndrome (DS), the most common genetic cause of intellectual disability, is associated with an ultra-high risk of developing Alzheimer's disease. However, there is individual variability in the onset of clinical dementia and in baseline cognitive abilities prior to decline, particularly in memory, executive functioning, and motor coordination. The LonDownS Consortium aims to determine risk and protective factors for the development of dementia and factors relating to cognitive abilities in people with DS. Here we describe our cognitive test battery and related informant measures along with reporting data from our baseline cognitive and informant assessments. METHODS: We developed a cognitive test battery to assess general abilities, memory, executive function, and motor coordination abilities in adults with DS, with informant ratings of similar domains also collected, designed to allow for data on a broad range of participants. Participants (n=305) had a range of ages and abilities, and included adults with and without a clinical diagnosis of dementia. RESULTS: Results suggest the battery is suitable for the majority of adults with DS, although approximately half the adults with dementia were unable to undertake any cognitive task. Many test outcomes showed a range of scores with low floor and ceiling effects. Non-verbal age-adjusted IQ scores had lower floor effects than verbal IQ scores. Before the onset of any cognitive decline, females aged 16-35 showed better verbal abilities compared to males. We also identified clusters of cognitive test scores within our battery related to visuospatial memory, motor coordination, language abilities, and processing speed / sustained attention. CONCLUSIONS: Our further studies will use baseline and longitudinal assessments to explore factors influencing cognitive abilities and cognitive decline related to ageing and onset of dementia in adults with DS.

Carer-led health interventions to monitor, promote and improve the health of adults with intellectual disabilities in the community: a systematic review.

Using carers to help assess, monitor, or promote health in people with intellectual disabilities (ID) may be one way of improving health outcomes in a population that experiences significant health inequalities. This paper provides a review of carer-led health interventions in various populations and healthcare settings, in order to investigate potential roles for carers in ID health care. We used rapid review methodology, using the Scopus database, citation tracking and input from ID healthcare professionals to identify relevant research. 24 studies were included in the final review. For people with ID, the only existing interventions found were carer-completed health diaries which, while being well received, failed to improve health outcomes. Studies in non-ID populations show that carers can successfully deliver screening procedures, health promotion interventions and interventions to improve coping skills, pain management and cognitive functioning. While such examples provide a useful starting point for the development of future carer-led health interventions for people with ID, the paucity of research in this area means that the most appropriate means of engaging carers in a way that will reliably impact on health outcomes in this population remains, as yet, unknown.

Assessment of an incentivised scheme to provide annual health checks in primary care for adults with intellectual disability: a longitudinal cohort study.

BACKGROUND: People with intellectual disabilities (ID) have many comorbidities but experience inequities in access to health care. National Health Service England uses an opt-in incentive scheme to encourage annual health checks of patients with ID in primary care. We investigated whether the first 3 years of the programme had improved health care of people with ID. METHODS: We did a longitudinal cohort study that used data from The Health Improvement Network primary care database. We did multivariate logistic regression to assess associations between various characteristics and whether or not practices had opted in to the incentivised scheme. FINDINGS: We assessed data for 8692 patients from 222 incentivised practices and those for 918 patients in 48 non-incentivised practices. More blood tests (eg, total cholesterol, odds ratio [OR] 1·88, 95% CI 1·47-2·41, p<0·0001) general health measurements (eg, smoking status, 6·0, 4·10-8·79, p<0·0001), specific health assessments (eg, hearing, 24·0, 11·5-49·9, p<0·0001), and medication reviews (2·23, 1·68-2·97, p<0·0001) were done in incentivised than in non-incentivised practices, and more health action plans (6·15, 1·41-26·9, p=0·0156) and secondary care referrals (1·47, 1·05-2·05, p=0·0256) were made. Identification rates were higher in incentivised practices for thyroid disorder (OR 2·72, 95% CI 1·09-6·81, p=0·0323), gastrointestinal disorders (1·94, 1·03-3·65, p=0·0390), and obesity (2·49, 1·76-3·53, p<0·0001). INTERPRETATION: Targeted annual health checks for people with ID in primary care could reduce health inequities. FUNDING: National Institute for Health Research.