Association of bradykinin receptor 2 (BDKRB2) variants with physical performance and muscle mass: Findings from the LACE sarcopenia trial.

INTRODUCTION: Understanding genetic contributors to sarcopenia (age-related loss of muscle strength and mass) is key to finding effective therapies. Variants of the bradykinin receptor 2 (BDKRB2) have been linked to athletic and muscle performance. The rs1799722-9 and rs5810761 T alleles have been shown to be overrepresented in endurance athletes, possibly due to increased transcriptional rates of the receptor. These variants have been rarely studied in older people or people with sarcopenia. METHODS: We performed a post hoc sub-study of the Leucine and ACE (LACE) inhibitor trial, which enrolled 145 participants aged ≥70 years with low grip strength and low gait speed. Participants' blood samples were genotyped for rs179972 using TaqMan and rs5810761 by amplification through Hotstar Taq. Genotypes were compared with outcomes of physical performance and body composition measures. RESULTS: Data from 136 individuals were included in the analysis. For rs1799722 the genotype frequency (TT: 17, CC: 48, CT: 71) remained in Hardy-Weinberg Equilibrium (HWE p = 0.248). There was no difference between the genotypes for six-Minute Walk Distance (6MWD) or Short Physical Performance Battery (SPPB). Men with the TT genotype had a significantly greater 6MWD than other genotypes (TT 400m vs CT 310m vs CC 314m, p = 0.027), and greater leg muscle mass (TT 17.59kg vs CT 15.04kg vs CC 15.65kg, p = 0.007). For rs5810761, the genotype frequency (-9-9: 31, +9+9: 43, -9+9: 60) remained in HWE (p = 0.269). The +9+9 genotype was associated with a significant change in SPPB score at 12 months (-9-9 0 vs -9+9 0 vs +9+9-1, p<0.001), suggesting an improvement. In men, the -9-9 genotype was associated with lower arm fat (-9-9 2.39kg vs -9+9 2.72kg vs +9+9 2.76kg, p = 0.019). CONCLUSION: In men, the rs1799722 TT genotype was associated with longer 6MWD and greater leg muscle mass, while the rs5810761 -9-9 genotype was associated with lower arm fat mass.

Activin type I receptor polymorphisms and body composition in older individuals with sarcopenia-Analyses from the LACE randomised controlled trial.

BACKGROUND: Ageing is associated with changes in body composition including an overall reduction in muscle mass and a proportionate increase in fat mass. Sarcopenia is characterised by losses in both muscle mass and strength. Body composition and muscle strength are at least in part genetically determined, consequently polymorphisms in pathways important in muscle biology (e.g., the activin/myostatin signalling pathway) are hypothesised to contribute to the development of sarcopenia. METHODS: We compared regional body composition measured by DXA with genotypes for two polymorphisms (rs10783486, minor allele frequency (MAF) = 0.26 and rs2854464, MAF = 0.26) in the activin 1B receptor (ACVR1B) determined by PCR in a cross-sectional analysis of DNA from 110 older individuals with sarcopenia from the LACE trial. RESULTS: Neither muscle mass nor strength showed any significant associations with either genotype in this cohort. Initial analysis of rs10783486 showed that males with the AA/AG genotype were taller than GG males (174±7cm vs 170±5cm, p = 0.023) and had higher arm fat mass, (median higher by 15%, p = 0.008), and leg fat mass (median higher by 14%, p = 0.042). After correcting for height, arm fat mass remained significantly higher (median higher by 4% padj = 0.024). No associations (adjusted or unadjusted) were seen in females. Similar analysis of the rs2854464 allele showed a similar pattern with the presence of the minor allele (GG/AG) being associated with greater height (GG/AG = 174±7 cm vs AA = 170 ±5cm, p = 0.017) and greater arm fat mass (median higher by 16%, p = 0.023). Again, the difference in arm fat remained after correction for height. No similar associations were seen in females analysed alone. CONCLUSION: These data suggest that polymorphic variation in the ACVR1B locus could be associated with body composition in older males. The activin/myostatin pathway might offer a novel potential target to prevent fat accumulation in older individuals.

Understanding the performance and reliability of NLP tools: a comparison of four NLP tools predicting stroke phenotypes in radiology reports.

Background: Natural language processing (NLP) has the potential to automate the reading of radiology reports, but there is a need to demonstrate that NLP methods are adaptable and reliable for use in real-world clinical applications. Methods: We tested the F1 score, precision, and recall to compare NLP tools on a cohort from a study on delirium using images and radiology reports from NHS Fife and a population-based cohort (Generation Scotland) that spans multiple National Health Service health boards. We compared four off-the-shelf rule-based and neural NLP tools (namely, EdIE-R, ALARM+, ESPRESSO, and Sem-EHR) and reported on their performance for three cerebrovascular phenotypes, namely, ischaemic stroke, small vessel disease (SVD), and atrophy. Clinical experts from the EdIE-R team defined phenotypes using labelling techniques developed in the development of EdIE-R, in conjunction with an expert researcher who read underlying images. Results: EdIE-R obtained the highest F1 score in both cohorts for ischaemic stroke, ≥93%, followed by ALARM+, ≥87%. The F1 score of ESPRESSO was ≥74%, whilst that of Sem-EHR is ≥66%, although ESPRESSO had the highest precision in both cohorts, 90% and 98%. For F1 scores for SVD, EdIE-R scored ≥98% and ALARM+ ≥90%. ESPRESSO scored lowest with ≥77% and Sem-EHR ≥81%. In NHS Fife, F1 scores for atrophy by EdIE-R and ALARM+ were 99%, dropping in Generation Scotland to 96% for EdIE-R and 91% for ALARM+. Sem-EHR performed lowest for atrophy at 89% in NHS Fife and 73% in Generation Scotland. When comparing NLP tool output with brain image reads using F1 scores, ALARM+ scored 80%, outperforming EdIE-R at 66% in ischaemic stroke. For SVD, EdIE-R performed best, scoring 84%, with Sem-EHR 82%. For atrophy, EdIE-R and both ALARM+ versions were comparable at 80%. Conclusions: The four NLP tools show varying F1 (and precision/recall) scores across all three phenotypes, although more apparent for ischaemic stroke. If NLP tools are to be used in clinical settings, this cannot be performed "out of the box." It is essential to understand the context of their development to assess whether they are suitable for the task at hand or whether further training, re-training, or modification is required to adapt tools to the target task.

ACE I/D genotype associates with strength in sarcopenic men but not with response to ACE inhibitor therapy in older adults with sarcopenia: Results from the LACE trial.

BACKGROUND: Angiotensin II (AII), has been suggested to promote muscle loss. Reducing AII synthesis, by inhibiting angiotensin converting enzyme (ACE) activity has been proposed as a method to inhibit muscle loss. The LACE clinical trial was designed to determine whether ACE inhibition would reduce further muscle loss in individuals with sarcopenia but suffered from low recruitment and returned a negative result. Polymorphic variation in the ACE promoter (I/D alleles) has been associated with differences in ACE activity and muscle physiology in a range of clinical conditions. This aim of this analysis was to determine whether I/D polymorphic variation is associated with muscle mass, strength, in sarcopenia or contributed to the lack of response to treatment in the LACE study. METHODS: Sarcopenic individuals were recruited into a 2x2 factorial multicentre double-blind study of the effects of perindopril and/or leucine versus placebo on physical performance and muscle mass. DNA extracted from blood samples (n = 130 72 women and 58 men) was genotyped by PCR for the ACE I/D polymorphism. Genotypes were then compared with body composition measured by DXA, hand grip and quadriceps strength before and after 12 months' treatment with leucine and/or perindopril in a cross-sectional analysis of the influence of genotype on these variables. RESULTS: Allele frequencies for the normal UK population were extracted from 13 previous studies (I = 0.473, D = 0.527). In the LACE cohort the D allele was over-represented (I = 0.412, D = 0.588, p = 0.046). This over-representation was present in men (I = 0.353, D = 0.647, p = 0.010) but not women (I = 0.458, D = 0.532, p = 0.708). In men but not women, individuals with the I allele had greater leg strength (II/ID = 18.00 kg (14.50, 21.60) vs DD = 13.20 kg (10.50, 15.90), p = 0.028). Over the 12 months individuals with the DD genotype increased in quadriceps strength but those with the II or ID genotype did not. Perindopril did not increase muscle strength or mass in any polymorphism group relative to placebo. CONCLUSION: Our results suggest that although ACE genotype was not associated with response to ACE inhibitor therapy in the LACE trial population, sarcopenic men with the ACE DD genotype may be weaker than those with the ACE I/D or II genotype.

Isosorbide Mononitrate and Cilostazol Treatment in Patients With Symptomatic Cerebral Small Vessel Disease: The Lacunar Intervention Trial-2 (LACI-2) Randomized Clinical Trial.

Importance: Cerebral small vessel disease (cSVD) is a common cause of stroke (lacunar stroke), is the most common cause of vascular cognitive impairment, and impairs mobility and mood but has no specific treatment. Objective: To test the feasibility, drug tolerability, safety, and effects of 1-year isosorbide mononitrate (ISMN) and cilostazol treatment on vascular, functional, and cognitive outcomes in patients with lacunar stroke. Design, Setting, and Participants: The Lacunar Intervention Trial-2 (LACI-2) was an investigator-initiated, open-label, blinded end-point, randomized clinical trial with a 2 × 2 factorial design. The trial aimed to recruit 400 participants from 26 UK hospital stroke centers between February 5, 2018, and May 31, 2021, with 12-month follow-up. Included participants had clinical lacunar ischemic stroke, were independent, were aged older than 30 years, had compatible brain imaging findings, had capacity to consent, and had no contraindications to (or indications for) the study drugs. Data analysis was performed on August 12, 2022. Interventions: All patients received guideline stroke prevention treatment and were randomized to ISMN (40-60 mg/d), cilostazol (200 mg/d), ISMN-cilostazol (40-60 and 200 mg/d, respectively), or no study drug. Main Outcomes: The primary outcome was recruitment feasibility, including retention at 12 months. Secondary outcomes were safety (death), efficacy (composite of vascular events, dependence, cognition, and death), drug adherence, tolerability, recurrent stroke, dependence, cognitive impairment, quality of life (QOL), and hemorrhage. Results: Of the 400 participants planned for this trial, 363 (90.8%) were recruited. Their median age was 64 (IQR, 56.0-72.0) years; 251 (69.1%) were men. The median time between stroke and randomization was 79 (IQR, 27.0-244.0) days. A total of 358 patients (98.6%) were retained in the study at 12 months, with 257 of 272 (94.5%) taking 50% or more of the allocated drug. Compared with those participants not receiving that particular drug, neither ISMN (adjusted hazard ratio [aHR], 0.80 [95% CI, 0.59 to 1.09]; P = .16) nor cilostazol (aHR, 0.77 [95% CI, 0.57 to 1.05]; P = .10) alone reduced the composite outcome in 297 patients. Isosorbide mononitrate reduced recurrent stroke in 353 patients (adjusted odds ratio [aOR], 0.23 [95% CI, 0.07 to 0.74]; P = .01) and cognitive impairment in 308 patients (aOR, 0.55 [95% CI, 0.36 to 0.86]; P = .008). Cilostazol reduced dependence in 320 patients (aHR, 0.31 [95% CI, 0.14 to 0.72]; P = .006). Combination ISMN-cilostazol reduced the composite (aHR, 0.58 [95% CI, 0.36 to 0.92]; P = .02), dependence (aOR, 0.14 [95% CI, 0.03 to 0.59]; P = .008), and any cognitive impairment (aOR, 0.44 [95% CI, 0.23 to 0.85]; P = .02) and improved QOL (adjusted mean difference, 0.10 [95% CI, 0.03 to 0.17]; P = .005) in 153 patients. There were no safety concerns. Conclusions and Relevance: These results show that the LACI-2 trial was feasible and ISMN and cilostazol were well tolerated and safe. These agents may reduce recurrent stroke, dependence, and cognitive impairment after lacunar stroke, and they could prevent other adverse outcomes in cSVD. Therefore, both agents should be tested in large phase 3 trials. Trial Registration: ClinicalTrials.gov Identifier: NCT03451591.

Research protocol - Assessing Post-Stroke Psychology Longitudinal Evaluation (APPLE) study: A prospective cohort study in stroke.

Background: Cognitive and mood problems have been highlighted as priorities in stroke research and guidelines recommend early screening. However, there is limited detail on the preferred approach.We aimed to (1) determine the optimal methods for evaluating psychological problems that pre-date stroke; (2) assess the test accuracy, feasibility and acceptability of brief cognitive and mood tests used at various time-points following stroke; (3) describe temporal changes in cognition and mood following stroke and explore predictors of change. Methods: We established a multi-centre, prospective, observational cohort with acute stroke as the inception point - Assessing Post-stroke Psychology Longitudinal Evaluation (APPLE). We approached patients admitted with stroke or transient ischaemic attack (TIA) from 11 different hospital sites across the United Kingdom. Baseline demographics, clinical, functional, cognitive, and mood data were collected. Consenting stroke survivors were followed up with more extensive evaluations of cognition and mood at 1, 6, 12 and 18 months. Results: Continuous recruitment was from February 2017 to February 2019. With 357 consented to full follow-up. Eighteen-month assessments were completed in September 2020 with permissions in-place for longer term in-person or electronic follow-up. A qualitative study has been completed, and a participant sample biobank and individual participant database are both available. Discussion: The APPLE study will provide guidance on optimal tool selection for cognitive and mood assessment both before and after stroke, as well as information on prognosis and natural history of neuropsychological problems in stroke. The study data, neuroimaging and tissue biobank are all available as a resource for future research.

Impact of Small Vessel Disease Progression on Long-term Cognitive and Functional Changes After Stroke.

BACKGROUND AND OBJECTIVES: The severity of white matter hyperintensities (WMH) at presentation with stroke is associated with poststroke dementia and dependency. However, WMH can decrease or increase after stroke; prediction of cognitive decline is imprecise; and there are few data assessing longitudinal interrelationships among changing WMH, cognition, and function after stroke, despite the clinical importance. METHODS: We recruited patients within 3 months of a minor ischemic stroke, defined as NIH Stroke Scale (NIHSS) score <8 and not expected to result in a modified Rankin Scale (mRS) score >2. Participants repeated MRI at 1 year and cognitive and mRS assessments at 1 and 3 years. We ran longitudinal mixed-effects models assessing change in Addenbrooke's Cognitive Examination-Revised (ACE-R) and mRS scores. For mRS score, we assessed longitudinal WMH volumes (cube root; percentage intracranial volume [ICV]), adjusting for age, NIHSS score, ACE-R, stroke subtype, and time to assessment. For ACE-R score, we additionally adjusted for ICV, mRS, premorbid IQ, and vascular risk factors. We then used a multivariate model to jointly assess changing cognition/mRS score, adjusted for prognostic variables, using all available data. RESULTS: We recruited 264 patients; mean age was 66.9 (SD 11.8) years; 41.7% were female; and median mRS score was 1 (interquartile range 1-2). One year after stroke, normalized WMH volumes were associated more strongly with 1-year ACE-R score (ß = -0.259, 95% CI -0.407 to -0.111 more WMH per 1-point ACE-R decrease, p = 0.001) compared to subacute WMH volumes and ACE-R score (ß = 0.105, 95% CI -0.265 to 0.054, p = 0.195). Three-year mRS score was associated with 3-year ACE-R score (ß = -0.272, 95% CI -0.429 to -0.115, p = 0.001). Combined change in baseline-1-year jointly assessed ACE-R/mRS scores was associated with fluctuating WMH volumes (F = 9.3, p = 0.03). DISCUSSION: After stroke, fluctuating WMH mean that 1-year, but not baseline, WMH volumes are associated strongly with contemporaneous cognitive scores. Covarying longitudinal decline in cognition and independence after stroke, central to dementia diagnosis, is associated with increasing WMH volumes.

Effect of perindopril or leucine on physical performance in older people with sarcopenia: the LACE randomized controlled trial.

BACKGROUND: This trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia. METHODS: Placebo-controlled, parallel group, double-blind, randomized two-by-two factorial trial. We recruited adults aged ≥ 70 years with sarcopenia, defined as low gait speed (<0.8 m/s on 4 m walk) and/or low handgrip strength (women < 20 kg, men < 30 kg) plus low muscle mass (using sex and body mass index category-specific thresholds derived from normative UK BioBank data) from 14 UK centres. Eligible participants were randomized to perindopril 4 mg or placebo, and to oral leucine powder 2.5 g or placebo thrice daily. The primary outcome was the between-group difference in the short physical performance battery (SPPB) score over 12-month follow-up by repeated-measures mixed models. Results were combined with existing systematic reviews using random-effects meta-analysis to derive summary estimates of treatment efficacy. RESULTS: We screened 320 people and randomized 145 participants compared with an original target of 440 participants. For perindopril [n = 73, mean age 79 (SD 6), female sex 39 (53%), mean SPPB 7.1 (SD 2.3)] versus no perindopril [n = 72, mean age 79 (SD 6), female sex 39 (54%), mean SPPB 6.9 (SD 2.4)], median adherence to perindopril was lower (76% vs. 96%; P < 0.001). Perindopril did not improve the primary outcome [adjusted treatment effect -0.1 points (95%CI -1.2 to 1.0), P = 0.89]. No significant treatment benefit was seen for any secondary outcome including muscle mass [adjusted treatment effect -0.4 kg (95%CI -1.1 to 0.3), P = 0.27]. More adverse events occurred in the perindopril group (218 vs. 165), but falls rates were similar. For leucine [n = 72, mean age 78 (SD 6), female sex 38 (53%), mean SPPB 7.0 (SD 2.1)] versus no leucine [n = 72, mean age 79 (SD 6), female sex 40 (55%), mean SPPB 7.0 (SD 2.5)], median adherence was the same in both groups (76% vs. 76%; P = 0.99). Leucine did not improve the primary outcome [adjusted treatment effect 0.1 point (95%CI -1.0 to 1.1), P = 0.90]. No significant treatment benefit was seen for any secondary outcome including muscle mass [adjusted treatment effect -0.3 kg (95%CI -1.0 to 0.4), P = 0.47]. Meta-analysis of angiotensin converting enzyme inhibitor/angiotensin receptor blocker trials showed no clinically important treatment effect for the SPPB [between-group difference -0.1 points (95%CI -0.4 to 0.2)]. CONCLUSIONS: Neither perindopril nor leucine improved physical performance or muscle mass in this trial; meta-analysis did not find evidence of efficacy of either ACE inhibitors or leucine as treatments to improve physical performance.

Protocol: The Lacunar Intervention Trial 2 (LACI-2). A trial of two repurposed licenced drugs to prevent progression of cerebral small vessel disease.

BACKGROUND: Small vessel disease causes a quarter of ischaemic strokes (lacunar subtype), up to 45% of dementia either as vascular or mixed types, cognitive impairment and physical frailty. However, there is no specific treatment to prevent progression of small vessel disease. AIM: We designed the LACunar Intervention Trial-2 (LACI-2) to test feasibility of a large trial testing cilostazol and/or isosorbide mononitrate (ISMN) by demonstrating adequate participant recruitment and retention in follow-up, drug tolerability, safety and confirm outcome event rates required to power a phase 3 trial. METHODS AND DESIGN: LACI-2 is an investigator-initiated, prospective randomised open label blinded endpoint (PROBE) trial aiming to recruit 400 patients with prior lacunar syndrome due to a small subcortical infarct. We randomise participants to cilostazol v no cilostazol and ISMN or no ISMN, minimising on key prognostic factors. All patients receive guideline-based best medical therapy. Patients commence trial drug at low dose, increment to full dose over 2-4 weeks, continuing on full dose for a year. We follow-up participants to one year for symptoms, tablet compliance, safety, recurrent vascular events, cognition and functional outcomes, Trails B and brain MRI. LACI-2 is registered ISRCTN 14911850, EudraCT 2016-002277-35.Trial outcome: Primary outcome is feasibility of recruitment and compliance; secondary outcomes include safety (cerebral or systemic bleeding, falls, death), efficacy (recurrent cerebral and cardiac vascular events, cognition on TICS, Trails B) and tolerability. SUMMARY: LACI-2 will determine feasibility, tolerability and provide outcome rates to power a large phase 3 trial to prevent progression of cerebral small vessel disease.

Study protocol for POSITIF, a randomised multicentre feasibility trial of a brief cognitive-behavioural intervention plus information versus information alone for the treatment of post-stroke fatigue.

BACKGROUND: Approximately, half of stroke survivors experience fatigue. Fatigue may persist for many months and interferes with participation in everyday activities and has a negative impact on social and family relationships, return to work, and quality of life. Fatigue is among the top 10 priorities for 'Life after Stroke' research for stroke survivors, carers, and clinicians. We previously developed and tested in a small uncontrolled pilot study a manualised, clinical psychologist-delivered, face-to-face intervention, informed by cognitive behavioural therapy (CBT). We then adapted it for delivery by trained therapists via telephone. We now aim to test the feasibility of this approach in a parallel group, randomised controlled feasibility trial (Post Stroke Intervention Trial In Fatigue, POSITIF). METHODS/DESIGN: POSITIF aims to recruit 75 stroke survivors between 3 months and 2 years post-stroke who would like treatment for their fatigue. Eligible consenting stroke survivors will be randomised to either a 7-session manualised telephone-delivered intervention based on CBT principles plus information about fatigue, or information only. The aims of the intervention are to (i) provide an explanation for post-stroke fatigue, in particular that it is potentially reversible (an educational approach), (ii) encourage participants to overcome the fear of taking physical activity and challenge negative thinking (a cognitive approach) and (iii) promote a balance between daily activities, rest and sleep and then gradually increase levels of physical activity (a behavioural approach). Fatigue, mood, quality of life, return to work and putative mediators will be assessed at baseline (just before randomisation), at the end of treatment and 6 months after randomisation. POSITIF will determine the feasibility of recruitment, adherence to the intervention and the resources required to deliver the intervention in a larger trial. DISCUSSION: The POSITIF feasibility trial will recruit until 31 January 2020. Data will inform the utility and design of a future adequately powered randomised controlled trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03551327. Registered on 11 June 2018.

Are antidementia drugs associated with reduced mortality after a hospital emergency admission in the population with dementia aged 65 years and older?

INTRODUCTION: People with dementia experience poor outcomes after hospital admission, with mortality being particularly high. There is no cure for dementia; antidementia medications have been shown to improve cognition and function, but their effect on mortality in real-world settings is little known. This study examines associations between treatment with antidementia medication and mortality in older people with dementia after an emergency admission. METHODS: The design is a retrospective cohort study of people aged ≥65 years, with a diagnosis of dementia and an emergency hospital admission between 01/01/2010 and 31/12/2016. Two classes of antidementia medication were considered: the acetylcholinesterase inhibitors and memantine. Mortality was examined using a Cox proportional hazards model with time-varying covariates for the prescribing of antidementia medication before or on admission and during one-year follow-up, adjusted for demographics, comorbidity, and community prescribing including anticholinergic burden. Propensity score analysis was examined for treatment selection bias. RESULTS: There were 9142 patients with known dementia included in this study, of which 45.0% (n = 4110) received an antidementia medication before or on admission; 31.3% (n = 2864) were prescribed one of the acetylcholinesterase inhibitors, 8.7% (n = 798) memantine, and 4.9% (n = 448) both. 32.9% (n = 1352) of these patients died in the year after admission, compared to 42.7% (n = 2148) of those with no antidementia medication on admission. The Cox model showed a significant reduction in mortality in patients treated with acetylcholinesterase inhibitors (hazard ratio [HR] = 0.78, 95% CI 0.72-0.85) or memantine (HR = 0.75, 95% CI 0.66-0.86) or both (HR = 0.76, 95% CI 0.68-0.94). Sensitivity analysis by propensity score matching confirmed the associations between antidementia prescribing and reduced mortality. DISCUSSION: Treatment with antidementia medication is associated with a reduction in risk of death in the year after an emergency hospital admission. Further research is required to determine if there is a causal relationship between treatment and mortality, and whether "symptomatic" therapy for dementia does have a disease-modifying effect.

Effect of Vitamin K2 on Postural Sway in Older People Who Fall: A Randomized Controlled Trial.

OBJECTIVES: Vitamin K is thought to be involved in both bone health and maintenance of neuromuscular function. We tested the effect of vitamin K2 supplementation on postural sway, falls, healthcare costs, and indices of physical function in older people at risk of falls. DESIGN: Parallel-group double-blind randomized placebo-controlled trial. SETTING: Fourteen primary care practices in Scotland, UK. PARTICIPANTS: A total of 95 community-dwelling participants aged 65 and older with at least two falls, or one injurious fall, in the previous year. INTERVENTION: Once/day placebo, 200 µg or 400 µg of oral vitamin K2 for 1 year. MEASUREMENTS: The primary outcome was anteroposterior sway measured using sway plates at 12 months, adjusted for baseline. Secondary outcomes included the Short Physical Performance Battery, Berg Balance Scale, Timed Up & Go Test, quality of life, health and social care costs, falls, and adverse events. RESULTS: Mean participant age was 75 (standard deviation [SD] = 7) years. Overall, 58 of 95 (61%) were female; 77 of 95 (81%) attended the 12-month visit. No significant effect of either vitamin K2 dose was seen on the primary outcome of anteroposterior sway (200 µg vs placebo: -.19 cm [95% confidence interval [CI] -.68 to .30; P = .44]; 400 µg vs placebo: .17 cm [95% CI -.33 to .66; P = .50]; or 400 µg vs 200 µg: .36 cm [95% CI -.11 to .83; P = .14]). Adjusted falls rates were similar in each group. No significant treatment effects were seen for other measures of sway or secondary outcomes. Costs were higher in both vitamin K2 arms than in the placebo arm. CONCLUSION: Oral vitamin K2 supplementation did not improve postural sway or physical function in older people at risk of falls. J Am Geriatr Soc 67:2102-2107, 2019.

Stability of Estimated Premorbid Cognitive Ability over Time after Minor Stroke and Its Relationship with Post-Stroke Cognitive Ability.

Considering premorbid or "peak" adult intelligence (IQ) is important when examining post-stroke cognition. The stability of estimated premorbid IQ and its relationship to current cognitive ability in stroke is unknown. We investigated changes in estimated premorbid IQ and current cognitive ability up to three years post-stroke. Minor stroke patients (NIHSS < 8) were assessed at one to three months, one and three years' post-stroke. The National Adult Reading Test (NART) and Addenbrooke's Cognitive Examination-Revised (ACE-R) were used to estimate premorbid IQ (NART IQ) and current cognitive ability respectively at each time-point. Baseline demographics, vascular and stroke characteristics were included. Of the 264 patients recruited (mean age 66), 158 (60%), 151 (57%), and 153 (58%) completed cognitive testing at each time-point respectively. NART IQ initially increased (mean difference (MD) = 1.32, 95% CI = 0.54 to 2.13, p < 0.001) before decreasing (MD = -4.269, 95% CI = -5.12 to -3.41, p < 0.001). ACE-R scores initially remained stable (MD = 0.29, 95% CI = -0.49 to 1.07, p > 0.05) before decreasing (MD = -1.05, 95% CI = -2.08 to -0.01, p < 0.05). Adjusting for baseline variables did not change the relationship between NART IQ and ACE-R with time. Increases in NART IQ were associated with more education. For ACE-R, older age was associated with declines, and higher NART IQ and more education was associated with increases. Across 3 years, we observed fluctuations in estimated premorbid IQ and minor changes in current cognitive ability. Future research should aim to identify variables associated with these changes. However, studies of post-stroke cognition should account for premorbid IQ.

Functional, cognitive and physical outcomes 3 years after minor lacunar or cortical ischaemic stroke.

OBJECTIVE: Many studies examining stroke outcomes focus on more severe strokes or have short follow-up periods, so the long-term outcomes post-minor ischaemic stroke are unclear. METHODS: We recruited participants from inpatient and outpatient services with a lacunar or minor cortical ischaemic stroke (National Institutes of Health Stroke Scale score <8) and assessed current and premorbid cognitive functioning (Addenbrooke's Cognitive Examination-Revised (ACE-R), National Adult Reading Test (NART)), physical functioning (Timed Get Up and Go (TUG), 9-Hole Peg Test (9HPT)), dependency (modified Rankin Scale (mRS)), depression (Beck's Depression Inventory) in-person and remotely (Stroke Impact Scale). RESULTS: We followed up 224/264 participants at 3 years (mean age at index stroke=67, 126 (56%) men, 25 non-contactable, 15 declined): 66/151 (44%) had cognitive impairment, mean ACE-R 88 (SD 9, range 54-100/100), 61/156 (39%) had depression and 26/223 (12%) were dependent (mRS=3-5). Cognitive impairment at 3 years affected all ACE-R subdomains and was associated with ACE-R 1 year (ß=1.054, p<0.001) and NART (ß=1.023, p<0.05). Poor physical function was associated with stroke severity (TUG, ß=1.064, p<0.01) and recurrent stroke (9HPT, ß=1.130, p<0.05 right, ß=1.214, p<0.05 left). Higher ACE-R scores were associated with faster TUG (ß=-0.279, p<0.05) and 9HPT (right ß=-0.257, p<0.05; left ß=-0.302, p=0.05) and inversely with dependency (mRS=3-5, OR 0.88, 95% CI 0.80 to 0.97). We adjusted analyses for demographic, stroke and known risk factors. In-person and remote assessments were highly correlated. CONCLUSIONS: Cognitive, physical impairments and depression are common and interrelated 3 years after minor stroke. Cognitive and physical impairments require rehabilitation after minor stroke and argue for better integration of stroke and dementia services.

Living at home after emergency hospital admission: prospective cohort study in older adults with and without cognitive spectrum disorder.

BACKGROUND: Cognitive spectrum disorders (CSDs) are common in hospitalised older adults and associated with adverse outcomes. Their association with the maintenance of independent living has not been established. The aim was to establish the role of CSDs on the likelihood of living at home 30 days after discharge or being newly admitted to a care home. METHODS: A prospective cohort study with routine data linkage was conducted based on admissions data from the acute medical unit of a district general hospital in Scotland. 5570 people aged ≥ 65 years admitted from a private residence who survived to discharge and received the Older Persons Routine Acute Assessment (OPRAA) during an incident emergency medical admission were included. The outcome measures were living at home, defined as a private residential address, 30 days after discharge and new care home admission at hospital discharge. Outcomes were ascertained through linkage to routine data sources. RESULTS: Of the 5570 individuals admitted from a private residence who survived to discharge, those without a CSD were more likely to be living at home at 30 days than those with a CSD (93.4% versus 81.7%; difference 11.7%, 95%CI 9.7-13.8%). New discharge to a care home affected 236 (4.2%) of the cohort, 181 (76.7%) of whom had a CSD. Logistic regression modelling identified that all four CSD categories were associated with a reduced likelihood of living at home and an increased likelihood of discharge to a care home. Those with delirium superimposed on dementia were the least likely to be living at home (OR 0.25), followed by those with dementia (OR 0.43), then unspecified cognitive impairment (OR 0.55) and finally delirium (OR 0.57). CONCLUSIONS: Individuals with a CSD are at significantly increased risk of not returning home after hospitalisation, and those with CSDs account for the majority of new admissions to care homes on discharge. Individuals with delirium superimposed on dementia are the most affected. We need to understand how to configure and deliver healthcare services to enable older people to remain as independent as possible for as long as possible and to ensure transitions of care are managed supportively.

Mortality in people with dementia, delirium, and unspecified cognitive impairment in the general hospital: prospective cohort study of 6,724 patients with 2 years follow-up.

PURPOSE: Cognitive impairment is common in older people admitted to hospital, but the outcomes are generally poorly understood, and previous research has shown inconsistent associations with mortality depending on the type of cognitive impairment examined and duration of follow-up. This study examines mortality in older people with any cognitive impairment during acute hospital admission. PATIENTS AND METHODS: Prospective cohort of 6,724 people aged ≥65 years with a structured cognitive assessment on acute admission were included in this study. Cognitive spectrum disorder (CSD) was defined as delirium alone, known dementia alone, delirium superimposed on known dementia, or unspecified cognitive impairment. Mortality associated with different types of CSD was examined using a non-proportional hazards model with 2-year follow-up. RESULTS: On admission, 35.4% of patients had CSD, of which 52.6% died within 2 years. After adjustment for demographics and comorbidity, delirium alone was associated with increased mortality in the 6 months post-admission (HR =1.45, 95% CI 1.28-1.65) and again after 1 year (HR =1.44, 95% CI 1.17-1.77). Patients with known dementia (alone or with superimposed delirium) had increased mortality only after 3 months from admission (HR =1.85, 95% CI 1.56-2.18 and HR =1.80, 95% CI 1.52-2.14) compared with patients with unspecified cognitive impairment after 6 months (HR =1.55, 95% CI 1.21-1.99). Similar but partially attenuated associations were seen after adjustment for functional ability. CONCLUSION: Mortality post-admission is high in older people with CSD. Immediate risk is highest in those with delirium, while dementia or unspecified cognitive impairment is associated with medium- to long-term risk. These findings suggest that individuals without dementia who develop delirium are more seriously ill (have required a larger acute insult in order to precipitate delirium) than those with pre-existing brain pathology (dementia). Further research to explain the mortality patterns observed is required in order to translate the findings into clinical care.

Effect of two different participant information sheets on recruitment to a falls trial: An embedded randomised recruitment trial.

BACKGROUND/AIMS: Recruitment to trials of intervention for older people who fall is challenging. Evidence suggests that the word falls has negative connotations for older people, and this may present a barrier to engaging with trials in this area. We therefore tested whether a participant information sheet that minimised reference to falls could improve recruitment rates. METHODS: We conducted a study within a trial, embedded within a randomised controlled trial of vitamin K versus placebo to improve postural sway in patients aged 65 and over with a history of falls. Potential participants were identified from primary care lists in 14 practices and were randomised to receive either a standard participant information sheet or an information sheet minimising use of the word falls, instead focussing on maintenance of health, fitness and balance. The primary outcome for this embedded trial was the proportion of responses expressing interest in participating received in each arm. Secondary outcomes were the proportion of those contacted attending a screening visit, consenting at screening, and the proportion contacted who were randomised into the main trial. RESULTS: In all, 4145 invitations were sent, with an overall response rate of 444 (10.7%). In all, 2148 individuals received the new information sheet (minimising reference to falls); 1997 received the standard information sheet. There was no statistically significant difference in response rate between those individuals sent the new information sheet and those sent the standard information sheet (10.1% vs 11.4%; difference 1.3% (95% confidence interval -0.6% to 3.2%); p = 0.19). Similarly, we found no statistically significant difference between the percentage of those who attended and consented at screening in the two groups (2.1% vs 2.7%; difference 0.6% (95% confidence interval: -0.4% to 1.6%); p = 0.20), and no statistically significant difference between the percentage randomised in the two groups (2.0% vs 2.6%; difference 0.6% (95% confidence interval -0.4% to 1.6%); p = 0.20). CONCLUSIONS: Use of a participant information sheet minimising reference to falls did not lead to a greater response rate in this trial targeting older people with a history of falls.

Cognitive ability, education and socioeconomic status in childhood and risk of post-stroke depression in later life: A systematic review and meta-analysis.

BACKGROUND: Depression after stroke is common and is associated with poorer recovery. Risk factors such as gender, age and stroke severity are established, but it is unclear whether factors from earlier in life might also contribute. METHODS: We searched MEDLINE, PsycINFO, EMBASE and meta-analysed all available evidence on childhood (premorbid) IQ, socioeconomic status (SES), education and stroke in adulthood. We included all studies reporting data on >50 patients, calculating overall odds ratios (OR), mean difference, correlation, 95% confidence intervals (CI) and 95% predictive intervals (PI) using random effects methods. We quality assessed all studies, performed sensitivity analyses, assessed heterogeneity and publication bias. RESULTS: We identified 33 studies including 2,664 participants with post-stroke depression and 5,460 without (314 participants not classified). Low education (< = 8 years) was associated with post-stroke depression in studies which defined depression as score of mild and above on a depression rating scale (OR 1.47 95% CI 1.10-1.97, p<0.01) but not in studies where depression was defined as severe depressive symptoms or a clinical diagnosis of major depression (OR 1.04 95% CI 0.90-1.31, p = 0.60). Low education was not associated with an increased risk for post-stroke depression in studies that adjusted for age and sex (OR 0.86 95% CI 0.50-1.48 p = 0.58). Those with post-stroke depression had fewer years of education than those without post-stroke depression (MD 0.68 95% CI 0.05-1.31 p = 0.04). Few studies adjusted for vascular risk factors or stroke severity. Heterogeneity between studies was moderate and was partly explained by severity of depression. In the one study identified premorbid IQ did not differ between those with post-stroke depression (mean IQ 10.1.8 SD 9.8) vs those without (mean IQ 104 SD 10.1). There were no studies that examined childhood socioeconomic status and risk of post-stroke depression. CONCLUSIONS: Having less education is associated with an increased risk of post-stroke depressive symptoms but with large confidence intervals and heterogeneity. Future studies should explore the relationship between early and late life risk factors to improve risk identification and to target prevention and treatment strategies.

Visual Rating Scales of White Matter Hyperintensities and Atrophy: Comparison of Computed Tomography and Magnetic Resonance Imaging.

GOAL: Magnetic resonance imaging (MRI) is the preferred modality for research on structural age-related brain changes. However, computed tomography (CT) is widely available and has practical and cost advantages over MRI for large-scale brain imaging research studies in acutely unwell patients. However, the relationships between MRI and CT measures of white matter hyperintensities (WMH) and atrophy are unclear. We examined the relationships between visual ratings of WMH, atrophy, and old infarcts in patients who had both CT and MRI scans. MATERIALS AND METHODS: Patients who had both CT and MRI scans in the International Stroke Trial-3 were studied. In both modalities, 2 raters independently completed standardized visual rating scales for WMH, and for central and superficial atrophy using a 5-point scale. In addition, 1 rater recorded old infarcts according to size and location. FINDINGS: Seventy patients with a mean age of 69 years were studied. There were moderate to substantial intrarater CT-MRI agreements for periventricular components of WMH scales (weighted Κappa = .55-.75). Agreements for basal ganglia ratings were lower (weighted Κappa = .18-.44), partly because of the misclassification of prominent perivascular spaces. Atrophy scales showed moderate to substantial CT-MRI agreements (weighted Κappa = .44-.70). MRI was more sensitive in the detection of smaller infarcts and cavitated lesions. CONCLUSIONS: Standardized visual rating scales of white matter lesions and atrophy mostly show substantial agreement between CT and MRI. Clinical CT scans have a strong potential for wider exploitation in research studies, particularly in acutely unwell populations.

The relation between total cerebral small vessel disease burden and gait impairment in patients with minor stroke.

Background and aims Individual MRI markers of cerebral small vessel disease are associated with gait impairment. The impact of total cerebral small vessel disease-related brain damage, expressed by a cerebral small vessel disease MRI burden score, on mobility after stroke, has not been considered, although this score gives a better representation of the overall effect of cerebral small vessel disease on the brain. We determined if the total cerebral small vessel disease burden is associated with gait impairment three years after minor stroke. Methods In total, 200 patients with minor lacunar or non-lacunar stroke (NIHSS ≤ 7) underwent a brain MRI at presentation. Presence of lacunes, white matter hyperintensities, cerebral microbleeds, and perivascular spaces were summed in a total cerebral small vessel disease MRI burden score (range 0-4). Gait disturbances, measured by timed-up-and-go test and self-reported stroke impact scale mobility domain were assessed three years after stroke. We tested associations adjusted for key variables by linear regression analysis. Results Total cerebral small vessel disease burden was not associated with gait impairment after minor stroke in all patients, nor in lacunar stroke patients ( n = 87). In non-lacunar stroke patients ( n = 113), total cerebral small vessel disease burden was associated with lower stroke impact scale mobility domain scores, independent of age, vascular risk factors, and stroke severity (unstandardized B -4.61; 95% CI -8.42; -0.79, p < 0.05). Conclusion Patients with non-lacunar stroke and a higher total cerebral small vessel disease burden have more subjective mobility impairment three years after stroke. The total cerebral small vessel disease MRI burden score is a possible marker to identify patients at risk for subjective gait impairment. These findings should be confirmed in larger studies.