The RESIST Study: Examining Cognitive Change in Rheumatoid Arthritis Patients with Mild Cognitive Impairment Being Treated with a TNF-Inhibitor Compared to a Conventional Synthetic Disease-Modifying Anti-Rheumatic Drug.

Background: Evidence suggests that TNF inhibitors (TNFi) used to treat rheumatoid arthritis (RA) may protect against Alzheimer's disease progression by reducing inflammation. Objective: To investigate whether RA patients with mild cognitive impairment (MCI) being treated with a TNFi show slower cognitive decline than those being treated with a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD). Methods: 251 participants with RA and MCI taking either a csDMARD (N = 157) or a TNFi (N = 94) completed cognitive assessments at baseline and 6-month intervals for 18 months. It was hypothesized that those taking TNFis would show less decline on the primary outcome of Free and Cued Selective Reminding Test with Immediate Recall (FCSRT-IR) and the secondary outcome of Montreal Cognitive Assessment (MoCA). Results: No significant changes in FCSRT-IR scores were observed in either treatment group. There was no significant difference in FCSRT-IR between treatment groups at 18 months after adjusting for baseline (mean difference = 0.5, 95% CI = -1.3, 2.3). There was also no difference in MoCA score (mean difference = 0.4, 95% CI = -0.4, 1.3). Conclusions: There was no cognitive decline in participants with MCI being treated with TNFis and csDMARDs, raising the possibility both classes of drug may be protective. Future studies should consider whether controlling inflammatory diseases using any approach is more important than a specific therapeutic intervention.

An Overview of Systematic Reviews and Meta-Analyses on the Effect of Medication Interventions Targeting Polypharmacy for Frail Older Adults.

Frailty refers to the lack of resilience and a reduction in a person's ability to recover following a health problem, and it is increasingly becoming a challenging aspect of ageing populations. Many older adults are exposed to polypharmacy; i.e., they continue to be on medications without timely re-evaluation. Medication reviews have proven successful in managing polypharmacy in the general population, but there is uncertainty regarding their effect among frail older adults. This overview of published systematic reviews assesses the impact of medication reviews on polypharmacy in frail older adults. Embase was searched from its inception to January 2021 and 28 systematic reviews were identified, out of which 10 were included in the overview. Medication reviews were the most common intervention in 8 out of 10 systematic reviews. The frailty score was reported as an outcome in one systematic review that found no evidence for fundamental pharmacological effects on frailty. Six systematic reviews reported a statistically significant reduction in the number of inappropriately prescribed medications. Four systematic reviews reported on hospital admissions, with two of them reporting a decrease in hospitalisations. The quality assessment was moderate in six and critically low in four of the systematic reviews. We conclude that medication reviews help in reducing the use of inappropriate medications in frail older adults, but that there is insufficient evidence in terms of frailty score and hospital admissions.

The Influence of Orthopedic Surgery on Circulating Metabolite Levels, and their Associations with the Incidence of Postoperative Delirium.

The mechanisms underlying the occurrence of postoperative delirium development are unclear and measurement of plasma metabolites may improve understanding of its causes. Participants (n = 54) matched for age and gender were sampled from an observational cohort study investigating postoperative delirium. Participants were ≥65 years without a diagnosis of dementia and presented for primary elective hip or knee arthroplasty. Plasma samples collected pre- and postoperatively were grouped as either control (n = 26, aged: 75.8 ± 5.2) or delirium (n = 28, aged: 76.2 ± 5.7). Widespread changes in plasma metabolite levels occurred following surgery. The only metabolites significantly differing between corresponding control and delirium samples were ornithine and spermine. In delirium cases, ornithine was 17.6% higher preoperatively, and spermine was 12.0% higher postoperatively. Changes were not associated with various perioperative factors. In binary logistic regression modeling, these two metabolites did not confer a significantly increased risk of delirium. These findings support the hypothesis that disturbed polyamine metabolism is an underlying factor in delirium that warrants further investigation.

Dietary patterns associated with renal impairment in the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA).

BACKGROUND: Dietary-based primary prevention guidelines for chronic kidney disease (CKD) treatment are lacking due to limited evidence. Single nutrient intake studies do not account for complex dietary interactions. We assessed associations between dietary patterns and renal function in the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA). DESIGN: A cross-sectional observational study used NICOLA baseline dietary data collected between February 2014 and March 2016 via a food frequency questionnaire for 2590 participants aged ≥ 50 years. Principal component analysis identified a posteriori dietary patterns. Renal function was characterised by estimated glomerular filtration rate (eGFR) using serum creatinine and cystatin-C. Associations were assessed according to quintiles of dietary pattern adherence and multivariable regression analysis examined associations with eGFR. RESULTS: Variation in three dietary patterns was significantly associated with eGFR. After adjustment for potential confounders, participants with least adherence to the 'healthy' dietary pattern 1 had a mean eGFR 3.4 ml/min/1.73m2 (95% confidence interval, [CI] - 5.0, - 1.7, p < 0.001) lower than the most adherent. Those with lowest adherence to the 'unhealthy' dietary pattern 2 had a mean eGFR 1.9 ml/min/1.73m2 (CI 0.2, 3.5, p = 0.03) higher than those with highest adherence. Participants with lowest adherence to dietary pattern 3, characterised by a high consumption of alcohol and coffee, had a mean eGFR 1.8 ml/min/1.73m2 (- 3.5, - 0.01, p = 0.05) lower than those with greatest adherence. CONCLUSIONS: Our findings identify independent associations between dietary patterns and eGFR. These findings can inform the development of diet-related primary prevention advice for CKD.

Association of renal impairment with cognitive dysfunction in the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA).

INTRODUCTION: Chronic kidney disease (CKD) is a recognized risk factor for cognitive impairment. Identification of those at greatest risk of cognitive impairment may facilitate earlier therapeutic intervention. This study evaluated associations between estimated glomerular filtration rate (eGFR) and cognitive function in the Northern Ireland Cohort for the Longitudinal Study of Ageing. METHODS: Data were available for 3412 participants ≥50 years of age living in non-institutionalized settings who attended a health assessment between February 2014 and March 2016. Measures of serum creatinine (SCr) and cystatin C (cys-C) were used for eGFR. Cognitive function was measured using the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). RESULTS: Following adjustment for potential confounders, a single unit decrease in eGFR was significantly associated with reduced cognitive function defined by an MMSE ≤24/30 {eGFR calculated using serum cys-C [eGFRcys]: ß = -0.01 [95% confidence interval (CI) -0.001 to -0.01], P = 0.01} and MoCA <26/30 [ß = -0.01 (95% CI -0.002 to -0.02), P = 0.02]. Similarly, CKD Stages 3-5 were also associated with a moderate increase in the odds of cognitive impairment (MMSE ≤24) following adjustment for confounders [eGFRcys: odds ratio 2.73 (95% CI 1.38-5.42), P = 0.004]. CONCLUSIONS: Decreased eGFRcys was associated with a significantly increased risk of cognitive impairment in a population-based cohort of older adults. However, there was no evidence of an association between cognitive impairment and the more commonly used eGFR calculated using SCr. eGFRcys may offer improved sensitivity over eGFRcr in the determination of renal function and associated risk of cognitive impairment.

Factors Associated with Mortality Including Nursing Home Transitions: A Retrospective Analysis of 25,418 People Prescribed Anti-Dementia Drugs in Northern Ireland.

BACKGROUND: Understanding factors associated with mortality after a dementia diagnosis can provide essential information to the person with dementia, their family, and caregivers. To date very little is known about the factors associated with mortality after a dementia diagnosis in Northern Ireland. OBJECTIVE: To determine how demographic and other factors such as deprivation and comorbidity medications influence mortality rates after a dementia diagnosis in Northern Ireland and whether these factors are influenced through nursing home transitions. METHODS: 25,418 people prescribed anti-dementia medication were identified through the enhanced prescribing database between 2010 and 2016. The impact of covariates including age, gender, marital status, deprivation measure, urban/rural classification, and comorbidity medications were examined using cox proportional hazard models with hazard ratios (HR) and 95% confidence intervals. RESULTS: Between 2010 and 2016, 12,129 deaths occurred, with 114 deaths/1,000 person years. Males had significantly higher mortality rates in comparison to females (HR = 1.28; 95% CI = 1.23-1.33); this was true regardless of whether the person with dementia transitioned to a nursing home. People prescribed anti-dementia drugs living with lower levels of deprivation had significantly lower mortality rates in comparison to people living with the highest levels of deprivation (HR = 0.93; 95% CI = 0.89-0.97). Diabetic (HR = 1.18; 95% CI = 1.07-1.29) and anti-arrhythmic (HR = 2.44; 95% CI = 1.01-5.91) medication in particular significantly influenced mortality. CONCLUSION: Male gender, higher comorbidity medications, and living in areas of higher deprivation significantly increased mortality rates for people prescribed anti-dementia drugs in our study population. When comorbidity medications were classified, only anti-arrhythmia and diabetic medications significantly increased mortality. Future research should continue to investigate factors which influence mortality after a dementia diagnosis.

Serum xanthophyll carotenoids are associated with estimated glomerular filtration rate in an aged cohort.

Progressive renal decline is associated with increasing oxidative stress. However, the majority of studies have investigated endogenous antioxidants in predominantly advanced stages of kidney disease. Many traditional risk factors associated with renal dysfunction have been linked with cognitive decline as the kidneys and brain share comparable anatomic and haemodynamic characteristics that leave them susceptible to common pathogenic mechanisms. The objective of this study was to examine serum dietary antioxidants and their association with renal function characterised by estimated glomerular filtration rate (eGFR) in a cross-sectional analysis of 570 participants. High performance liquid chromatography quantified serum levels of retinol, α-tocopherol, γ-tocopherol and six carotenoids (α-carotene, ß-carotene, ß-cryptoxanthin, lutein, lycopene and zeaxanthin) in participants. Multiple regression analyses were used to evaluate associations while adjusting for potential confounders. A sensitivity analysis was performed in cognitively-intact participants only. Serum levels of the xanthophyll carotenoid lutein were positively associated with eGFR in analyses adjusted for age (years), gender, smoking, APOE4 status and Alzheimer's disease. Retinol was inversely associated with eGFR, although was no longer significant in the smaller sensitivity analysis. Our findings identify significant associations between the xanthophyll carotenoids and eGFR. Further investigations are required to confirm these findings.

CSF Beta-amyloid 1-42 Concentration Predicts Delirium Following Elective Arthroplasty Surgery in an Observational Cohort Study.

OBJECTIVE: To test the hypothesis that APOE ε4 status and cerebrospinal fluid (CSF) Aß42, T-tau and P-tau would independently predict the risk of postoperative delirium. BACKGROUND: Delirium following surgery is common and associated with adverse outcomes. Age and cognitive impairment are consistent risk factors for postoperative delirium. METHODS: This observational cohort study recruited 282 participants aged 65 years or older, without a diagnosis of dementia, admitted for primary elective hip or knee arthroplasty. Cognitive tests were undertaken preoperatively, blood and CSF were sampled at the time of spinal anesthesia, and participants were assessed daily postoperatively for delirium. RESULTS: Increasing age (P = 0.04), preoperative comorbidity (P = 0.03), type of surgery (P = 0.05), intravenous opioid usage (P = 0.04), and low CSF Aß42 (P < 0.01) were independent predictors of postoperative delirium. CONCLUSIONS: This study is the first to show an independent association between CSF Aß42 and delirium incidence in an elective surgical population, suggesting that postoperative delirium may indicate incipient Alzheimer disease.

Diet and Inflammation in Cognitive Ageing and Alzheimer's Disease.

PURPOSE OF REVIEW: Nutrition is known to modulate the immune system and may alter neuroinflammatory processes implicated in the pathogenesis of Alzheimer's disease (AD) and progression of neurodegeneration. Here, we review the evidence for healthy dietary patterns and age-related cognition and discuss potential neuroinflammatory actions of diet on cognitive function. RECENT FINDINGS: Anti-inflammatory dietary patterns such as the Mediterranean diet (MD) and dietary approaches to stop hypertension (DASH) may be neuroprotective. Several dietary components consumed in the MD and DASH (omega-3 fatty acids, antioxidants and polyphenols) can inhibit neuroinflammation associated with AD. Anti-inflammatory diets may also attenuate neuroinflammation via indirect immune pathways from the gut microbiome and systemic circulation. Diet may influence cognitive ageing via several inflammatory pathways. However, data from human studies are lacking and the exact mechanisms linking diet to cognitive function remain elusive. Further dietary intervention studies are required to investigate diet-associated neurological change from the earliest through to latest stages of cognitive decline. Furthermore, incorporation of neuroimaging measures in intervention studies would advance current understanding of the mechanistic effects of dietary modification on neuroinflammation in the ageing brain.

Cerebrospinal Fluid Spermidine, Glutamine and Putrescine Predict Postoperative Delirium Following Elective Orthopaedic Surgery.

Delirium is a marker of brain vulnerability, associated with increasing age, pre-existing cognitive impairment and, recently, cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease. This nested case-control study used a targeted quantitative metabolomic methodology to profile the preoperative CSF of patients (n = 54) who developed delirium following arthroplasty (n = 28) and those who did not (n = 26). The aim was to identify novel preoperative markers of delirium, and to assess potential correlations with clinical data. Participants without a diagnosis of dementia (≥65 years) undergoing elective primary hip or knee arthroplasty were postoperatively assessed for delirium once-daily for three days. Groups were compared using multivariate, univariate and receiving operator characteristic (ROC) methods. Multivariate modelling using Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) of metabolomic data readily distinguished between delirium and control groups (R2 ≤ 0.56; Q2 ≤ 0.10). Three metabolites (spermidine, putrescine and glutamine) significantly differed between groups (P < 0.05; FDR < 0.07), and performed well as CSF biomarkers (ROC > 0.75). The biomarker performance of the two polyamines (spermidine/putrescine) was enhanced by ratio with CSF Aß42 (ROC > 0.8), and spermidine significantly correlated with Aß42 (pearson r = -0.32; P = 0.018). These findings suggest that spermidine and putrescine levels could be useful markers of postoperative delirium risk, particularly when combined with Aß42, and this requires further investigation.

Confocal infrared imaging with optical coherence tomography provides superior detection of a number of common macular lesions compared to colour fundus photography.

PURPOSE: To compare diagnostic accuracy of confocal infrared reflectance (IR), with and without optical coherence tomography (OCT), to colour fundus photography (CFP) in the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA) Study. METHODS: Cross-sectional observational study of participants in NICOLA. CFP, IR and IR/OCT of 640 eyes were graded for hard, soft and reticular pseudodrusen; geographic atrophy; choroidal neovascularisation; naevus; epiretinal membrane; and haemorrhages. Test characteristics (sensitivity and specificity) for each imaging modality with respect to each retinal feature were calculated. RESULTS: With CFP as the reference standard, sensitivity of IR by itself ranged from 75% for RPD to 93.5% for hard drusen and specificity was above 90% for all features except hard drusen (71.7%). For IR combined with OCT, sensitivity ranged from 80% for choroidal neovascularisation to 96.5% for hard drusen. When IR alone was the reference standard, CFP sensitivity was high for naevi (97.5%) but reduced markedly for epiretinal membrane (48.5%). When the combination of IR and OCT was the reference standard, sensitivity for CFP was least for epiretinal membrane (31.5%), low for geographic atrophy and reticular pseudodrusen (77.8% and 76.2% respectively) and high for all other lesion types. CONCLUSION: Our findings support the use of confocal IR with OCT as a screening tool for a variety of features of macular disease in community optometric practice.

Multi-Kernel Learning with Dartel Improves Combined MRI-PET Classification of Alzheimer's Disease in AIBL Data: Group and Individual Analyses.

Magnetic resonance imaging (MRI) and positron emission tomography (PET) are neuroimaging modalities typically used for evaluating brain changes in Alzheimer's disease (AD). Due to their complementary nature, their combination can provide more accurate AD diagnosis or prognosis. In this work, we apply a multi-modal imaging machine-learning framework to enhance AD classification and prediction of diagnosis of subject-matched gray matter MRI and Pittsburgh compound B (PiB)-PET data related to 58 AD, 108 mild cognitive impairment (MCI) and 120 healthy elderly (HE) subjects from the Australian imaging, biomarkers and lifestyle (AIBL) dataset. Specifically, we combined a Dartel algorithm to enhance anatomical registration with multi-kernel learning (MKL) technique, yielding an average of >95% accuracy for three binary classification problems: AD-vs.-HE, MCI-vs.-HE and AD-vs.-MCI, a considerable improvement from individual modality approach. Consistent with t-contrasts, the MKL weight maps revealed known brain regions associated with AD, i.e., (para)hippocampus, posterior cingulate cortex and bilateral temporal gyrus. Importantly, MKL regression analysis provided excellent predictions of diagnosis of individuals by r2 = 0.86. In addition, we found significant correlations between the MKL classification and delayed memory recall scores with r2 = 0.62 (p < 0.01). Interestingly, outliers in the regression model for diagnosis were mainly converter samples with a higher likelihood of converting to the inclined diagnostic category. Overall, our work demonstrates the successful application of MKL with Dartel on combined neuromarkers from different neuroimaging modalities in the AIBL data. This lends further support in favor of machine learning approach in improving the diagnosis and risk prediction of AD.

Observational cohort study examining apolipoprotein E status and preoperative neuropsychological performance as predictors of post-operative delirium in an older elective arthroplasty population.

Introduction: delirium following surgery is common and is associated with negative outcomes. Preoperative cognitive impairment has been shown to be a risk factor for post-operative delirium. Often the cognitive tests used are cumbersome. This study tests the hypothesis that the quantification of brain vulnerability, using Apolipoprotein E (ApoE) status and neuropsychological tests, both traditional and more easily administered, can quantify the risk of post-operative delirium following elective primary arthroplasty surgery. Methods: this observational cohort study recruited participants aged 65 years or older admitted prior to elective primary hip or knee arthroplasty. Baseline data was collected and participants underwent neuropsychological testing and had blood taken for ApoE genotyping preoperatively. Post-operatively participants were assessed daily for delirium using the Confusion Assessment Method (CAM) and charts were reviewed where possible for reports of delirium. Univariate and multivariate analyses of preoperative factors were undertaken to identify independent predictors of delirium. Results: between March 2012 and October 2014, 315 participants completed the study with an overall incidence of post-operative delirium of 40/315 (12.7%). Of these 18 fulfilled the CAM criteria for delirium and 22 were deemed delirious by consensus decision based on chart review. ApoE genotype was not associated with post-operative delirium in this cohort. Time taken to complete Colour Trails 2, errors in mini mental state examination and level of pain preoperatively were independent predictors of post-operative delirium. Conclusions: this study challenges the assertion that ApoE4 genotype predicts post-operative delirium. It replicates previous work suggesting cognitive impairment predicts post-operative delirium and shows for the 1st time that simple cognitive tests can be as effective as more detailed tests.

Pisa syndrome due to donepezil: pharmacokinetic interactions to blame?

We report a case of Pisa syndrome (PS) due to the acetylcholinesterase inhibitor donepezil which may have been precipitated by pharmacokinetic interactions with commonly used medications. PS is defined as a reversible lateral bending of the trunk with a tendency to lean to one side. This is a rare but very distressing complication with this commonly used medication which was not initially recognised, leading to increasing disability for the patient and significant carer stress. Cessation of donepezil and modulation of potential interacting medications resulted in complete resolution.

Statin withdrawal in people with dementia.

BACKGROUND: There are approximately 24 million people worldwide with dementia; this is likely to increase to 81 million by 2040. Dementia is a progressive condition, and usually leads to death eight to ten years after first symptoms. End-of-life care should emphasise treatments that optimise quality of life and physicians should minimise unnecessary or non-beneficial interventions. Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors; they have become the cornerstone of pharmacotherapy for the management of hypercholesterolaemia but their ability to provide benefit is unclear in the last weeks or months of life. Withdrawal of statins may improve quality of life in people with advanced dementia, as they will not be subjected to unnecessary polypharmacy or side effects. However, they may help to prevent further vascular events in people of advanced age who are at high risk of such events. OBJECTIVES: To evaluate the effects of withdrawal or continuation of statins in people with dementia on: cognitive outcomes, adverse events, behavioural and functional outcomes, mortality, quality of life, vascular morbidity, and healthcare costs. SEARCH METHODS: We searched ALOIS (medicine.ox.ac.uk/alois/), the Cochrane Dementia and Cognitive Improvement Group Specialised Register on 11 February 2016. We also ran additional searches in MEDLINE, EMBASE, PsycINFO, CINAHL, Clinical.Trials.gov and the WHO Portal/ICTRP on 11 February 2016, to ensure that the searches were as comprehensive and as up-to-date as possible. SELECTION CRITERIA: We included all randomised, controlled clinical trials with either a placebo or 'no treatment' control group. We applied no language restrictions. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria, using standard methodological procedures expected by Cochrane. We found no studies suitable for inclusion therefore analysed no data. MAIN RESULTS: The search strategy identified 28 unique references, all of which were excluded. AUTHORS' CONCLUSIONS: We found no evidence to enable us to make an informed decision about statin withdrawal in dementia. Randomised controlled studies need to be conducted to assess cognitive and other effects of statins in participants with dementia, especially when the disease is advanced.

Age-associated changes of brain copper, iron, and zinc in Alzheimer's disease and dementia with Lewy bodies.

Disease-, age-, and gender-associated changes in brain copper, iron, and zinc were assessed in postmortem neocortical tissue (Brodmann area 7) from patients with moderate Alzheimer's disease (AD) (n = 14), severe AD (n = 28), dementia with Lewy bodies (n = 15), and normal age-matched control subjects (n = 26). Copper was lower (20%; p < 0.001) and iron higher (10-16%; p < 0.001) in severe AD compared with controls. Intriguingly significant Group*Age interactions were observed for both copper and iron, suggesting gradual age-associated decline of these metals in healthy non-cognitively impaired individuals. Zinc was unaffected in any disease pathologies and no age-associated changes were apparent. Age-associated changes in brain elements warrant further investigation.

Encouraging lifestyle behaviour change in mild cognitive impairment patients: development of appropriate educational material.

OBJECTIVES: A healthy lifestyle may help maintain cognitive function and reduce the risk of developing dementia. This study employed a focus group approach in order to gain insight into opinions of mild cognitive impairment (MCI) patients, caregivers (CG) and health professionals (HP) regarding lifestyle and its relationship with cognition. The qualitative data were used to design, develop and pilot test educational material (EM) to help encourage lifestyle behaviour change. METHOD: Data gathering phase: structured interviews were conducted with HP (n = 10), and focus groups with MCI patients (n = 24) and CG (n = 12). EM was developed and pilot tested with a new group of MCI patients (n = 21) and CG (n = 6). RESULTS: HP alluded to the lack of clinical trial evidence for a lifestyle and MCI risk link. Although they felt that lifestyle modifications should be recommended to MCI patients, they appeared hesitant in communicating this information and discussions were often patient-driven. MCI patients lacked awareness of the lifestyle cognition link. Participants preferred EM to be concise, eye-catching and in written format, with personal delivery of information favoured. Most pilot testers approved of the EM but were heterogeneous in terms of lifestyle, willingness to change and support needed to change. CONCLUSION: MCI patients need to be made more aware of the importance of lifestyle for cognition. EM such as those developed here, which are specifically tailored for this population would be valuable for HP who, currently, appear reticent in initiating lifestyle-related discussions. Following further evaluation, the EM could be used in health promotion activities targeting MCI patients.