Protocol for a double-blind placebo-controlled randomised controlled trial assessing the impact of oral semaglutide in amyloid positivity (ISAP) in community dwelling UK adults.

INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), currently marketed for type 2 diabetes and obesity, may offer novel mechanisms to delay or prevent neurotoxicity associated with Alzheimer's disease (AD). The impact of semaglutide in amyloid positivity (ISAP) trial is investigating whether the GLP-1 RA semaglutide reduces accumulation in the brain of cortical tau protein and neuroinflammation in individuals with preclinical/prodromal AD. METHODS AND ANALYSIS: ISAP is an investigator-led, randomised, double-blind, superiority trial of oral semaglutide compared with placebo. Up to 88 individuals aged ≥55 years with brain amyloid positivity as assessed by positron emission tomography (PET) or cerebrospinal fluid, and no or mild cognitive impairment, will be randomised. People with the low-affinity binding variant of the rs6971 allele of the Translocator Protein 18 kDa (TSPO) gene, which can interfere with interpreting TSPO PET scans (a measure of neuroinflammation), will be excluded.At baseline, participants undergo tau, TSPO PET and MRI scanning, and provide data on physical activity and cognition. Eligible individuals are randomised in a 1:1 ratio to once-daily oral semaglutide or placebo, starting at 3 mg and up-titrating to 14 mg over 8 weeks. They will attend safety visits and provide blood samples to measure AD biomarkers at weeks 4, 8, 26 and 39. All cognitive assessments are repeated at week 26. The last study visit will be at week 52, when all baseline measurements will be repeated. The primary end point is the 1-year change in tau PET signal. ETHICS AND DISSEMINATION: The study was approved by the West Midlands-Edgbaston Research Ethics Committee (22/WM/0013). The results of the study will be disseminated through scientific presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ISRCTN71283871.

Predicting incident delirium diagnoses using data from primary-care electronic health records.

IMPORTANCE: risk factors for delirium in hospital inpatients are well established, but less is known about whether delirium occurring in the community or during an emergency admission to hospital care might be predicted from routine primary-care records. OBJECTIVES: identify risk factors in primary-care electronic health records (PC-EHR) predictive of delirium occurring in the community or recorded in the initial episode in emergency hospitalisation. Test predictive performance against the cumulative frailty index. DESIGN: Stage 1: case-control; Stages 2 and 3: retrospective cohort. SETTING: clinical practice research datalink: PC-EHR linked to hospital discharge data from England. SUBJECTS: Stage 1: 17,286 patients with delirium aged ≥60 years plus 85,607 controls. Stages 2 and 3: patients ≥ 60 years (n = 429,548 in 2015), split into calibration and validation groups. METHODS: Stage 1: logistic regression to identify associations of 110 candidate risk measures with delirium. Stage 2: calibrating risk factor weights. Stage 3: validation in independent sample using area under the curve (AUC) receiver operating characteristic. RESULTS: fifty-five risk factors were predictive, in domains including: cognitive impairment or mental illness, psychoactive drugs, frailty, infection, hyponatraemia and anticholinergic drugs. The derived model predicted 1-year incident delirium (AUC = 0.867, 0.852:0.881) and mortality (AUC = 0.846, 0.842:0.853), outperforming the frailty index (AUC = 0.761, 0.740:0.782). Individuals with the highest 10% of predicted delirium risk accounted for 55% of incident delirium over 1 year. CONCLUSIONS: a risk factor model for delirium using data in PC-EHR performed well, identifying individuals at risk of new onsets of delirium. This model has potential for supporting preventive interventions.

The Association of Grip Strength With Severity and Duration of Parkinson's: A Cross-Sectional Study.

BACKGROUND: Weakness is reported in Parkinson's but always unadjusted for recognized factors that influence muscle strength such as participants' age, gender, and body size. This may obscure the true association of Parkinson's with muscle strength. OBJECTIVE: To evaluate the relationship between grip strength, Parkinson's severity, and duration adjusting for these factors. METHODS: Age, gender, height, weight, grip strength, Unified Parkinson's Disease Rating Score (UPDRS) motor score, Hoehn and Yahr (H&Y) stage, disease duration, number of comorbidities and medications, Barthel score, Mini Mental State Examination (MMSE) score, and Malnutrition Universal Screening Tool (MUST) score were recorded. RESULTS: Fifty-seven of 79 (72%) people with Parkinson's resident in one town were recruited. Age, gender, height, and Parkinson's severity were the most significant determinants of grip strength. Each unit increase in UPDRS motor score and H&Y stage was associated with lower grip strength in univariate linear regression analyses adjusted for gender: -0.3 kg strength (95% confidence interval = -0.51, -0.09), P = .006 for each additional UPDRS point, and -3.87 kg strength (95% confidence interval = -6.54, -1.21), P = .005 for each additional H&Y stage. Disease duration was not associated with grip strength. In multivariate regression, Parkinson's severity remained strongly associated with grip strength (UPDRS score P = .09; H&Y stage P = .04). CONCLUSIONS: This is the first demonstration that increasing severity of Parkinson's was associated with weaker grip after adjustment for known influences on muscle strength. Participants' age, gender, and body size also had a significant impact on strength. Adjustment of reported values for all these factors is essential to allow accurate reporting of grip strength values in intervention trials and comparison between different groups.

Grip strength and its determinants among older people in different healthcare settings.

BACKGROUND: low muscle strength is central to geriatric syndromes including sarcopenia and frailty. It is well described in community-dwelling older people, but the epidemiology of grip strength of older people in rehabilitation or long-term care has been little explored. OBJECTIVE: to describe grip strength of older people in rehabilitation and nursing home settings. DESIGN: cross-sectional epidemiological study. SETTING: three healthcare settings in one town. SUBJECTS: hundred and one inpatients on a rehabilitation ward, 47 community rehabilitation referrals and 100 nursing home residents. METHODS: grip strength, age, height, weight, body mass index, number of co-morbidities and medications, Barthel score, Mini-Mental State Examination (MMSE), nutritional status and number of falls in the last year were recorded. RESULTS: grip strength differed substantially between healthcare settings for both men and women (P < 0.0001). Nursing home residents had the lowest age-adjusted mean grip strength and community rehabilitation referrals the highest. Broadly higher grip strength was associated in univariate analyses with younger age, greater height and weight, fewer comorbidities, higher Barthel score, higher MMSE score, better nutritional status and fewer falls. However, after mutual adjustment for these factors, the difference in grip strength between settings remained significant. The Barthel score was the characteristic most strongly associated with grip strength. CONCLUSIONS: older people in rehabilitation and care home settings had lower grip strength than reported for those living at home. Furthermore grip strength varied widely between healthcare settings independent of known major influences. Further research is required to ascertain whether grip strength may help identify people at risk of adverse health outcomes within these settings.

Male sex hormones and systemic inflammation in Alzheimer disease.

Several studies have shown that the levels of sex hormones in men with Alzheimer disease (AD) differ from men without AD. Therefore, male sex hormones have been postulated as risk modifiers in AD, possibly through immunomodulatory effects on known inflammatory AD risk factors, such as tumor necrosis factor α (TNF-α). We conducted a cross-sectional study of sex hormones and TNF-α levels in 94 community-dwelling men with AD. Comparisons were made with normal values derived from the literature. Men with AD had lower free testosterone levels than non-AD men (1-sample t test: age <80, P=0.0002; age ≥80, P<0.0001), and higher luteinizing hormone (LH) levels (Wilcoxon signed rank test: age <80, P=0.001; age ≥80, P<0.0001). Within the cohort of men with AD, there was a positive correlation between LH and TNF-α (Spearman r=0.25, P=0.019), and this remained significant after correcting for age (partial r=0.21, P=0.05). These data support the hypothesis that sex hormones and the immune system influence each other in AD. Furthermore, modulatory effects between LH and TNF-α may provide a mechanism for an effect of male sex hormones on AD risk.

Systemic inflammation and Alzheimer's disease.

A number of studies demonstrate disturbances of the central innate immune system in AD (Alzheimer's disease). In animal and human studies, there is evidence of close communication between systemic and central innate immune systems. Animal models of neurodegeneration show evidence of an exaggerated central innate immune response following systemic inflammation. Clinical studies of AD show evidence of increased cognitive decline and exaggerated sickness behaviour in response to systemic inflammation. Recognition of this communication pathway offers alternative explanations for a number of recognized risk factors in the development and progression of AD and highlights the potential of the manipulation of systemic innate immunity as a novel therapeutic approach.