Toward the right treatment at the right time: Modeling the trajectory of cognitive decline to identify the earliest age of change in people with Alzheimer's disease.

Introduction: Age is the greatest risk factor for Alzheimer's disease (AD). A limitation of randomized control trials in AD is a lack of specificity in the age ranges of participants who are enrolled in studies of disease-modifying therapies. We aimed to apply Emax (i.e., maximum effect) modeling as a novel approach to identity ideal treatment windows. Methods: Emax curves were fitted to longitudinal cognitive data of 101 participants with AD and 1392 healthy controls. We included the Mini-Mental State Examination (MMSE) and tests of verbal fluency and executive functioning. Results: In people with AD, the earliest decline in the MMSE could be detected in the 67-71 age band while verbal fluency declined from the 41-45 age band. In healthy controls, changes in cognition showed a later trajectory of decline. Discussion: Emax modeling could be used to design more efficient trials which has implications for randomized control trials targeting the earlier stages of AD.

Adapting prescribing criteria for amyloid-targeted antibodies for adults with Down syndrome.

Prior authorization criteria for Federal Drug Administration (FDA) approved immunotherapeutics, among the class of anti-amyloid monoclonal antibodies (mAbs), established by state drug formulary committees, are tailored for adults with late-onset Alzheimer's disease. This overlooks adults with Down syndrome (DS), who often experience dementia at a younger age and with different diagnostic assessment outcomes. This exclusion may deny DS adults access to potential disease-modifying treatments. To address this issue, an international expert panel convened to establish adaptations of prescribing criteria suitable for DS patients and parameters for access to Centers for Medicare & Medicaid Services (CMS) registries. The panel proposed mitigating disparities by modifying CMS and payer criteria to account for younger onset age, using alternative language and assessment instruments validated for cognitive decline in the DS population. The panel also recommended enhancing prescribing clinicians' diagnostic capabilities for DS and initiated awareness-raising activities within healthcare organizations. These efforts facilitated discussions with federal officials, aimed at achieving equity in access to anti-amyloid immunotherapeutics, with implications for national authorities worldwide evaluating these and other new disease-modifying therapeutics for Alzheimer's disease.

Age of Alzheimer's disease diagnosis in people with Down syndrome and associated factors: Results from the Horizon 21 European Down syndrome consortium.

INTRODUCTION: People with Down syndrome (DS) have high risk of developing Alzheimer's disease (AD). This study examined mean ages of AD diagnosis and associations with co-occurring conditions among adults with DS from five European countries. METHODS: Data from 1335 people with DS from the Horizon 21 European DS Consortium were used for the analysis. RESULTS: Mean ages of AD diagnosis ranged between 51.4 (SD 7.0) years (United Kingdom) and 55.6 (SD 6.8) years (France). Sleep-related and mental health problems were associated with earlier age of AD diagnosis. The higher number of co-occurring conditions the more likely the person with DS is diagnosed with AD at an earlier age. DISCUSSION: Mean age of AD diagnosis in DS was relatively consistent across countries. However, co-occurring conditions varied and impacted on age of diagnosis, suggesting that improvements can be made in diagnosing and managing these conditions to delay onset of AD in DS. HIGHLIGHTS: Mean age of AD diagnosis was relatively consistent between countries Sleep problems and mental health problems were associated with earlier age of AD diagnosis APOE ε4 carriers were diagnosed with AD at an earlier age compared to non-carriers Number of co-occurring conditions was associated with earlier age of AD diagnosis No differences between level of intellectual disability and mean age of AD diagnosis.

Common mental health disorders and cognitive decline in a longitudinal Down syndrome cohort.

BACKGROUND: Down syndrome is the most common genetic cause of intellectual disability and Alzheimer's disease. In the general population, common mental disorders (CMDs), including anxiety, depression and obsessive-compulsive disorder, are linked to cognitive decline and higher risk for dementia. It is not known how CMDs affect longer-term cognitive outcomes in Down syndrome, and there is often diagnostic uncertainty in older people with Down syndrome and psychiatric comorbidity. AIMS: To study the influence of CMDs on cognitive ability and whether they are related longitudinally to development of clinical signs of Alzheimer's disease in Down syndrome. METHOD: We followed 115 individuals with Down syndrome, 27 of whom were diagnosed with a CMD, over approximately 3 years. Changes in cognitive and behavioural outcomes between baseline and follow-up assessment were analysed, with comparisons made between those with and without a comorbid CMD. Age, gender, apolipoprotein E status and level of intellectual disability were included as covariates. RESULTS: No significant association between presence of a CMD and poorer performance on cognitive tasks or informant-rated decline over time was observed (P > 0.05). CONCLUSIONS: Our results suggest that a diagnosis of a CMD does not have a significant negative effect on long-term cognitive or behavioural outcomes in individuals with Down syndrome. In individuals with stable or treated CMD, subsequent cognitive decline is likely indicative of Alzheimer's disease rather than a consequence of mental disorder.

Identifying individuals with intellectual disability who access mental health support and are at high risk for adverse clinical outcomes: cohort study.

BACKGROUND: People with intellectual disability often experience aggressive challenging behaviour and mental health issues. It can be difficult to identify those who are at higher risk of adverse clinical outcomes when in clinical care. AIMS: To characterise potential subgroups in adults with intellectual disability referred to mental health services in those presenting with aggressive behaviour or common mental disorders (CMDs). METHOD: There were 836 adults (≥18 years) with intellectual disability and a record of aggressive challenging behaviour, and 205 patients with intellectual disability and CMDs, who were seen in specialist mental health services over a 5-year period. Cluster analysis was used to define patient characteristics associated with clinical outcome. RESULTS: Distinct patient groups with differentiated profiles were observed in people with intellectual disability displaying aggressive challenging behaviour, and in those presenting with CMDs. Characteristics of the aggressive behaviour group who experienced adverse outcomes included being <30 years old, being male, more mentions of aggression and agitation in their clinical record, a diagnosis of pervasive developmental disorder and prescription of psychotropic medication. Characteristics of the CMD cluster that experienced adverse clinical outcomes were being older, being a White male, having a mild intellectual disability and physical health concerns. CONCLUSIONS: People with intellectual disability who experience adverse clinical outcomes can be identified with a cluster analysis approach of common features, but differ by clinical presentation. This could be used not only to stratify this clinically heterogeneous population in terms of response to interventions, but also improve precision in the development of tailored interventions.

A tool for safer prescribing in vulnerable adults: the continuing development of the Medichec app and website.

AIMS AND METHOD: Adverse effects are a common concern when prescribing and reviewing medication, particularly in vulnerable adults such as older people and those with intellectual disability. This paper describes the development of an app giving information on side-effects, called Medichec, and provides a description of the processes involved in its development and how drugs were rated for each side-effect. Medications with central anticholinergic action, dizziness, drowsiness, hyponatraemia, QTc prolongation, bleeding and constipation were identified using the British National Formulary (BNF) and frequency of occurrence of these effects was determined using the BNF, product information and electronic searches, including PubMed. RESULTS: Medications were rated using a traffic light system according to how commonly the adverse effect was known to occur or the severity of the effect. CLINICAL IMPLICATIONS: Medichec can facilitate access to side-effects information for multiple medications, aid clinical decision-making, optimise treatment and improve patient safety in vulnerable adults.

Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels.

BACKGROUND: People with Down syndrome (DS) show clinical signs of accelerated ageing. Causative mechanisms remain unknown and hypotheses range from the (essentially untreatable) amplified-chromosomal-instability explanation, to potential actions of individual supernumerary chromosome-21 genes. The latter explanation could open a route to therapeutic amelioration if the specific over-acting genes could be identified and their action toned-down. METHODS: Biological age was estimated through patterns of sugar molecules attached to plasma immunoglobulin-G (IgG-glycans, an established "biological-ageing-clock") in n = 246 individuals with DS from three European populations, clinically characterised for the presence of co-morbidities, and compared to n = 256 age-, sex- and demography-matched healthy controls. Isogenic human induced pluripotent stem cell (hiPSCs) models of full and partial trisomy-21 with CRISPR-Cas9 gene editing and two kinase inhibitors were studied prior and after differentiation to cerebral organoids. FINDINGS: Biological age in adults with DS is (on average) 18.4-19.1 years older than in chronological-age-matched controls independent of co-morbidities, and this shift remains constant throughout lifespan. Changes are detectable from early childhood, and do not require a supernumerary chromosome, but are seen in segmental duplication of only 31 genes, along with increased DNA damage and decreased levels of LaminB1 in nucleated blood cells. We demonstrate that these cell-autonomous phenotypes can be gene-dose-modelled and pharmacologically corrected in hiPSCs and derived cerebral organoids. Using isogenic hiPSC models we show that chromosome-21 gene DYRK1A overdose is sufficient and necessary to cause excess unrepaired DNA damage. INTERPRETATION: Explanation of hitherto observed accelerated ageing in DS as a developmental progeroid syndrome driven by DYRK1A overdose provides a target for early pharmacological preventative intervention strategies. FUNDING: Main funding came from the "Research Cooperability" Program of the Croatian Science Foundation funded by the European Union from the European Social Fund under the Operational Programme Efficient Human Resources 2014-2020, Project PZS-2019-02-4277, and the Wellcome Trust Grants 098330/Z/12/Z and 217199/Z/19/Z (UK). All other funding is described in details in the "Acknowledgements".

The mismatch negativity as an index of cognitive abilities in adults with Down syndrome.

Down syndrome (DS) is associated with an ultra-high risk of developing Alzheimer's disease (AD). Understanding variability in pre-AD cognitive abilities may help understand cognitive decline in this population. The mismatch negativity (MMN) is an event-related potential component reflecting the detection of deviant stimuli that is thought to represent underlying memory processes, with reduced MMN amplitudes being associated with cognitive decline. To further understand the MMN in adults with DS without AD, we explored the relationships between MMN, age, and cognitive abilities (memory, language, and attention) in 27 individuals (aged 17-51) using a passive auditory oddball task. Statistically significant MMN was present only in 18 individuals up to 41 years of age and the latency were longer than canonical parameters reported in the literature. Reduced MMN amplitude was associated with lower memory scores, while longer MMN latencies were associated with poorer memory, verbal abilities, and attention. Therefore, the MMN may represent a valuable index of cognitive abilities in DS. In combination with previous findings, we hypothesize that while MMN response and amplitude may be associated with AD-related memory loss, MMN latency may be associated with speech signal processing. Future studies may explore the potential impact of AD on MMN in people with DS.

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.

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.

Multiple morbidity across the lifespan in people with Down syndrome or intellectual disabilities: a population-based cohort study using electronic health records.

BACKGROUND: The Down syndrome phenotype is well established, but our understanding of its morbidity patterns is limited. We comprehensively estimated the risk of multiple morbidity across the lifespan in people with Down syndrome compared with the general population and controls with other forms of intellectual disability. METHODS: In this matched population-based cohort-study design, we used electronic health-record data from the UK Clinical Practice Research Datalink (CRPD) from Jan 1, 1990, to June 29, 2020. We aimed to explore the pattern of morbidities throughout the lifespan of people with Down syndrome compared with people with other intellectual disabilities and the general population, to identify syndrome-specific health conditions and their age-related incidence. We estimated incidence rates per 1000 person-years and incidence rate ratios (IRRs) for 32 common morbidities. Hierarchical clustering was used to identify groups of associated conditions using prevalence data. FINDINGS: Between Jan 1, 1990, and June 29, 2020, a total of 10 204 people with Down syndrome, 39 814 controls, and 69 150 people with intellectual disabilities were included. Compared with controls, people with Down syndrome had increased risk of dementia (IRR 94·7, 95% CI 69·9-128·4), hypothyroidism (IRR 10·6, 9·6-11·8), epilepsy (IRR 9·7, 8·5-10·9), and haematological malignancy (IRR 4·7, 3·4-6·3), whereas asthma (IRR 0·88, 0·79-0·98), cancer (solid tumour IRR 0·75, 0·62-0·89), ischaemic heart disease (IRR 0·65, 0·51-0·85), and particularly hypertension (IRR 0·26, 0·22-0·32) were less frequent in people with Down syndrome than in controls. Compared to people with intellectual disabilities, risk of dementia (IRR 16·60, 14·23-19·37), hypothyroidism (IRR 7·22, 6·62-7·88), obstructive sleep apnoea (IRR 4·45, 3·72-5·31), and haematological malignancy (IRR 3·44, 2·58-4·59) were higher in people with Down syndrome, with reduced rates for a third of conditions, including new onset of dental inflammation (IRR 0·88, 0·78-0·99), asthma (IRR 0·82, 0·73-0·91), cancer (solid tumour IRR 0·78, 0·65-0·93), sleep disorder (IRR 0·74, 0·68-0·80), hypercholesterolaemia (IRR 0·69, 0·60-0·80), diabetes (IRR 0·59, 0·52-0·66), mood disorder (IRR 0·55, 0·50-0·60), glaucoma (IRR 0·47, 0·29-0·78), and anxiety disorder (IRR 0·43, 0·38-0·48). Morbidities in Down syndrome could be categorised on age-related incidence trajectories, and their prevalence clustered into typical syndromic conditions, cardiovascular diseases, autoimmune disorders, and mental health conditions. INTERPRETATION: Multiple morbidity in Down syndrome shows distinct patterns of age-related incidence trajectories and clustering that differ from those found in the general population and in people with other intellectual disabilities, with implications for provision and timing of health-care screening, prevention, and treatment for people with Down syndrome. FUNDING: The European Union's Horizon 2020 Research and Innovation Programme, the Jérôme Lejeune Foundation, the Alzheimer's Society, the Medical Research Council, the Academy of Medical Sciences, the Wellcome Trust, and William Harvey Research Limited.

Innovating Therapies for Down Syndrome: An International Virtual Conference of the T21 Research Society.

Research focused on Down syndrome continued to gain momentum in the last several years and is advancing our understanding of how trisomy 21 (T21) modifies molecular and cellular processes. The Trisomy 21 Research Society (T21RS) is the premier scientific organization for researchers and clinicians studying Down syndrome. During the COVID pandemic, T21RS held its first virtual conference program, sponsored by the University of California at Irvine, on June 8-10, 2021 and brought together 342 scientists, families, and industry representatives from over 25 countries to share the latest discoveries on underlying cellular and molecular mechanisms of T21, cognitive and behavioral changes, and comorbidities associated with Down syndrome, including Alzheimer's disease and Regression Disorder. Presentations of 91 cutting-edge abstracts reflecting neuroscience, neurology, model systems, psychology, biomarkers, and molecular and pharmacological therapeutic approaches demonstrate the compelling interest and continuing advancement toward innovating biomarkers and therapies aimed at ameliorating health conditions associated with T21.

Recording of intellectual disability in general hospitals in England 2006-2019: Cohort study using linked datasets.

BACKGROUND: Accurate recognition and recording of intellectual disability in those who are admitted to general hospitals is necessary for making reasonable adjustments, ensuring equitable access, and monitoring quality of care. In this study, we determined the rate of recording of intellectual disability in those with the condition who were admitted to hospital and factors associated with the condition being unrecorded. METHODS AND FINDINGS: Retrospective cohort study using 2 linked datasets of routinely collected clinical data in England. We identified adults with diagnosed intellectual disability in a large secondary mental healthcare database and used general hospital records to investigate recording of intellectual disability when people were admitted to general hospitals between 2006 and 2019. Trends over time and factors associated with intellectual disability being unrecorded were investigated. We obtained data on 2,477 adults with intellectual disability who were admitted to a general hospital in England at least once during the study period (total number of admissions = 27,314; median number of admissions = 5). People with intellectual disability were accurately recorded as having the condition during 2.9% (95% CI 2.7% to 3.1%) of their admissions. Broadening the criteria to include a nonspecific code of learning difficulty increased recording to 27.7% (95% CI 27.2% to 28.3%) of all admissions. In analyses adjusted for age, sex, ethnicity, and socioeconomic deprivation, having a mild intellectual disability and being married were associated with increased odds of the intellectual disability being unrecorded in hospital records. We had no measure of quality of hospital care received and could not relate this to the presence or absence of a record of intellectual disability in the patient record. CONCLUSIONS: Recognition and recording of intellectual disability in adults admitted to English general hospitals needs to be improved. Staff awareness training, screening at the point of admission, and data sharing between health and social care services could improve care for people with intellectual disability.

Complement dysregulation and Alzheimer's disease in Down syndrome.

INTRODUCTION: Down syndrome (DS) is associated with immune dysregulation and a high risk of early onset Alzheimer's disease (AD). Complement is a key part of innate immunity and driver of pathological inflammation, including neuroinflammation in AD. Complement dysregulation has been reported in DS; however, the pattern of dysregulation and its relationship to AD risk is unclear. METHODS: Plasma levels of 14 complement biomarkers were measured in 71 adults with DS and 46 controls to identify DS-associated dysregulation; impact of apolipoprotein E (APOE) ε4 genotype, single nucleotide polymorphisms (SNPs) in CLU and CR1, and dementia on complement biomarkers was assessed. RESULTS: Plasma levels of complement activation products (TCC, iC3b), proteins (C1q, C3, C9), and regulators (C1 inhibitor, factor H, FHR4, clusterin) were significantly elevated in DS versus controls while FI and sCR1 were significantly lower. In DS with AD (n = 13), C3 and FI were significantly decreased compared to non-AD DS (n = 58). Neither APOE genotype nor CLU SNPs impacted complement levels, while rs6656401 in CR1 significantly impacted plasma sCR1 levels. CONCLUSIONS: Complement is dysregulated in DS, likely reflecting the generalized immune dysregulation state; measurement may help identify inflammatory events in individuals with DS. Complement biomarkers differed in DS with and without AD and may aid diagnosis and/or prediction. HIGHLIGHTS: Complement is significantly dysregulated in plasma of people with DS who show changes in levels of multiple complement proteins compared to controls. People with DS and dementia show evidence of additional complement dysregulation with significantly lower levels of C3 and factor I compared to those without dementia. rs6656401 in CR1 was associated with significantly elevated sCR1 plasma levels in DS.

Investigating brain alterations in the Dp1Tyb mouse model of Down syndrome.

Down syndrome (DS) is one of the most common birth defects and the most prevalent genetic form of intellectual disability. DS arises from trisomy of chromosome 21, but its molecular and pathological consequences are not fully understood. In this study, we compared Dp1Tyb mice, a DS model, against their wild-type (WT) littermates of both sexes to investigate the impact of DS-related genetic abnormalities on the brain phenotype. We performed in vivo whole brain magnetic resonance imaging (MRI) and hippocampal 1H magnetic resonance spectroscopy (MRS) on the animals at 3 months of age. Subsequently, ex vivo MRI scans and histological analyses were conducted post-mortem. Our findings unveiled the following neuroanatomical and biochemical alterations in the Dp1Tyb brains: a smaller surface area and a rounder shape compared to WT brains, with DS males also presenting smaller global brain volume compared with the counterpart WT. Regional volumetric analysis revealed significant changes in 26 out of 72 examined brain regions, including the medial prefrontal cortex and dorsal hippocampus. These alterations were consistently observed in both in vivo and ex vivo imaging data. Additionally, high-resolution ex vivo imaging enabled us to investigate cerebellar layers and hippocampal sub-regions, revealing selective areas of decrease and remodelling in these structures. An analysis of hippocampal metabolites revealed an elevation in glutamine and the glutamine/glutamate ratio in the Dp1Tyb mice compared to controls, suggesting a possible imbalance in the excitation/inhibition ratio. This was accompanied by the decreased levels of taurine. Histological analysis revealed fewer neurons in the hippocampal CA3 and DG layers, along with an increase in astrocytes and microglia. These findings recapitulate multiple neuroanatomical and biochemical features associated with DS, enriching our understanding of the potential connection between chromosome 21 trisomy and the resultant phenotype.

Aggressive challenging behavior in adults with intellectual disability: An electronic register-based cohort study of clinical outcome and service use.

BACKGROUND: Aggressive challenging behavior in people with intellectual disability is a frequent reason for referral to secondary care services and is associated with direct harm, social exclusion, and criminal sanctions. Understanding the factors underlying aggressive challenging behavior and predictors of adverse clinical outcome is important in providing services and developing effective interventions. METHODS: This was a retrospective total-population cohort study using electronic records linked with Hospital Episode Statistics data. Participants were adults with intellectual disability accessing secondary services at a large mental healthcare provider in London, United Kingdom, between 2014 and 2018. An adverse outcome was defined as at least one of the following: admission to a mental health hospital, Mental Health Act assessment, contact with a psychiatric crisis team or attendance at an emergency department. RESULTS: There were 1,515 patient episodes related to 1,225 individuals, of which 1,019 episodes were reported as displaying aggressive challenging behavior. Increased episode length, being younger, psychotropic medication use, pervasive developmental disorder (PDD), more mentions of mood instability, agitation, and irritability, more contact with mental health professionals, and more mentions of social and/or home care package in-episode were all associated with increased odds of medium-high levels of aggression. Risk factors for an adverse clinical outcome in those who exhibited aggression included increased episode length, personality disorder, common mental disorder (CMD), more mentions of agitation in-episode, and contact with mental health professionals. PDD predicted better outcome. CONCLUSIONS: Routinely collected data confirm aggressive challenging behavior as a common concern in adults with intellectual disability who are referred for specialist support and highlight factors likely to signal an adverse outcome. Treatment targets may include optimizing management of CMDs and agitation.

Dietary Vitamin K1 intake is associated with lower long-term fracture-related hospitalization risk: the Perth longitudinal study of ageing women.

This study examined the association between dietary Vitamin K1 intake with fracture-related hospitalizations over 14.5 years in community-dwelling older Australian women (n = 1373, ≥70 years). Dietary Vitamin K1 intake at baseline (1998) was estimated using a validated food frequency questionnaire and a new Australian Vitamin K nutrient database, which was supplemented with published data. Over 14.5 years, any fracture (n = 404, 28.3%) and hip fracture (n = 153, 10.7%) related hospitalizations were captured using linked health data. Plasma Vitamin D status (25OHD) and the ratio of undercarboxylated osteocalcin (ucOC) to total osteocalcin (tOC) from serum was assessed at baseline. Estimates of dietary Vitamin K1 intake were supported by a significant inverse association with ucOC : tOC; a marker of Vitamin K status (r = -0.12, p < 0.001). Compared to women with the lowest Vitamin K1 intake (Quartile 1, <61 µg d-1), women with the highest Vitamin K1 intake (Quartile 4, ≥99 µg d-1) had lower hazards for any fracture- (HR 0.69 95%CI 0.52-0.91, p < 0.001) and hip fracture-related hospitalization (HR 0.51 95%CI 0.32-0.79, p < 0.001), independent of 25OHD levels, as part of multivariable-adjusted analysis. Spline analysis suggested a nadir in the relative hazard for any fracture-related hospitalizations at a Vitamin K1 intake of approximately 100 µg day-1. For hip fractures, a similar relationship was apparent. Higher dietary Vitamin K1 is associated with lower long-term risk for any fracture- and hip fracture-related hospitalizations in community-dwelling older women.

Diabetes and Obesity in Down Syndrome Across the Lifespan: A Retrospective Cohort Study Using U.K. Electronic Health Records.

OBJECTIVE: Down syndrome (DS) is the most common form of chromosomal trisomy. Genetic factors in DS may increase the risk for diabetes. This study aimed to determine whether DS is associated with an increased incidence of diabetes and the relationship with obesity across the life span compared with control patients. RESEARCH DESIGN AND METHODS: This matched population-based cohort study analyzed UK Clinical Practice Research Datalink data from 1990 to 2020. RESULTS: A total of 9,917 patients with DS and 38,266 control patients were analyzed. Diabetes rates were higher in patients with DS (incidence rate ratio 3.67; 95% CI 2.43-5.55; P < 0.0001) and peaked at a younger age (median age at diagnosis 38 [interquartile range 28-49] years vs. 53 [43-61] years in control patients). Incidence rates (per 1,000 person-years) for type 1 diabetes mellitus were 0.44 (95% CI 0.31-0.61) in patients with DS vs. 0.13 (0.09-0.17) in control patients. Type 2 diabetes mellitus (T2DM) rates were higher in patients with DS versus control patients in age-groups from 5 years up to 34 years. In patients with DS, peak mean BMI was higher and at a younger age (males 31.2 kg/m2 at age 31 years; females 32.1 kg/m2 at 43 years) versus control patients (males 29.5 kg/m2 at 54 years; females 29.2 kg/m2 at 51 years). Obesity was associated with an increased incidence of T2DM. CONCLUSIONS: At younger ages, the incidence of diabetes in patients with DS is up to four times that of control patients. Peak mean BMI is higher and established earlier in DS, contributing to T2DM risk. Further investigation into the relationship between obesity and diabetes in DS is required to inform treatment and prevention measures.

Structural Connectivity in Down Syndrome and Alzheimer's Disease.

Down syndrome (DS) arises from the triplication of chromosome 21, which leads to an atypical neurodevelopment and the overproduction of the amyloid precursor protein, predisposing to early Alzheimer's disease (AD). Not surprisingly, trisomy 21 is widely considered a model to study predementia stages of AD. After decades, in which neural loss was the main focus, research in AD is now moving toward understanding the neurodegenerative aspects affecting white matter. Motivated by the development of magnetic resonance imaging (MRI)-based diffusion techniques, this shift in focus has led to several exploratory studies on both young and older individuals with DS. In this review, we synthesise the initial efforts made by researchers in characterising in-vivo structural connectivity in DS, together with the AD footprint on top of such pre-existing connectivity related to atypical brain development. The white matter structures found to be affected in DS are the corpus callosum and all the main long-association fibres, namely the inferior fronto-occipital fasciculus, the inferior and superior longitudinal fasciculus, the uncinate fasciculus and the cingulum bundle. Furthermore, the cingulum bundle and the corpus callosum appear to be particularly sensitive to early AD changes in this population. Findings are discussed in terms of their functional significance, alongside methodological considerations and implications for future research.