Search

Delirium is an acute change in attention and cognition occurring in ~65% of severe SARS-CoV-2 cases. It is also common following surgery and an indicator of brain vulnerability and risk for the development of dementia. In this work we analyzed the underlying role of metabolism in delirium-susceptibility in the postoperative setting using metabolomic profiling of cerebrospinal fluid and blood taken from the same patients prior to planned orthopaedic surgery. Distance correlation analysis and Random Forest (RF) feature selection were used to determine changes in metabolic networks. We found significant concentration 2 differences in several amino acids, acylcarnitines and polyamines linking delirium-prone patients to known factors in Alzheimer’s disease such as monoamine oxidase B (MAOB) protein. Subsequent computational structural comparison between MAOB and angiotensin converting enzyme 2 as well as protein-protein docking analysis showed that there potentially is strong binding of SARS-CoV-2 spike protein to MAOB. The possibility that SARS-CoV-2 influences MAOB activity leading to the observed neurological and platelet-based complications of SARS-CoV-2 infection requires further investigation.

BACKGROUND: Drugs modifying angiotensin II signalling could reduce Alzheimer's disease pathology, thus decreasing the rate of disease progression. We investigated whether the angiotensin II receptor antagonist losartan, compared with placebo, could reduce brain volume loss, as a measure of disease progression, in clinically diagnosed mild-to-moderate Alzheimer's disease.METHODS: In this double-blind, multicentre, randomised controlled trial, eligible patients aged 55 years or older, previously untreated with angiotensin II drugs and diagnosed (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria) with mild-to-moderate Alzheimer's disease, and who had capacity to consent, were recruited from 23 UK National Health Service hospital trusts. After undergoing a 4-week, open-label phase of active treatment then washout, participants were randomly assigned (1:1) oral over-encapsulated preparations of either 100 mg losartan (after an initial two-dose titration stage) or matched placebo daily for 12 months. Randomisation, minimised by age and baseline medial temporal lobe atrophy score, was undertaken online or via pin-access service by telephone. Participants, their study companions, and study personnel were masked to group assignment. The primary outcome, analysed by the intention-to-treat principle (ie, participants analysed in the group to which they were randomised, without imputation for missing data), was change in whole brain volume between baseline and 12 months, measured using volumetric MRI and determined by boundary shift interval (BSI) analysis. The trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN93682878) and the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT 2012-003641-15), and is completed.FINDINGS: Between July 22, 2014, and May 17, 2018, 261 participants entered the open-label phase. 211 were randomly assigned losartan (n=105) or placebo (n=106). Of 197 (93%) participants who completed the study, 171 (81%) had complete primary outcome data. The mean brain volume (BSI) reduction was 19·1 mL (SD 10·3) in the losartan group and 20·0 mL (10·8) in the placebo group. The difference in total volume reduction between groups was -2·29 mL (95% CI -6·46 to 0·89; p=0·14). The number of adverse events was low (22 in the losartan group and 20 in the placebo group) with no differences between treatment groups. There was one treatment-related death per treatment group.INTERPRETATION: 12 months of treatment with losartan was well tolerated but was not effective in reducing the rate of brain atrophy in individuals with clinically diagnosed mild-to-moderate Alzheimer's disease. Further research is needed to assess the potential therapeutic benefit from earlier treatment in patients with milder cognitive impairment or from longer treatment periods.FUNDING: Efficacy and Mechanism Evaluation Programme (UK Medical Research Council and National Institute for Health Research).

Background:Dementia is a progressive syndrome characterised by deterioration in memory, thinking and behaviour, and by impaired ability to perform daily activities. Two classes of drug ‐ cholinesterase inhibitors (donepezil, galantamine and rivastigmine) and memantine ‐ are widely licensed for dementia due to Alzheimer's disease, and rivastigmine is also licensed for Parkinson's disease dementia. These drugs are prescribed to alleviate symptoms and delay disease progression in these and sometimes in other forms of dementia. There are uncertainties about the benefits and adverse effects of these drugs in the long term and in severe dementia, about effects of withdrawal, and about the most appropriate time to discontinue treatment.Objectives:To evaluate the effects of withdrawal or continuation of cholinesterase inhibitors or memantine, or both, in people with dementia on: cognitive, neuropsychiatric and functional outcomes, rates of institutionalisation, adverse events, dropout from trials, mortality, quality of life and carer‐related outcomes.Search methods:We searched the Cochrane Dementia and Cognitive Improvement Group’s Specialised Register up to 17 October 2020 using terms appropriate for the retrieval of studies of cholinesterase inhibitors or memantine. The Specialised Register contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources.Selection criteria:We included all randomised, controlled clinical trials (RCTs) which compared withdrawal of cholinesterase inhibitors or memantine, or both, with continuation of the same drug or drugs.Data collection and analysis:Two review authors independently assessed citations and full‐text articles for inclusion, extracted data from included trials and assessed risk of bias using the Cochrane risk of bias tool. Where trials were sufficiently similar, we pooled data for outcomes in the short term (up to 2 months after randomisation), medium term (3‐11 months) and long term (12 months or more). We assessed the overall certainty of the evidence for each outcome using GRADE methods.Main results:We included six trials investigating cholinesterase inhibitor withdrawal, and one trial investigating withdrawal of either donepezil or memantine. No trials assessed withdrawal of memantine only. Drugs were withdrawn abruptly in five trials and stepwise in two trials. All participants had dementia due to Alzheimer's disease, with severities ranging from mild to very severe, and were taking cholinesterase inhibitors without known adverse effects at baseline. The included trials randomised 759 participants to treatment groups relevant to this review. Study duration ranged from 6 weeks to 12 months. There were too few included studies to allow planned subgroup analyses. We considered some studies to be at unclear or high risk of selection, performance, detection, attrition or reporting bias.Compared to continuing cholinesterase inhibitors, discontinuing treatment may be associated with worse cognitive function in the short term (standardised mean difference (SMD) ‐0.42, 95% confidence interval (CI) ‐0.64 to ‐0.21; 4 studies; low certainty), but the effect in the medium term is very uncertain (SMD ‐0.40, 95% CI ‐0.87 to 0.07; 3 studies; very low certainty). In a sensitivity analysis omitting data from a study which only included participants who had shown a relatively poor prior response to donepezil, inconsistency was reduced and we found that cognitive function may be worse in the discontinuation group in the medium term (SMD ‐0.62; 95% CI ‐0.94 to ‐0.31). Data from one longer‐term study suggest that discontinuing a cholinesterase inhibitor is probably associated with worse cognitive function at 12 months (mean difference (MD) ‐2.09 Standardised Mini‐Mental State Examination (SMMSE) points, 95% CI ‐3.43 to ‐0.75; moderate certainty).Discontinuation may make little or no difference to functional status in the short term (SMD ‐0.25, 95% CI ‐0.54 to 0.04; 2 studies; low certainty), and its effect in the medium term is uncertain (SMD ‐0.38, 95% CI ‐0.74 to ‐0.01; 2 studies; very low certainty). After 12 months, discontinuing a cholinesterase inhibitor probably results in greater functional impairment than continuing treatment (MD ‐3.38 Bristol Activities of Daily Living Scale (BADLS) points, 95% CI ‐6.67 to ‐0.10; one study; moderate certainty). Discontinuation may be associated with a worsening of neuropsychiatric symptoms over the short term and medium term, although we cannot exclude a minimal effect (SMD ‐ 0.48, 95% CI ‐0.82 to ‐0.13; 2 studies; low certainty; and SMD ‐0.27, 95% CI ‐0.47 to ‐0.08; 3 studies; low certainty, respectively). Data from one study suggest that discontinuing a cholinesterase inhibitor may result in little to no change in neuropsychiatric status at 12 months (MD ‐0.87 Neuropsychiatric Inventory (NPI) points; 95% CI ‐8.42 to 6.68; moderate certainty).We found no clear evidence of an effect of discontinuation on dropout due to lack of medication efficacy or deterioration in overall medical condition (odds ratio (OR) 1.53, 95% CI 0.84 to 2.76; 4 studies; low certainty), on number of adverse events (OR 0.85, 95% CI 0.57 to 1.27; 4 studies; low certainty) or serious adverse events (OR 0.80, 95% CI 0.46 to 1.39; 4 studies; low certainty), and on mortality (OR 0.75, 95% CI 0.36 to 1.55; 5 studies; low certainty). Institutionalisation was reported in one trial, but it was not possible to extract data for the groups relevant to this review.Authors' conclusionsThis review suggests that discontinuing cholinesterase inhibitors may result in worse cognitive, neuropsychiatric and functional status than continuing treatment, although this is supported by limited evidence, almost all of low or very low certainty. As all participants had dementia due to Alzheimer's disease, our findings are not transferable to other dementia types. We were unable to determine whether the effects of discontinuing cholinesterase inhibitors differed with baseline dementia severity. There is currently no evidence to guide decisions about discontinuing memantine. There is a need for further well‐designed RCTs, across a range of dementia severities and settings. We are aware of two ongoing registered trials. In making decisions about discontinuing these drugs, clinicians should exercise caution, considering the evidence from existing trials along with other factors important to patients and their carers.

Objective: Anticholinergic burden refers to the cumulative effect of medications which contain anticholinergic properties. We assessed how anticholinergic burden and different types of anticholinergic medications influence mortality rates among people with dementia in Northern Ireland. Our secondary aim was to determine what demographic characteristics predict the anticholinergic burden of people with dementia. Methods: Data were extracted from the Enhanced Prescribing database for 25,418 people who were prescribed at least one dementia management medication between 2010 and 2016.Information was also extracted on the number of times each available anticholinergic drug was prescribed between 2010 and 2016, allowing the calculation of an overall anticholinergic burden. Cox proportional hazard models were used to determine how anticholinergic burden influenced mortality whilst multilevel model regression determined what demographic characteristics influence overall anticholinergic burden. Results: Of the 25,418 people with dementia, only 15% (n ¼ 3880) had no anticholinergic burden. Diazepam (42%) and risperidone (18%) were the two most commonly prescribed drugs. Unadjusted Cox proportional hazard models indicated that higher anticholinergic burden was associated with significantly higher mortality rates in comparison to people with dementia who had no anticholinergic burden (HR ¼ 1.59: 95% CI ¼ 1.07-2.36). In particular, urological (HR ¼ 1.20: 95%CI ¼ 1.05-1.38) and respiratory (HR ¼ 1.17: 95% CI ¼ 1.08-1.27) drugs significantly increased mortality rates. People with dementia living in areas with low levels of deprivation had significantly lower anticholinergic burden (HR=-.39: 95% CI=-.47:-30).Conclusions: Reducing anticholinergic burden is essential for people with dementia. Further research should address the unfavourable prognosis of people living with dementia in highly deprived areas.

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, β-carotene, β-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.

Purpose of ReviewNutrition 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 FindingsAnti-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.SummaryDiet 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.

BACKGROUND: This is an update of a Cochrane Review first published in 2006 (McGuinness 2006), and previously updated in 2009 (McGuinness 2009). Hypertension is a risk factor for dementia. Observational studies suggest antihypertensive treatment is associated with lower incidences of cognitive impairment and dementia. There is already clear evidence to support the treatment of hypertension after stroke.OBJECTIVES: To assess whether pharmacological treatment of hypertension can prevent cognitive impairment or dementia in people who have no history of cerebrovascular disease.SEARCH METHODS: We searched the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group, CENTRAL, MEDLINE, Embase, three other databases, as well as many trials registries and grey literature sources, most recently on 7 July 2020.SELECTION CRITERIA: We included randomised controlled trials (RCTs) in which pharmacological interventions to treat hypertension were given for at least 12 months. We excluded trials of pharmacological interventions to lower blood pressure in non-hypertensive participants. We also excluded trials conducted solely in people with stroke.DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. We collected information regarding incidence of dementia, cognitive decline, change in blood pressure, adverse effects and quality of life. We assessed the certainty of evidence using GRADE.MAIN RESULTS: We included 12 studies, totaling 30,412 participants, in this review. Eight studies compared active treatment with placebo. Of the four non-placebo-controlled studies, two compared intensive versus standard blood pressure reduction. The two final included studies compared different classes of antihypertensive drug. Study durations varied from one to five years. The combined result of four placebo-controlled trials that reported incident dementia indicated no evidence of a difference in the risk of dementia between the antihypertensive treatment group and the placebo group (236/7767 versus 259/7660, odds ratio (OR) 0.89, 95% confidence interval (CI) 0.72 to 1.09; very low certainty evidence, downgraded due to study limitations and indirectness). The combined results from five placebo-controlled trials that reported change in Mini-Mental State Examination (MMSE) may indicate a modest benefit from antihypertensive treatment (mean difference (MD) 0.20, 95% CI 0.10 to 0.29; very low certainty evidence, downgraded due to study limitations, indirectness and imprecision). The certainty of evidence for both cognitive outcomes was downgraded on the basis of study limitations and indirectness. Study durations were too short, overall, to expect a significant difference in dementia rates between groups. Dementia and cognitive decline were secondary outcomes for most studies. Additional sources of bias include: the use of antihypertensive medication by the placebo group in the placebo-controlled trials; failure to reach recruitment targets; and early termination of studies on safety grounds. Meta-analysis of the placebo-controlled trials reporting results found a mean change in systolic blood pressure of -9.25 mmHg (95% CI -9.73, -8.78) between treatment (n = 8973) and placebo (n = 8820) groups, and a mean change in diastolic blood pressure of -2.47 mmHg (95% CI -2.70, -2.24) between treatment (n = 7700) and placebo (n = 7509) groups (both low certainty evidence downgraded on the basis of study limitations and inconsistency). Three trials - SHEP 1991, LOMIR MCT IL 1996 and MRC 1996 - reported more withdrawals due to adverse events in active treatment groups than placebo groups. Participants on active treatment in Syst Eur 1998 were less likely to discontinue treatment due to side effects, and participants on active treatment in HYVET 2008 reported fewer 'serious adverse events' than in the placebo group. There was no evidence of a difference in withdrawals rates between groups in SCOPE 2003, and results were unclear for Perez Stable 2000 and Zhang 2018. Heterogeneity precluded meta-analysis. Five of the placebo-controlled trials provided quality of life (QOL) data. Heterogeneity again precluded meta-analysis. SHEP 1991, Syst Eur 1998 and HYVET 2008 reported no evidence of a difference in QOL measures between active treatment and placebo groups over time. The SCOPE 2003 sub-study (Degl'Innocenti 2004) showed a smaller drop in QOL measures in the active treatment compared to the placebo group. LOMIR MCT IL 1996 reported an improvement in a QOL measure at twelve months in one active treatment group and deterioration in another.AUTHORS' CONCLUSIONS: High certainty randomised controlled trial evidence regarding the effect of hypertension treatment on dementia and cognitive decline does not yet exist. The studies included in this review provide low certainty evidence (downgraded primarily due to study limitations and indirectness) that pharmacological treatment of hypertension, in people without prior cerebrovascular disease, leads to less cognitive decline compared to controls. This difference is below the level considered clinically significant. The studies included in this review also provide very low certainty evidence that pharmacological treatment of hypertension, in people without prior cerebrovascular disease, prevents dementia.

Introduction:The increasing number of people with dementia (PwD) is a significant health and financial challenge for countries. PwD often transition to a care home. This study explored factors predicting transition to care homes for PwD and the place and causes of death.Methods:Data about dementia medication, care home transitions, demographic characteristics, deaths, and hospital admissions were extracted from national databases from 2010 to 2016.Results:PwD (n = 25,418) were identified through prescriptions of dementia medication, from which 11,930 transitioned to care homes. A logistic regression showed that increased age, female sex, living in less deprived and urban areas, and hospital admissions predicted this transition. PwD who transition to care homes are more likely to die there. The most common cause of death was dementia.Discussion:Certain demographic characteristics are significant predictors for care home transitions and they should be considered in the development of early community‐based care services to delay transitions. In the last decades, dementia has been reported more frequently in death certificates

Background Type 2 diabetes is a risk factor for Alzheimer’s disease (AD), and AD brain shows impaired insulin signalling. The role of peripheral insulin resistance on AD aetiopathogenesis in non-diabetic patients is still debated. Here we evaluated the influence of insulin resistance on brain glucose metabolism, grey matter volume and white matter lesions (WMLs) in non-diabetic AD subjects. Methods In total, 130 non-diabetic AD subjects underwent MRI and [18F]FDG PET scans with arterial cannula insertion for radioactivity measurement. T1 Volumetric and FLAIR sequences were acquired on a 3-T MRI scanner. These subjects also had measurement of glucose and insulin levels after a 4-h fast on the same day of the scan. Insulin resistance was calculated by the updated homeostatic model assessment (HOMA2). For [18F]FDG analysis, cerebral glucose metabolic rate (rCMRGlc) parametric images were generated using spectral analysis with arterial plasma input function. Results In this non-diabetic AD population, HOMA2 was negatively associated with hippocampal rCMRGlc, along with total grey matter volumes. No significant correlation was observed between HOMA2, hippocampal volume and WMLs. Conclusions In non-diabetic AD, peripheral insulin resistance is independently associated with reduced hippocampal glucose metabolism and with lower grey matter volume, suggesting that peripheral insulin resistance might influence AD pathology by its action on cerebral glucose metabolism and on neurodegeneration.

Access to affordable, objective and scalable biomarkers of brain function is needed to transform the healthcare burden of neuropsychiatric and neurodegenerative disease. Electroencephalography (EEG) recordings, both resting and in combination with targeted cognitive tasks, have demonstrated utility in tracking disease state and therapy response in a range of conditions from schizophrenia to Alzheimer's disease. But conventional methods of recording this data involve burdensome clinic visits, and behavioural tasks that are not effective in frequent repeated use. This paper aims to evaluate the technical and human-factors feasibility of gathering large-scale EEG using novel technology in the home environment with healthy adult users. In a large field study, 89 healthy adults aged 40–79 years volunteered to use the system at home for 12 weeks, 5 times/week, for 30 min/session. A 16-channel, dry-sensor, portable wireless headset recorded EEG while users played gamified cognitive and passive tasks through a tablet application, including tests of decision making, executive function and memory. Data was uploaded to cloud servers and remotely monitored via web-based dashboards. Seventy-eight participants completed the study, and high levels of adherence were maintained throughout across all age groups, with mean compliance over the 12-week period of 82% (4.1 sessions per week). Reported ease of use was also high with mean System Usability Scale scores of 78.7. Behavioural response measures (reaction time and accuracy) and EEG components elicited by gamified stimuli (P300, ERN, Pe and changes in power spectral density) were extracted from the data collected in home, across a wide range of ages, including older adult participants. Findings replicated well-known patterns of age-related change and demonstrated the feasibility of using low-burden, large-scale, longitudinal EEG measurement in community-based cohorts. This technology enables clinically relevant data to be recorded outside the lab/clinic, from which metrics underlying cognitive ageing could be extracted, opening the door to potential new ways of developing digital cognitive biomarkers for disorders affecting the brain.

Older people with dementia in long-term care constitute a complex population. It is important to establish at an early stage after admission the reasons for the placement and gain a good understanding of the background problems and agree a comprehensive care plan which should pay particular attention to management of infections, attitudes to hospitalisation, and palliative care. We discuss the pertinent clinical issues along with the importance of vaccination. The emergence of telemedicine is important. No chapter on long-term care of people with dementia is complete without consideration of the effects and legacy of COVID-19. Finally, a case history illustrating some common issues, and how they might be addressed, is included.

Approximately one-third of people with dementia in the United Kingdom live alone. People living alone with dementia may receive different treatment for dementia and may have different comorbidities compared to people who live with a caregiver. This study explored differences in medication and demographic characteristics between people living alone with dementia and those living with a caregiver in Northern Ireland. People with dementia were identified through the first date that a dementia management medication was prescribed between 2010 and 2016. In total, 25,418 people were prescribed a dementia management medication. Data for whether people with dementia lived alone was extracted through the National Health Application and Infrastructure Services and from national datasets through the Honest Broker Service. Approximately 35% (n= 8,828) of people with dementia in Northern Ireland lived alone. People with dementia who lived alone were younger (mean= 75 years, SD= 8.50) compared to people who lived with a caregiver (mean= 77 years, SD= 7.82). Binary logistic regression highlighted that people who lived alone were more likely to be treated with donepezil medication for dementia and less likely to receive antidepressants. These findings indicate that living alone did not affect treatment for dementia and comorbidity medication in people on dementia medication.

Disruptions of brain metabolism are considered integral to the pathogenesis of dementia, but thus far little is known of how dementia with Lewy bodies (DLB) impacts the brain metabolome. DLB is less well known than other neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease which is perhaps why it is under-investigated. This exploratory study aimed to address current knowledge gaps in DLB research and search for potentially targetable biochemical pathways for therapeutics. It also aimed to better understand metabolic similarities and differences with other dementias. Combined metabolomic analyses of 1H NMR and tandem mass spectrometry of neocortical post-mortem brain tissue (Brodmann region 7) from autopsy confirmed cases of DLB (n = 15) were compared with age/gender-matched, non-cognitively impaired healthy controls (n = 30). Following correction for multiple comparisons, only 2 metabolites from a total of 219 measured compounds significantly differed. Putrescine was suppressed (55.4%) in DLB and O-phosphocholine was elevated (52.5%). We identified a panel of 5 metabolites (PC aa C38:4, O-Phosphocholine, putrescine, 4-Aminobutyrate, and SM C16:0) capable of accurately discriminating between DLB and control subjects. Deep Learning (DL) provided the best predictive model following 10-fold cross validation (AUROC (95% CI) = 0.80 (0.60–1.0)) with sensitivity and specificity equal to 0.92 and 0.88, respectively. Altered brain levels of putrescine and O-phosphocholine indicate that the Kennedy pathway and polyamine metabolism are perturbed in DLB. These are accompanied by a consistent underlying trend of lipid dysregulation. As yet it is unclear whether these are a cause or consequence of DLB onset.

After publication of our article [1] the authors have notified us that the name of Prof. Christian Holscher had been inadvertently forgotten when compiling the list of authors. Dr. Holscher developed the concept of testing liraglutide in Alzheimer’s mouse model, has done the preclinical experiments, and is a co-applicant of the Alzheimer ociety UK grant that partially funds the study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of extra-respiratory signs and symptoms. One such manifestation is delirium, an acute confusional state occurring in 60-70% of severe SARS-CoV-2 cases. Delirium is also a common clinical syndrome following planned orthopedic surgery. This investigation initially explored the underlying role of metabolism in delirium-susceptibility in this setting. Metabolomics profiles of cerebrospinal fluid (CSF) and blood taken prior to surgery found significant concentration differences of several amino acids, acylcarnitines and polyamines were observed in delirium-prone patients. Phenethylamine (PEA) concentrations in delirium-prone patients was significantly lower in CSF than in blood, whilst in age- and gender-matched controls the opposite was observed (adjusted p values: 1.8x10-6 (control) and 1.788x10-10 (delirium)). PEA is metabolised by monoamine oxidase B (MAOB), a putative enzyme target for the treatment of Alzheimers disease, Parkinsons disease and depression. Our computational structural comparisons of MAOB and angiotensin converting enzyme (ACE) 2 found high similarity, specifically within the SARS-CoV-2 spike protein. MAOB structural alignment to ACE2 was 51% overall, but this was over 95% in the ACE2-spike protein binding region. Thus, it is possible that the spike protein interacts with MAOB on a molecular level. A previously published metabolomic dataset of control subjects and patients with either mild or severe COVID-19 was then analysed. Major concentration differences in some metabolites attributed to altered MAO activity were detected. Therefore, our hypothesis is that the SARS-CoV-2 influences MAOB activity, which is one potential cause for the many observed neurological and platelet based complications of SARS-CoV-2 infection.

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.

Background Dementia is a worldwide concern. Its global prevalence is increasing. At present, there is no medication licensed to prevent or delay the onset of dementia. Inflammation has been suggested as a key factor in dementia pathogenesis. Therefore, medications with anti-inflammatory properties could be beneficial for dementia prevention. Objectives To evaluate the effectiveness and adverse effects of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) for the primary or secondary prevention of dementia. Search methods We searched ALOIS, the specialised register of the Cochrane Dementia and Cognitive Improvement Group up to 9 January 2020. ALOIS contains records of clinical trials identified from monthly searches of several major healthcare databases, trial registries and grey literature sources. We ran additional searches across MEDLINE (OvidSP), Embase (OvidSP) and six other databases to ensure that the searches were as comprehensive and up-to-date as possible. We also reviewed citations of reference lists of included studies. Selection criteria We searched for randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing aspirin or other NSAIDs with placebo for the primary or secondary prevention of dementia. We included trials with cognitively healthy participants (primary prevention) or participants with mild cognitive impairment (MCI) or cognitive complaints (secondary prevention). Data collection and analysis We used standard methodological procedures according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the strength of evidence for each outcome using the GRADE approach. Main results We included four RCTs with 23,187 participants. Because of the diversity of these trials, we did not combine data to give summary estimates, but presented a narrative description of the evidence. We identified one trial (19,114 participants) comparing low-dose aspirin (100 mg once daily) to placebo. Participants were aged 70 years or older with no history of dementia, cardiovascular disease or physical disability. Interim analysis indicated no significant treatment effect and the trial was terminated slightly early after a median of 4.7 years' follow-up. There was no evidence of a difference in incidence of dementia between aspirin and placebo groups (risk ratio (RR) 0.98, 95% CI 0.83 to 1.15; high-certainty evidence). Participants allocated aspirin had higher rates of major bleeding (RR 1.37, 95% CI 1.17 to 1.60, high-certainty evidence) and slightly higher mortality (RR 1.14, 95% CI 1.01 to 1.28; high-certainty evidence). There was no evidence of a difference in activities of daily living between groups (RR 0.84, 95% CI 0.70 to 1.02; high-certainty evidence). We identified three trials comparing non-aspirin NSAIDs to placebo. All three trials were terminated early due to adverse events associated with NSAIDs reported in other trials. One trial (2528 participants) investigated the cyclo-oxygenase-2 (COX-2) inhibitor celecoxib (200 mg twice daily) and the non-selective NSAID naproxen (220 mg twice daily) for preventing dementia in cognitively healthy older adults with a family history of Alzheimer's disease (AD). Median follow-up was 734 days. Combining both NSAID treatment arms, there was no evidence of a difference in the incidence of AD between participants allocated NSAIDs and those allocated placebo (RR 1.91, 95% CI 0.89 to 4.10; moderate-certainty evidence). There was also no evidence of a difference in rates of myocardial infarction (RR 1.21, 95% CI 0.61 to 2.40), stroke (RR 1.82, 95% CI 0.76 to 4.37) or mortality (RR 1.37, 95% CI 0.78 to 2.43) between treatment groups (all moderate-certainty evidence). One trial (88 participants) assessed the effectiveness of celecoxib (200 mg or 400 mg daily) in delaying cognitive decline in participants aged 40 to 81 years with mild age-related memory loss but normal memory performance scores. Mean duration of follow-up was 17.6 months in the celecoxib group and 18.1 months in the placebo group. There was no evidence of a difference between groups in test scores in any of six cognitive domains. Participants allocated celecoxib experienced more gastrointestinal adverse events than those allocated placebo (RR 2.66, 95% CI 1.05 to 6.75; low-certainty evidence). One trial (1457 participants) assessed the effectiveness of the COX-2 inhibitor rofecoxib (25 mg once daily) in delaying or preventing a diagnosis of AD in participants with MCI. Median duration of study participation was 115 weeks in the rofecoxib group and 130 weeks in the placebo group. There was a higher incidence of AD in the rofecoxib than the placebo group (RR 1.32, 95% CI 1.01 to 1.72; moderate-certainty evidence). There was no evidence of a difference between groups in cardiovascular adverse events (RR 1.07, 95% CI 0.68 to 1.66; moderate-certainty evidence) or mortality (RR 1.62, 95% CI 0.85 to 3.05; moderate-certainty evidence). Participants allocated rofecoxib had more upper gastrointestinal adverse events (RR 3.53, 95% CI 1.17 to 10.68; moderate-certainty evidence). Reported annual mean difference scores showed no evidence of a difference between groups in activities of daily living (year 1: no data available; year 2: 0.0, 95% CI -0.1 to 0.2; year 3: 0.1, 95% CI -0.1 to 0.3; year 4: 0.1, 95% CI -0.1 to 0.4; moderate-certainty evidence). Authors' conclusions There is no evidence to support the use of low-dose aspirin or other NSAIDs of any class (celecoxib, rofecoxib or naproxen) for the prevention of dementia, but there was evidence of harm. Although there were limitations in the available evidence, it seems unlikely that there is any need for further trials of low-dose aspirin for dementia prevention. If future studies of NSAIDs for dementia prevention are planned, they will need to be cognisant of the safety concerns arising from the existing studies.

Background: Observational Pain Tools (OPTs) are widely recommended in healthcare policies, clinical guidelines and recommendations for pain assessment and management. However, it is unclear whether and how these tools are used for patients with advanced dementia approaching the end of life. Aim: To explore hospice, secondary and primary care physicians’ and nurses’ use of OPTs with patients dying with advanced dementia and their perspectives on practice development and training needs. Methods: Twenty-three physicians and 24 nurses with experience of caring for people dying with advanced dementia were recruited from primary care surgeries (n=5), hospitals (n=6), hospices (n=4) and nursing homes (n=10). Semi-structured, face-to-face interviews were conducted. Interviews were digitally recorded, transcribed verbatim and thematic analysis applied to identify core themes. Results: Three key themes emerged: (1) use of OPTs in this vulnerable patient population; (2) barriers to the use of OPTs and lack of perceived ‘added value’ and (3) perspectives on practice development and training in pain assessment in advanced dementia at end of life. Just over one-quarter of participants (n=13) routinely used OPTs. Reasons for non-use included perceived limitations of such tools, difficulties with their use and integration with existing practice and lack of perceived ‘added value’. Most participants strongly emphasised a need for ongoing training and development which facilitated transfer of knowledge and multidisciplinary skills across professions and specialties. Conclusions: Health professionals require ongoing support in developing and integrating change to existing pain assessment protocols and approaches. These findings have important implications for health education, practice and policy.

Background: Anti-hypertensives that modify the renin angiotensin system may reduce Alzheimer’s disease pathology and reduce the rate of disease progression. We report a phase II, two arm, double-blind, placebo-controlled, randomised trial (ISRCTN: 93682878; EudraCT: 2012-003641-15) of losartan to test the efficacy of Reducing pathology in Alzheimer’s Disease through Angiotensin TaRgeting (RADAR). Study population: Men and women aged at least 55 years with mild-to-moderate Alzheimer’s disease (AD) Interventions: Randomly allocated 100mg encapsulated generic losartan or placebo once daily for 12 months after successful completion of a 2 week open-label phase and 2 weeks placebo washout to establish drug tolerability. Outcomes: The primary outcome is the rate of whole brain atrophy as a surrogate measure of disease progression. Secondary outcomes include changes to (i) white matter hyperintensity (WMH) volume and cerebral blood flow (CBF) (also surrogate markers of cognitive decline and disease progression); (ii) performance on a standard series of assessments of memory, cognitive function, activities of daily living and quality of life. Assessments: Major assessments (for all outcomes) and relevant safety monitoring of blood pressure and bloods will be at baseline and 12 months. Additional cognitive assessment will also be conducted at 6 months along with safety blood pressure and blood monitoring. Monitoring of blood pressure, bloods and reported side effects will occur during the open-label phase and during the majority of the post-randomisation dispensing visits. Sample Size: 228 participants to provide at least 182 subjects with final assessments to provide 84% power to detect a 25% difference in atrophy rate (therapeutic benefit) change over 12 months at an alpha level of 0.05. Analysis: Intention-to-treat analysis, estimating between-group differences in outcomes derived from appropriate (linear or logistic) multivariable regression models adjusting for minimisation variables.

AIMS AND OBJECTIVES: To explore hospice, acute care and nursing home nurses' experiences of pain management for people with advanced dementia in the final month of life. To identify the challenges, facilitators and practice areas requiring further support.BACKGROUND: Pain management in end-stage dementia is a fundamental aspect of end of life care; however, it is unclear what challenges and facilitators nurses experience in practice, whether these differ across care settings, and whether training needs to be tailored to the context of care.DESIGN: A qualitative study using semi-structured interviews and thematic analysis to examine data.METHODS: 24 registered nurses caring for people dying with advanced dementia were recruited from ten nursing homes, three hospices, and two acute hospitals across a region of the United Kingdom. Interviews were conducted between June 2014 and September 2015.RESULTS: Three core themes were identified: challenges administering analgesia, the nurse-physician relationship, and interactive learning and practice development. Patient-related challenges to pain management were universal across care settings; nurse- and organisation-related barriers differed between settings. A need for interactive learning and practice development, particularly in pharmacology, was identified.CONCLUSIONS: Achieving pain management in practice was highly challenging. A number of barriers were identified; however, the manner and extent to which these impacted on nurses differed across hospice, nursing home and acute care settings. Needs-based training to support and promote practice development in pain management in end-stage dementia is required.RELEVANCE TO CLINICAL PRACTICE: Nurses considered pain management fundamental to end of life care provision; however, nurses working in acute care and nursing home settings may be under-supported and under-resourced to adequately manage pain in people dying with advanced dementia. Nurse-to-nurse mentoring and ongoing needs-assessed interactive case-based learning could help promote practice development in this area. Nurses require continuing professional development in pharmacology. This article is protected by copyright. All rights reserved.

OBJECTIVE: To test the hypothesis that APOE ε4 status and cerebrospinal fluid (CSF) Aβ42, 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 Aβ42 (P < 0.01) were independent predictors of postoperative delirium.CONCLUSIONS: This study is the first to show an independent association between CSF Aβ42 and delirium incidence in an elective surgical population, suggesting that postoperative delirium may indicate incipient Alzheimer disease.

Background Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue currently approved for type 2 diabetes and obesity. Preclinical evidence in transgenic models of Alzheimer’s disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the proliferation of neuronal progenitor cells. The primary objective of the study is to evaluate the change in cerebral glucose metabolic rate after 12 months of treatment with liraglutide in participants with Alzheimer’s disease compared to those who are receiving placebo. Methods/design ELAD is a 12-month, multi-centre, randomised, double-blind, placebo-controlled, phase IIb trial of liraglutide in participants with mild Alzheimer’s dementia. A total of 206 participants will be randomised to receive either liraglutide or placebo as a daily injection for a year. The primary outcome will be the change in cerebral glucose metabolic rate in the cortical regions (hippocampus, medial temporal lobe, and posterior cingulate) from baseline to follow-up in the treatment group compared with the placebo group. The key secondary outcomes are the change from baseline to 12 months in z scores for clinical and cognitive measures (Alzheimer’s Disease Assessment Scale—Cognitive Subscale and Executive domain scores of the Neuropsychological Test Battery, Clinical Dementia Rating Sum of Boxes, and Alzheimer’s Disease Cooperative Study—Activities of Daily Living) and the incidence and severity of treatment-emergent adverse events or clinically important changes in safety assessments. Other secondary outcomes are 12-month change in magnetic resonance imaging volume, diffusion tensor imaging parameters, reduction in microglial activation in a subgroup of participants, reduction in tau formation and change in amyloid levels in a subgroup of participants measured by tau and amyloid imaging, and changes in composite scores using support machine vector analysis in the treatment group compared with the placebo group. Discussion Alzheimer’s disease is a leading cause of morbidity worldwide. As available treatments are only symptomatic, the search for disease-modifying therapies is a priority. If the ELAD trial is successful, liraglutide and GLP-1 analogues will represent an important class of compounds to be further evaluated in clinical trials for Alzheimer’s treatment. Trial registration ClinicalTrials.gov, NCT01843075. Registration 30 April 2013. Electronic supplementary material The online version of this article (10.1186/s13063-019-3259-x) contains supplementary material, which is available to authorized users.

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 0.75). The biomarker performance of the two polyamines (spermidine/putrescine) was enhanced by ratio with CSF Aβ42 (ROC > 0.8), and spermidine significantly correlated with Aβ42 (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 Aβ42, and this requires further investigation.

BACKGROUND people with dementia (PWD), and their carers, face challenges with medicines management activities. As interventions to support medicines management for PWD are developed, consideration must be given to the outcomes chosen to measure their effectiveness. A Core Outcome Set (COS) is a minimum set of outcomes to be measured in all trials in a particular clinical area, which seeks to reduce heterogeneity of outcome reporting across trials. OBJECTIVE to develop a COS for trials assessing the effectiveness of medicines management interventions for PWD in primary care. METHODS a comprehensive list of outcomes was compiled through a systematic review and semi-structured interviews with PWD (n = 18), their carers (n = 15), community pharmacists (n = 15) and general practitioners (n = 15). These outcomes were rated by a Delphi panel (n = 52) on a nine-point Likert scale from 1 (limited importance) to 9 (critical) during three sequential rounds of questionnaire distribution. The Delphi panel comprised participants with expertise in dementia and medicines management, including academics and healthcare professionals. An outcome was eligible for inclusion in the COS if ≥70% of participants rated it critical and

Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts. (C) 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Background Mild cognitive impairment (MCI) among an aging global population is a growing challenge for healthcare providers and payers. In many cases, MCI is an ominous portent for dementia. Early and accurate diagnosis of MCI provides a window of opportunity to improve the outcomes using a personalized care plan including lifestyle modifications to reduce the impact of modifiable risk factors (for example, blood pressure control and increased physical activity), cognitive training, dietary advice, and nutritional support. Souvenaid is a once-daily drink containing a mixture of precursors and cofactors (long-chain omega-3 fatty acids, uridine, choline, B vitamins, vitamin C, vitamin E, and selenium), which was developed to support the formation and function of neuronal membranes and synapses. Healthcare providers, patients, and carers require expert advice about the use of Souvenaid. Methods An international panel of experts was convened to review the evidence and to make recommendations about the diagnosis and management of MCI, identification of candidates for Souvenaid, and use of Souvenaid in real-world practice. This article provides a summary of the expert opinions and makes recommendations for clinical practice and future research. Summary of opinion Early diagnosis of MCI requires the use of suitable neuropsychological tests combined with a careful clinical history. A multimodal approach is recommended; dietary and nutritional interventions should be considered alongside individualized lifestyle modifications. Although single-agent nutritional supplements have failed to produce cognitive benefits for patients with MCI, a broader nutritional approach warrants consideration. Evidence from randomized controlled trials suggests that Souvenaid should be considered as an option for some patients with early Alzheimer’s disease (AD), including those with MCI due to AD (prodromal AD). Conclusion Early and accurate diagnosis of MCI provides a window of opportunity to improve the outcomes using a multimodal management approach including lifestyle risk factor modification and consideration of the multinutrient Souvenaid. Electronic supplementary material The online version of this article (10.1186/s13195-019-0528-6) contains supplementary material, which is available to authorized users.

Background: Pain management is a cornerstone of palliative care. The clinical issues encountered by physicians when managing pain in patients dying with advanced dementia, and how these may impact on prescribing and treatment, are unknown. Aim: To explore physicians’ experiences of pain management for patients nearing the end of life, the impact of these on prescribing and treatment approaches, and the methods employed to overcome these challenges. Design: Qualitative, semi-structured interview study exploring barriers to and facilitators of pain management, prescribing and treatment decisions, and training needs. Thematic analysis was used to elicit key themes. Setting/participants: A total of 23 physicians, responsible for treating patients with advanced dementia approaching the end of life, were recruited from primary care ( n = 9), psychiatry ( n = 7) and hospice care ( n = 7). Results: Six themes emerged: diagnosing pain, complex prescribing and treatment approaches, side effects and adverse events, route of administration, importance of sharing knowledge and training needs. Knowledge exchange was often practised through liaison with physicians from other specialities. Cross-speciality mentoring and the creation of knowledge networks were believed to improve pain management in this patient population. Conclusion: Pain management in end-stage dementia is complex, requiring cross-population of knowledge between palliative care specialists and non-specialists, in addition to collateral information provided by other health professionals and patients’ families. Regular, cost- and time-effective mentoring and ongoing professional development are perceived to be essential in empowering physicians to meet clinical challenges in this area.

Background: Delirium is a common post-operative complication, particularly in older adults undergoing major or emergency procedures. It is associated with increased length of intensive care and hospital stay, post-operative mortality and subsequent dementia risk. Current methods of predicting delirium incidence, duration and severity have limitations. Investigation of blood and cerebrospinal fluid (CSF) biomarkers linked to delirium may improve understanding of the underlying pathophysiology, particularly with regard to the extent this is shared or distinct with underlying dementia. Together, these have the potential for development of better risk stratification tools and perioperative interventions. Methods: 200 patients over the age of 70 scheduled for surgery with routine spinal anaesthetic will be recruited from UK hospitals. Their cognitive and functional baseline status will be assessed pre-operatively by telephone. Time-matched CSF and blood samples will be taken at the time of surgery and analysed for known biomarkers of neurodegeneration and neuroinflammation. Patients will be assessed daily for delirium until hospital discharge and will have regular cognitive follow-up for two years. Primary outcomes will be change in modified Telephone Interview for Cognitive Status (TICS-m) score at 12 months and rate of change of TICS-m score. Delirium severity, duration and biomarker levels will be treated as exposures in a random effects linear regression models. PRIMED Risk has received regulatory approvals from Health Research Authority and London – South East Research Ethics Committee. Discussion: The main anticipated output from this study will be the quantification of biomarkers of acute and chronic contributors to cognitive impairment after surgery. In addition, we aim to develop better risk prediction models for adverse cognitive outcomes.

Brain is a lipid-rich tissue, and fatty acids (FAs) play a crucial role in brain function, including neuronal cell growth and development. This study used GC-MS to survey all detectable FAs in the human parietal cortex (Brodmann area 7). These FAs were accurately quantified in 27 cognitively normal age-matched controls, 16 cases of moderate Alzheimer’s disease (AD), 30 severe AD, and 14 dementia with Lewy bodies (DLB). A total of 24 FA species were identified. Multiple comparison procedures, using stepdown permutation tests, noted higher levels of 13 FAs but the majority of changes were in moderate AD and DLB, rather than severe AD. Subjects with moderate AD and DLB pathology exhibited significantly higher levels of a number of FAs (13 FAs and 12 FAs, respectively). These included nervonic, lignoceric, cis-13,16-docosadienoic, arachidonic, cis-11,14,17-eicosatrienoic, erucic, behenic, α-linolenic, stearic, oleic, cis-10-heptanoic, and palmitic acids. The similarities between moderate AD and DLB were quite striking—arachidic acid was the only FA which was higher in moderate AD than control, and was not similarly affected in DLB. Furthermore, there were no significant differences between moderate AD and DLB. The associations between each FA and a number of variables, including diagnosis, age, gender, Aβ plaque load, tau load, and frontal tissue pH, were also investigated. To conclude, the development of AD or DLB pathology affects brain FA composition but, intriguingly, moderate AD neuropathology impacts this to a much greater extent. Post-mortem delay is a potential confounding factor, but the findings here suggest that there could be a more dynamic metabolic response in the earlier stages of the disease pathology.

Background: Age is a major risk factor for most common neurodegenerative diseases. Although an increased research focus on diseases of aging, there is little information regarding the metabolite changes in the aging blood in healthy older adults. Such information could help us to understand neurocognitive changes associated with aging and also further improve the validity and reproducibility of future metabolite biomarkers for neurodegenerative diseases. Materials and Methods: The purpose of this study was to assess how the metabolomic profiles of noncognitively impaired elderly participants changes with aging. Using a targeted liquid chromatography-mass spectrometry/MS metabolomics approach, this study examined 17 noncognitively impaired elderly participants (T0; 78.10 +/- 6.30 y; mini-mental state exam = 29.29 +/- 0.85) and the same 17 subjects were followed-up similar to 5 years later (T5; 83.29 +/- 6.13 y; mini-mental state exam = 27.47 +/- 1.62). Results: The concentrations of 187 plasma metabolites determined were used to build a partial least squares-discriminant model which found that metabolomic profiles taken 5 years (T5) from baseline (T0) were distinctly different (R2= 0.95; Q2 = 0.90). When metabolites levels at T5 were compared with T0, 68 of the 73 phosphatidylcholines, 25 of the 40 acylcarnitines, and 2 of the 14 lysophosphatidylcholines were increased, whereas 3 of the 14 lysophosphatidylcholines and 2 of the 14 sphingomyelins were decreased. Moreover, 20 of the 42 amino acids concentrations were significantly different between the 2 time points. Fourteen amino acids were increased at T5, whereas 6 amino acids were decreased. Conclusions: The plasma metabolome changes with age in elderly, noncognitively impaired subjects, and this could aid in developing valid and sensitive metabolite biomarkers for human disease.

This is a conference abstract from the Alzheimer's Association International Conference 2019 in Los Angeles, California from 14-18 July 2019.

INTRODUCTION:Cerebral small-vessel disease has been implicated in the development of Alzheimer’sdisease (AD). The retinal microvasculature enables non-invasive visualization andevaluation of the systemic microcirculation. We evaluated retinal microvascular parametersin a case-control study of AD patients and cognitively-normal controls. METHODS:Retinal images were computationally analyzed and quantitative retinal parameters (caliber,fractal dimension, tortuosity, and bifurcation) measured. Regression models were used tocompute odds ratios (OR) and confidence intervals (CI) for AD with adjustment forconfounders. RESULTS:Retinal images were available in 213 AD participants and 294 cognitively-normal controls.Persons with lower venular fractal dimension (OR per standard deviation [SD] increase, 0.77[CI: 0.62–0.97]) and lower arteriolar tortuosity (OR per SD increase, 0.78 [CI: 0.63–0.97])were more likely to have AD following appropriate adjustment. DISCUSSION:Patients with AD have a sparser retinal microvascular network and retinal microvascularvariation may represent similar pathophysiological events within the cerebralmicrovasculature of patients with AD.

Few pain studies have made community-dwelling people with dementia (PWD) their focus. The aim of this study was to determine the prevalence of pain among this patient population and to explore medication use. Moreover, we sought to investigate patient and caregiver variables associated with the presence of pain. Community-dwelling PWD and their caregivers were recruited between May 2009 and July 2012 from outpatient memory clinics in Northern Ireland to take part in a face-to-face structured interview with a researcher. Patients' cognitive status and presence of depression were established. A full medication history was taken. Both patients and caregivers were asked to rate patients' pain, at the time of the interview and on an average day, using a 7-point verbal descriptor scale. From the 206 patients who were eligible to take part, 75 patient-caregiver dyads participated in the study (participation rate = 36.4%). The majority of patients (92.0%) had dementia classed as mild or moderate. Pain was commonly reported among the sample, with 57.3% of patients and 70.7% of caregivers reporting patient pain on an average day. Significant differences were found between patients' and caregivers' reports of pain. Two-fifths of patients (40.0%) were prescribed analgesia. Antipsychotic, hypnotic and anxiolytic drug use was low, whereas antidepressant drugs were prescribed more commonly. Presence of pain was unaffected by dementia severity; however, the use of prescribed analgesic medication was a significant predictor of the presence of pain in these patients, whether reported by the patient or their caregiver 'right now' or 'on an average day' (P < 0.001). Patient and caregiver recruitment was challenging, and remains a barrier to research in this area in the future.

IntroductionOxidative stress has been implicated in the pathogenesis of Alzheimer's disease (AD). We investigated associations between serum levels of lipophilic antioxidants and AD.MethodsSerum concentrations of retinol, two forms of vitamin E (α- and γ-tocopherol) and six carotenoids were quantified by high-performance liquid chromatography from patients with AD (n = 251) and cognitively intact controls (n = 308) and assessed by regression analyses.ResultsSerum levels of α-tocopherol and all six carotenoids were significantly lower in patients with AD compared with cognitively intact controls (P < .001). In contrast, γ-tocopherol was significantly higher in the serum of patients with AD (odds ratio = 1.17 [confidence intervals: 1.05–1.31]).DiscussionOur findings implicate compromised serum antioxidant defenses in AD pathogenesis and differing biological roles for vitamin E isoforms. This highlights the need for improved understanding in the balanced upregulation of exogenous antioxidants related to dietary intake or supplement use in future nutritional intervention studies.

BACKGROUND: Alzheimer's disease (AD) prevalence is increasing globally and typically progresses for several years prior to clinical presentation of dementia. Renal dysfunction and vascular disease have been reported in association with dementia in several cross-sectional and longitudinal studies, and may contribute to AD risk. Experimental and observational studies suggest amyloid-β (Aβ) clearance may be impaired in chronic kidney disease (CKD) indicating a mechanism for increased AD risk.OBJECTIVE: The objective of this study was to compare estimated glomerular filtration rate (eGFR) between individuals with AD and cognitively intact controls, controlling for potential confounding factors.METHODS: A cross-sectional, case-control study was carried out in 317 cognitively normal participants and 253 cases with a clinical diagnosis of AD in a UK tertiary care dementia clinic. Associations were considered using logistic regression adjusting for confounding variables (age, APOEɛ4 genotype, systolic blood pressure, education (left school at 14), and smoking status).RESULTS: AD cases were older than cognitively intact controls, had lower MMSE scores, were more likely to have at least one APOEɛ4 allele, had higher rates of smoking, were more likely to be taking aspirin and/or clopidogrel, and had lower blood pressure. We found no significant association between eGFR and AD both before and following adjustment for appropriate confounders.CONCLUSION: This study failed to find an association between eGFR and AD in a cross-sectional sample study of elderly white individuals.

Background: In dementia care, a large number of treatment decisions are made by family carers on behalf of their family member who lacks decisional capacity; advance care planning can support such carers in the decision-making of care goals. However, given the relative importance of advance care planning in dementia care, the prevalence of advance care planning in dementia care is poor. Aim: To evaluate the effectiveness of advance care planning with family carers in dementia care homes. Design: Paired cluster randomized controlled trial. The intervention comprised a trained facilitator, family education, family meetings, documentation of advance care planning decisions and intervention orientation for general practitioners and nursing home staff. Setting/participants: A total of 24 nursing homes with a dementia nursing category located in Northern Ireland, United Kingdom. Family carers of nursing home residents classified as having dementia and judged as not having decisional capacity to participate in advance care planning discussions. Results: The primary outcome was family carer uncertainty in decision-making about the care of the resident (Decisional Conflict Scale). There was evidence of a reduction in total Decisional Conflict Scale score in the intervention group compared with the usual care group (−10.5, 95% confidence interval: −16.4 to −4.7; p < 0.001). Conclusion: Advance care planning was effective in reducing family carer uncertainty in decision-making concerning the care of their family member and improving perceptions of quality of care in nursing homes. Given the global significance of dementia, the implications for clinicians and policy makers include them recognizing the importance of family carer education and improving communication between family carers and formal care providers.

Background: Medication adherence is vital to ensuring optimal patient outcomes, particularly amongst multimorbid older people prescribed multiple medications. Interventions targeting adherence often lack a theoretical underpinning and this may impact on effectiveness. The theoretical domains framework (TDF) of behaviour can aid intervention development by systematically identifying key determinants of medication adherence.\ud \ud \ud Objectives: This study aimed to (i) identify determinants (barriers, facilitators) of adherence to multiple medications from older people's perspectives; (ii) identify key domains to target for behaviour change; and (iii) map key domains to intervention components [behaviour change techniques (BCTs)] that could be delivered in an intervention by community pharmacists.\ud Method\ud \ud Focus groups were conducted with older people (>65 years) receiving ≥4 medications. Questions explored the 12 domains of the TDF (eg “Knowledge,” “Emotion”). Data were analysed using the framework method and content analysis. Identification of key domains and mapping to intervention components (BCTs) followed established methods.\ud \ud \ud Results: Seven focus groups were convened (50 participants). A wide range of determinants were identified as barriers (eg forgetfulness, prioritization of medications) and facilitators (eg social support, personalized routines) of adherence to multiple medications. Eight domains were identified as key targets for behaviour change (eg “Social influences,” “Memory, attention and decision processes,” “Motivation and goals”) and mapped to 11 intervention components (BCTs) to include in an intervention [eg “Social support or encouragement (general),” “Self-monitoring of the behaviour,” “Goal-setting (behaviour)”].\ud \ud \ud Conclusion: This study used a theoretical underpinning to identify potential intervention components (BCTs). Future work will incorporate the selected BCTs into an intervention that will undergo feasibility testing in community pharmacies.