Publications by authors named "Neil Pendleton"

174 Publications

Associations between chronotype and employment status in a longitudinal study of an elderly population.

Chronobiol Int 2022 08 10;39(8):1118-1131. Epub 2022 May 10.

Division of Diabetes, Endocrinology & Gastroenterology, The University of Manchester, Manchester, UK.

Individuals with an 'evening' chronotype tend to sleep and wake later than people described to be 'morning' type if given a free choice. Since early awakening times, due to school and occupation, may be more challenging for those with evening chronotype, they are expected to be at greater risk of adverse health, occupational and educational outcomes. Our objectives are to investigate associations between chronotype and occupational, educational and health outcomes in a longitudinal cohort. We use sleep, sociodemographic and health data from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, 1982 through 2010. The relationship between employment and longitudinal midsleep trajectories were estimated using linear mixed models. Associations between employment status and Cornell Medical Index, Beck Depression Inventory scores, cortisol concentrations at different times of the day stratified by chronotype were estimated using regression. The relationship between chronotype, occupational success, education, and cognition were also examined using regression methods. In older adults, compared to non-employed participants, employed participants get up 0.45 hours earlier. Evening-type employed individuals had earlier midsleep time compared to their non-employed counterparts and had abnormal longitudinal trajectories with an increasing trend as they aged. Employed individuals with evening chronotype had a higher risk of depression than employed morning-types. Moreover, employed individuals with evening chronotype had a higher cortisol concentration at 14:00 h than non-employed individuals. In addition, memory score was lower in individuals with morning chronotype, however processing speed was higher in individuals with morning chronotype compared to evening. Morning-types had a higher age when they finished full time education. Relative to evening-types, those with morning chronotype were 6.5% more likely to be in a job classed as professional or intermediate. Our findings suggest that evening-types are at a disadvantage with regards to occupational, educational and health outcomes in older adults due to their vulnerability to circadian and sleep disruption.
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http://dx.doi.org/10.1080/07420528.2022.2071158DOI Listing
August 2022

Reproductive hormone levels, androgen receptor CAG repeat length and their longitudinal relationships with decline in cognitive subdomains in men: The European Male Ageing Study.

Physiol Behav 2022 08 26;252:113825. Epub 2022 Apr 26.

Geriatric Medicine, University Hospitals Leuven, Leuven, Belgium; Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium. Electronic address:

Objective: It has been proposed that endogenous sex hormone levels may present a modifiable risk factor for cognitive decline. However, the evidence for effects of sex steroids on cognitive ageing is conflicting. We therefore investigated associations between endogenous hormone levels, androgen receptor CAG repeat length, and cognitive domains including visuoconstructional abilities, visual memory, and processing speed in a large-scale longitudinal study of middle-aged and older men.

Methods: Men aged 40-79 years from the European Male Ageing Study (EMAS) underwent cognitive assessments and measurements of hormone levels at baseline and follow-up (mean = 4.4 years, SD ± 0.3 years). Hormone levels measured included total and calculated free testosterone and estradiol, dihydrotestosterone, luteinizing hormone, follicle-stimulating hormone, dehydroepiandrosterone sulphate and sex hormone-binding globulin. Cognitive function was assessed using the Rey-Osterrieth Complex Figure Copy and Recall, the Camden Topographical Recognition Memory and the Digit Symbol Substitution Test. Multivariate linear regressions were used to examine associations between baseline and change hormone levels, androgen receptor CAG repeat length, and cognitive decline.

Results: Statistical analyses included 1,827 and 1,423 participants for models investigating relationships of cognition with hormone levels and CAG repeat length, respectively. In age-adjusted models, we found a significant association of higher baseline free testosterone (β=-0.001, p=0.005) and dihydrotestosterone levels (β=-0.065, p=0.003) with greater decline on Rey-Osterrieth Complex Figure Recall over time. However, these effects were no longer significant following adjustment for centre, health, and lifestyle factors. No relationships were observed between any other baseline hormone levels, change in hormone levels, or androgen receptor CAG repeat length with cognitive decline in the measured domains.

Conclusions: In this large-scale prospective study there was no evidence for an association between endogenous sex hormone levels or CAG repeat length and cognitive ageing in men. These data suggest that sex steroid levels do not affect visuospatial function, visual memory, or processing speed in middle-aged and older men.
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http://dx.doi.org/10.1016/j.physbeh.2022.113825DOI Listing
August 2022

The effect of season of birth on brain epigenome-wide DNA methylation of older adults.

J Dev Orig Health Dis 2022 Jun 26;13(3):367-377. Epub 2021 Jul 26.

Division of Neuroscience & Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.

Perinatal light exposure predisposes towards health and behaviour in adulthood. Season of birth is associated with psychiatric, allergic, cardiovascular and metabolic problems. It has been proposed that early-life environmental light disrupts the development of biological rhythms which, in turn, influence later-life health. However, the mechanisms linking perinatal seasonal light to later-life biological rhythm and health in humans are unknown. In this study, we investigated the association between season of birth and epigenome-wide DNA methylation of two postmortem human brain regions (16 hypothalamus, 14 temporal cortex). We did not find statistically significant differences at the whole epigenome level, either because we lacked statistical power or that no association exists. However, when we examined 24 CpG sites that had the highest significance or differential methylation, we identified regions which may be associated with circadian rhythm entrainment, cholinergic neurotransmission and neural development. Amongst methylation of the core clock genes, we identified that hypothalamus Neuronal PAS Domain Protein 2 (NPAS2) gene has hypermethylated regions in long photoperiod-born individuals. In addition, we found nominal associations between season of birth and genes linked to chronotype and narcolepsy. Season of birth-related brain DNA methylation profile was different than a previously reported blood methylation profile, suggesting a tissue-specific mechanism of perinatal light programming. Overall, we are the first to analyse the relationship between season of birth and human brain DNA methylation. Further studies with larger sample sizes are required to confirm an imprinting effect of perinatal light on the circadian clock.
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http://dx.doi.org/10.1017/S2040174421000453DOI Listing
June 2022

Home-based exercise for people living with frailty and chronic kidney disease: A mixed-methods pilot randomised controlled trial.

PLoS One 2021 1;16(7):e0251652. Epub 2021 Jul 1.

Department of Renal Medicine, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, United Kingdom.

Background: Frailty is associated with adverse health outcomes in people with chronic kidney disease (CKD). Evidence supporting targeted interventions is needed. This pilot randomised controlled trial (RCT) aimed to inform the design of a definitive RCT evaluating the effectiveness of a home-based exercise intervention for pre-frail and frail older adults with CKD.

Methods: Participants were recruited from nephrology outpatient clinics to this two-arm parallel group mixed-methods pilot RCT. Inclusion criteria were: ≥65 years old; CKD G3b-5; and Clinical Frailty Scale score ≥4. Participants categorised as pre-frail or frail using the Frailty Phenotype were randomised to a 12-week progressive multi-component home-based exercise programme or usual care. Primary outcome measures included eligibility, recruitment, adherence, outcome measure completion and participant attrition rate. Semi-structured interviews were conducted with participants to explore trial and intervention acceptability.

Results: Six hundred and sixty-five patients had an eligibility assessment with 217 (33%; 95% CI 29, 36) eligible. Thirty-five (16%; 95% CI 12, 22) participants were recruited. Six were categorised as robust and withdrawn prior to randomisation. Fifteen participants were randomised to exercise and 14 to usual care. Eleven (73%; 95% CI 45, 91) participants completed ≥2 exercise sessions/week. Retained participants completed all outcome measures (n = 21; 100%; 95% CI 81, 100). Eight (28%; 95% CI 13, 47) participants were withdrawn. Fifteen participated in interviews. Decision to participate/withdraw was influenced by perceived risk of exercise worsening symptoms. Participant perceived benefits included improved fitness, balance, strength, well-being, energy levels and confidence.

Conclusions: This pilot RCT demonstrates that progression to definitive RCT is possible provided recruitment and retention challenges are addressed. It has also provided preliminary evidence that home-based exercise may be beneficial for people living with frailty and CKD.

Trial Registration: ISRCTN87708989; https://clinicaltrials.gov/.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251652PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248609PMC
November 2021

Superior Frontal Gyrus Locus DNA Methylation in Alzheimer's Disease.

J Alzheimers Dis Rep 2021 Apr 6;5(1):275-282. Epub 2021 Apr 6.

Department of Life Sciences, Manchester Metropolitan University, Manchester, UK.

Background: The ɛ4 allele is the strongest known genetic risk factor for sporadic Alzheimer's disease (AD). The neighboring gene has also been implicated in AD due to its close proximity to .

Objective: Here we tested whether methylation of the locus may influence ApoE protein levels and AD pathology.

Methods: DNA methylation levels across the locus and ApoE levels were measured in superior frontal gyrus tissues of 62 human brains genotyped for and scored for AD neuropathology.

Results: Methylation levels within the CpG island in the promoter or CpG island in Exon 4 did not differ between ɛ4 carriers versus non-carriers. However, ɛ4 carriers had significantly higher methylation the promoter compared with non-carriers. Although DNA methylation at , promoter region, or did not differ between AD pathological groups, there was a negative association between methylation and CERAD scores. ApoE protein concentrations did not significantly different between ɛ4 carriers and non-carriers, or between AD pathological groups. Finally, there was no correlation between ApoE protein concentrations and DNA methylation levels.

Conclusion: gene methylation may not be affected by genotype, relate to AD pathology or ApoE protein levels in the superior frontal gyrus, though, DNA methylation at the ApoE promoter differed between genotype. DNA methylation at associated with amyloid-β plaques and longitudinal fluid intelligence. In sum, these results suggest a complicated regulation of the locus in the brain in controlling ApoE protein levels and AD neuropathology.
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http://dx.doi.org/10.3233/ADR-201000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150259PMC
April 2021

Social care costs for community-dwelling older people living with frailty.

Health Soc Care Community 2022 05 26;30(3):e804-e811. Epub 2021 May 26.

Academic Unit of Ageing and Stroke Research, University of Leeds, Leeds, UK.

International evidence indicates that older people with frailty are more likely to access social care services, compared to nonfrail older people. There is, however, no robust evidence on costs of social care provided for community-dwelling older people living with frailty in their own homes. The main objective of this study was to examine the relationship between community-dwelling older people living with frailty, defined using the cumulative deficit model, and annual formal social care costs for the 2012-2018 period. A secondary objective was to estimate formal social care spending for every 1% reduction in the number of older people who develop frailty over 1 year. Secondary analysis of prospective cohort data from two large nationally representative community-based cohort studies in England was performed. Respondents aged ≥75 were used in the main analysis and respondents aged 65-74 in sensitivity testing. We used regression tree modelling for formal social care cost analysis including frailty, age, gender, age at completing education and living with partner as key covariates. We employed a minimum node size stopping criteria to limit tree complexity and overfitting and applied 'bootstrap aggregating' to improve robustness. We assessed the impact of an intervention for every 1% decrease in the number of individuals who become frail over 1 year in England. Results show that frailty is the strongest predictor of formal social care costs. Mean social care costs for people who are not frail are £321, compared with £2,895 for individuals with frailty. For every 1% of nonfrail people not transitioning to frailty savings of £4.4 million in annual expenditures on formal social care in England are expected, not including expenditure on care homes. Given considerably higher costs for individuals classed as frail compared to nonfrail, a successful intervention avoiding or postponing the onset of frailty has the potential to considerably reduce social care costs.
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http://dx.doi.org/10.1111/hsc.13450DOI Listing
May 2022

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Neuropsychopharmacology 2021 09 25;46(10):1788-1801. Epub 2021 May 25.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.
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http://dx.doi.org/10.1038/s41386-021-01023-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357785PMC
September 2021

Early changes in visuospatial episodic memory can help distinguish primary age-related tauopathy from Alzheimer's disease.

Neuropathol Appl Neurobiol 2021 12 29;47(7):1114-1116. Epub 2021 May 29.

Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK.

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http://dx.doi.org/10.1111/nan.12726DOI Listing
December 2021

Erratum: Frailty is independently associated with worse health-related quality of life in chronic kidney disease: a secondary analysis of the Frailty Assessment in Chronic Kidney Disease study.

Clin Kidney J 2021 Mar 4;14(3):1035. Epub 2020 May 4.

Department of Renal Medicine, Lancashire Teaching Hospitals NHS Foundation Trust, Preston,UK.

[This corrects the article DOI: 10.1093/ckj/sfz038.].
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http://dx.doi.org/10.1093/ckj/sfaa066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986437PMC
March 2021

Analysis of human total antibody repertoires in TIF1γ autoantibody positive dermatomyositis.

Commun Biol 2021 03 26;4(1):419. Epub 2021 Mar 26.

Division of Population Health, Health Services Research & Primary Care, University of Manchester, Manchester, UK.

We investigate the accumulated microbial and autoantigen antibody repertoire in adult-onset dermatomyositis patients sero-positive for TIF1γ (TRIM33) autoantibodies. We use an untargeted high-throughput approach which combines immunoglobulin disease-specific epitope-enrichment and identification of microbial and human antigens. We observe antibodies recognizing a wider repertoire of microbial antigens in dermatomyositis. Antibodies recognizing viruses and Poxviridae family species are significantly enriched. The identified autoantibodies recognise a large portion of the human proteome, including interferon regulated proteins; these proteins cluster in specific biological processes. In addition to TRIM33, we identify autoantibodies against eleven further TRIM proteins, including TRIM21. Some of these TRIM proteins share epitope homology with specific viral species including poxviruses. Our data suggest antibody accumulation in dermatomyositis against an expanded diversity of microbial and human proteins and evidence of non-random targeting of specific signalling pathways. Our findings indicate that molecular mimicry and epitope spreading events may play a role in dermatomyositis pathogenesis.
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http://dx.doi.org/10.1038/s42003-021-01932-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997983PMC
March 2021

Does the association between cognition and education differ between older adults with gradual or rapid trajectories of cognitive decline?

Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 2021 Mar 8:1-21. Epub 2021 Mar 8.

Cathie Marsh Institute for Social Research, University of Manchester, Manchester, UK.

Education is associated with improved baseline cognitive performance in older adults, but the association with maintenance of cognitive function is less clear. Education may be associated with different types of active cognitive reserve in those following different cognitive trajectories. We used data on n = 5642 adults aged >60 from the English Longitudinal Study of Aging (ELSA) over 5 waves (8 years). We used growth mixture models to test if the association between educational attainment and rate of change in verbal fluency or immediate recall varied by latent class trajectory. For recall, 91.5% (n = 5164) of participants were in a gradual decline class and 8.5% (n = 478) in a rapid decline class. For fluency, 90.0% (n = 4907) were in a gradual decline class and 10.0% (n = 561) were in a rapid decline class. Educational attainment was associated with improved baseline performance for both verbal fluency and recall. In the rapidly declining classes, educational attainment was not associated with rate of change for either outcome. In the verbal fluency gradual decline class, education was associated with higher (an additional 0.05-0.38 words per 2 years) or degree level education (an additional 0.04-0.42 words per 2 years) when compared to those with no formal qualifications. We identified no evidence of a protective effect of education against rapid cognitive decline. There was some evidence of active cognitive reserve for verbal fluency but not recall, which may reflect a small degree of domain-specific protection against age-related cognitive decline.
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http://dx.doi.org/10.1080/13825585.2021.1889958DOI Listing
March 2021

Early life factors and COVID-19 infection in England: A prospective analysis of UK Biobank participants.

Early Hum Dev 2021 04 4;155:105326. Epub 2021 Feb 4.

Division of Informatics, Imaging & Data Sciences, The University of Manchester, UK.

This study aims to examine whether maternal smoking, birth weight, birth month and breastfeeding are associated with COVID-19 infection and hospitalisation. Maternal smoking was positively associated with COVID-19 infection. Breastfeeding was negatively associated with COVID-19 infection. The odds of being hospitalised due to COVID-19 were higher among those who had lower birthweight and mothers who were smoking during pregnancy.
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http://dx.doi.org/10.1016/j.earlhumdev.2021.105326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860946PMC
April 2021

Influence of APOE genotype in primary age-related tauopathy.

Acta Neuropathol Commun 2020 12 7;8(1):215. Epub 2020 Dec 7.

Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, Salford Royal Hospital, The University of Manchester, Salford, M6 8HD, UK.

The term "Primary age-related tauopathy" (PART) was coined in 2014 to describe the common neuropathological observation of neurofibrillary tangles without associated beta-amyloid (Aβ) pathology. It is possible for PART pathology to be present in both cognitively normal and cognitively impaired individuals. Genetically, Apolipoprotein E (APOE) ε4 has been shown to occur less commonly in PART than in Alzheimer's disease (AD). Here, we investigate the relationships between PART, AD and those pathologically normal for age, with an emphasis on APOE and cognition, using 152 selected participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age and the Manchester arm of the Brains for Dementia Research cohort. APOE genotype differed between PART and AD with APOE ε2 more common in the former and APOE ε4 more common in the latter. Individuals with definite PART were less likely to be cognitively impaired than those with AD and those with pathology considered pathologically normal for age. We postulate that the lack of Aβ in definite PART cases may be due either to an increased frequency of APOE ε2 or decreased frequency of APOE ε4 as their resulting protein isoforms have differing binding properties in relation to Aβ. Similarly, an increased frequency of APOE ε2 or decreased frequency of APOE ε4 may lead to decreased levels of cognitive impairment, which raises questions regarding the impact of Aβ pathology on overall cognition in elderly subjects. We suggest that it may be possible to use the increased frequency of APOE ε2 in definite PART to assist neuropathological diagnosis.
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http://dx.doi.org/10.1186/s40478-020-01095-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720601PMC
December 2020

Mid to late-life scores of depression in the cognitively healthy are associated with cognitive status and Alzheimer's disease pathology at death.

Int J Geriatr Psychiatry 2021 05 20;36(5):713-721. Epub 2020 Nov 20.

Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK.

Objectives: Early diagnosis of Alzheimer's disease (AD) is essential for early interventions. Symptoms of depression could represent a prodromal stage of AD. Very early mood alterations may help to stratify those at highest risk of late-life AD. We aim to investigate associations between baseline/longitudinal scores for depression, presence of cognitive impairment and/or AD pathology at death.

Methods/design: Between 1991 and 2015, participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age underwent 10 waves of assessment using the Geriatric Depression Scale (GDS). AD pathology at death was evaluated in 106 eligible cases. Analyses aimed to examine associations between GDS scores, cognitive status and AD pathology (as measured by Braak stage, Thal phase and CERAD).

Results: Baseline GDS scores were significantly higher for those cognitively impaired at death than those cognitively normal. Significantly higher baseline GDS scores were found for those with greater Consortium to Establish a Registry for Alzheimer's Disease (CERAD) scores than those with lower CERAD scores. Similarly, significantly higher baseline GDS scores were found for those with a greater Braak stage than those with lower tau burden. These correlations remained after controlling for age at death, education and APOE ε4, but were less robust. Mean longitudinal GDS scores associated with cognition but not pathology.

Conclusions: GDS scores collected approximately 20 years before death were associated with cognitive status and AD pathology at death. We postulate that early AD-related pathological change produces raised GDS scores due to an overlapping neural basis with depression, and that this may be considered as an early diagnostic marker for AD.
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http://dx.doi.org/10.1002/gps.5470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048934PMC
May 2021

Implementation of a frailty screening programme and Geriatric Assessment Service in a nephrology centre: a quality improvement project.

J Nephrol 2021 Aug 10;34(4):1215-1224. Epub 2020 Oct 10.

Department of Renal Medicine, Lancashire Teaching Hospitals NHS Foundation Trust, Royal Preston Hospital, Sharoe Green Lane, Preston, PR2 9HT, UK.

Introduction: The aims of this quality improvement project were to: (1) proactively identify people living with frailty and CKD; (2) introduce a practical assessment, using the principles of the comprehensive geriatric assessment (CGA), for people living with frailty and chronic kidney disease (CKD) able to identify problems; and (3) introduce person-centred management plans for people living with frailty and CKD.

Methods: A frailty screening programme, using the Clinical Frailty Scale (CFS), was introduced in September 2018. A Geriatric Assessment (GA) was offered to patients with CFS ≥ 5 and non-dialysis- or dialysis-dependent CKD. Renal Frailty Multidisciplinary Team (MDT) meetings were established to discuss needs identified and implement a person-centred management plan.

Results: A total of 450 outpatients were screened using the CFS. One hundred and fifty patients (33%) were screened as frail. Each point increase in the CFS score was independently associated with a hospitalisation hazard ratio of 1.35 (95% CI 1.20-1.53) and a mortality hazard ratio of 2.15 (95% CI 1.63-2.85). Thirty-five patients received a GA and were discussed at a MDT meeting. Patients experienced a median of 5.0 (IQR 3.0) problems, with 34 (97%) patients experiencing at least three problems.

Conclusions: This quality improvement project details an approach to the implementation of a frailty screening programme and GA service within a nephrology centre. Patients living with frailty and CKD at risk of adverse outcomes can be identified using the CFS. Furthermore, a GA can be used to identify problems and implement a person-centred management plan that aims to improve outcomes for this vulnerable group of patients.
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http://dx.doi.org/10.1007/s40620-020-00878-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357770PMC
August 2021

Healthcare system performance and socioeconomic inequalities in hearing and visual impairments in 17 European countries.

Eur J Public Health 2021 02;31(1):79-86

Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

Background: Socioeconomic status is associated with health status among older adults, including hearing and vision impairments, and healthcare system performance is an important consideration in examining that association. We explored the link between a country's healthcare system performance and the hearing and visual impairments of its people in Europe.

Methods: This study enrolled 65 332 individuals aged 50+ from 17 countries participating in the Survey of Health, Ageing and Retirement in Europe Wave 6. We used latent class analysis to identify groups of countries based on six domains of healthcare system performance. We then performed multiple logistic regressions to quantify the association between socioeconomic status and hearing and visual impairments adjusted for demographic and other co-variates; finally, we compared the patterns of observed associations in each of the country groups.

Results: The latent class analysis separated countries into three groups based on the performance of their healthcare systems: poor, moderate and high. Respondents in countries with moderate and poor healthcare performance were more likely to experience hearing and visual impairment than those in countries with high healthcare performance. With respect to hearing and visual impairments, wealth gradients at the individual level varied among countries in different healthcare performance groups, with less wealth associated with worse hearing and seeing only in the countries with moderate and poor healthcare performance.

Conclusion: The relationships between wealth and hearing and visual impairments differ among countries with different healthcare performance.
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http://dx.doi.org/10.1093/eurpub/ckaa155DOI Listing
February 2021

Cognitively stimulating activities and risk of probable dementia or cognitive impairment in the English Longitudinal Study of Ageing.

SSM Popul Health 2020 Dec 26;12:100656. Epub 2020 Aug 26.

Cathie Marsh Institute for Social Research, Humanities Bridgeford Street Building, University of Manchester, Manchester, M13 9PL, UK.

Objectives: To examine the association between cognitive stimulating activities (CSA) in later life (internet/email use, employment, volunteering, evening classes, social club membership and newspaper reading) and risk of cognitive impairment or dementia using marginal structural models to account for time-varying confounding affected by prior exposure.

Methods: Data were used from the English Longitudinal Study of Ageing waves 1 (2002) to 7 (2014), a nationally representative sample of adults in England aged ≥50. Self-reported participation in CSAs were measured as binary exposures from waves 2 (2004) to 6 (2012), with final sample sizes between n = 3937 and n = 2530 for different CSAs. Baseline exposure and covariates were used to create inverse probability of treatment and censoring weights (IPTCW). IPTCW repeated measures Poisson and linear regression were used to estimate each CSAs effect on risk of probable cognitive impairment or dementia at wave 7 (defined as a score of ≤11/27 on a modified telephone interview for cognitive status (TICS-27)). Results were compared to standard regression adjustment.

Results: Internet use at any wave (Risk ratios between 0.62 and 0.69) and volunteering in waves 3 to 6 (RRs between 0.516 and 0.633) were associated with reduced risk of cognitive impairment in IPTCW models. Standard estimates were similar for both internet use and volunteering.Newspaper reading (RR 95% Confidence interval 0.74-0.99) and social club membership (RR 95% CI 0.54-0.86) at wave 6 were significantly associated with risk of cognitive impairment in standard models, but not in the IPTCW models (RR 95% CI 0.82-1.11 and 0.60-1.08 respectively). Employment and evening classes were not associated with cognitive impairment in either model.

Conclusions: We found that volunteering and internet use were associated with reduced risk of cognitive impairment. Associations between newspaper reading or social club membership and cognitive impairment may be due to time-varying confounding affected by prior exposure.
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http://dx.doi.org/10.1016/j.ssmph.2020.100656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495111PMC
December 2020

Epigenetic Regulation of BMAL1 with Sleep Disturbances and Alzheimer's Disease.

J Alzheimers Dis 2020 ;77(4):1783-1792

Department of Life Sciences, Manchester Metropolitan University, Manchester, United Kingdom.

Background: An early symptom of Alzheimer's disease (AD) is a disturbance of the circadian rhythm that is associated with disrupted sleep/wake cycles.

Objective: To investigate if BMAL1, a key gene that drives the circadian cycle, is epigenetically regulated in brains in relation to longitudinal changes in cognition, sleep quality, and AD neuropathology.

Methods: Frontal cortex tissues were acquired from the Manchester Brain Bank (N = 96). DNA methylation at six CpG sites at the promoter of BMAL1, determined using bisulfite pyrosequencing, was tested for associations with Braak stage, CERAD score and Thal phase, longitudinal changes in cognition, sleep measurements and cross-section measures of depressive symptoms (BDI score).

Results: Methylation across all the CpGs strongly correlated with each other. We found increased CpG2 methylation with higher Braak (t(92), p = 0.015) and CERAD (t(94), p = 0.044) stages. No significance was found between longitudinal fluid intelligence, processing speed and memory tests, but methylation at CpG1 (r = 0.20, p = 0.05) and CpG4 (r = 0.20, p = 0.05) positively correlated with vocabulary. CpG2 positively correlated with cross-sectional fluid intelligence (r = 0.20 p = 0.05) and vocabulary (r = 0.22 p = 0.03). Though longitudinal analysis revealed no significance between sleep duration, midsleep and efficiency for any of the CpG sites, CpG3 (B = 0.03, 95% CI, p = 0.03) and CpG5 (B = 0.04, 95% CI, p = 0.01) significantly correlated with night wake. CpG4 correlated with depressive symptoms (B = -0.27, 95% CI, p = 0.02).

Conclusion: Methylation of BMAL1 associated with tau pathology, changes in cognitive measures, a measure of sleep and depressive symptoms, suggesting an involvement of the circadian cycle.
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http://dx.doi.org/10.3233/JAD-200634DOI Listing
September 2021

Influence of Genotype on Mortality and Cognitive Impairment.

J Alzheimers Dis Rep 2020 Jul 23;4(1):281-286. Epub 2020 Jul 23.

Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK.

While many studies have examined the associations between genotype and mortality, findings have often been conflicting and it remains unclear whether genotype affects longevity. Using selected individuals from the Manchester arm of the Brains for Dementia Research programme and University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, we investigated relationships between genotype and age at death in both cognitively normal and cognitively impaired individuals. Results indicated that carrying the 4 allele led to a reduced chance in an individual reaching 80+ years and remaining cognitively healthy. Conversely, 2 carriers tended to live longer and remain cognitively normal. These findings add to the evidence that genotype influences longevity, especially in cognitively impaired individuals who carry the 4 allele.
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http://dx.doi.org/10.3233/ADR-200203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458549PMC
July 2020

Normative Estimates and Agreement Between 2 Measures of Health-Related Quality of Life in Older People With Frailty: Findings From the Community Ageing Research 75+ Cohort.

Value Health 2020 08 18;23(8):1056-1062. Epub 2020 Jul 18.

Academic Unit of Elderly Care and Rehabilitation, Bradford Institute for Health Research, Bradford Teaching Hospital NHS Foundation Trust, Bradford, Leeds Institute of Health Sciences, Leeds, England, UK.

Background: Previous studies have summarized evidence on health-related quality of life for older people, identifying a range of measures that have been validated, but have not sought to present results by degree of frailty. Furthermore, previous studies did not typically use quality-of-life measures that generate an overall health utility score. Health utility scores are a necessary component of quality-adjusted life-year calculations used to estimate the cost-effectiveness of interventions.

Methods: We calculated normative estimates in mean and standard deviation for EQ-5D-5L, short-form 36-item health questionnaire in frailty (SF-36), and short-form 6-dimension (SF-6D) for a range of established frailty models. We compared response distributions across dimensions of the measures and investigated agreement using Bland-Altman and interclass correlation techniques.

Results: The EQ-5D-5L, SF-36, and SF-6D scores decrease and their variability increases with advancing frailty. There is strong agreement between the EQ-5D-5L and SF-6D across the spectrum of frailty. Agreement is lower for people who are most frail, indicating that different components of the 2 instruments may have greater relevance for people with advancing frailty in later life. There is a greater risk of ceiling effects using the EQ-5D-5L rather than the SF-6D.

Conclusions: We recommend the SF-36/SF-6D as an appropriate measure of health-related quality of life for clinical trials if fit older people are the planned target. In trials of interventions involving older people with increasing frailty, we recommend that both the EQ-5D-5L and SF36/SF6D are included, and are used in sensitivity analyses as part of cost-effectiveness evaluation.
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http://dx.doi.org/10.1016/j.jval.2020.04.1830DOI Listing
August 2020

The Contribution of Vascular Pathology Toward Cognitive Impairment in Older Individuals with Intermediate Braak Stage Tau Pathology.

J Alzheimers Dis 2020 ;77(3):1005-1015

Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK.

Background: The pathological features of Alzheimer's disease (AD) are well described but little is known as to how both neurodegeneration and vascular changes might interact in causing cognitive impairment.

Objective: The present study aims to investigate relationships between vascular and AD pathology in cognitively healthy and cognitively impaired individuals with a particular emphasis on those at intermediate Braak tau stages.

Methods: We investigated the interplay between Braak tau stage and measures of vascular pathology as described by the vascular cognitive impairment neuropathology guidelines (VCING) in 185 brains from the Brains for Dementia Research programme and The University of Manchester Longitudinal Study of Cognition in Healthy Old Age. VCING asserts that at least one large (>10 mm) infarct, moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, and moderate/severe arteriosclerosis in occipital white matter accurately predicts the contribution of cerebrovascular pathology to cognitive impairment.

Results: We found that the extent of arteriosclerosis in the occipital white matter did not differ between cognitive groups at intermediate (III-IV) Braak stages whereas moderate/severe leptomeningeal occipital cerebral amyloid angiopathy was greater in cognitively impaired than normal individuals at Braak stage III-IV. This finding remained significant after controlling for effects of age, sex, CERAD score, Thal phase, presence/severity of primary age-related tauopathy, presence/severity of limbic-predominant age-related TDP43 encephalopathy and small vessel disease in basal ganglia.

Conclusion: Interventions targeting cerebral amyloid angiopathy may contribute to delay the onset of cognitive impairment in individuals with intermediate Alzheimer's type pathology.
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http://dx.doi.org/10.3233/JAD-200339DOI Listing
September 2021

The EX-FRAIL CKD trial: a study protocol for a pilot randomised controlled trial of a home-based EXercise programme for pre-frail and FRAIL, older adults with Chronic Kidney Disease.

BMJ Open 2020 06 22;10(6):e035344. Epub 2020 Jun 22.

Department of Renal Medicine, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, Lancashire, UK.

Introduction: Frailty is highly prevalent in adults with chronic kidney disease (CKD) and is associated with adverse health outcomes including falls, poorer health-related quality of life (HRQOL), hospitalisation and mortality. Low physical activity and muscle wasting are important contributors to physical frailty in adults with CKD. Exercise training may improve physical function and frailty status leading to associated improvements in health outcomes, including HRQOL. The EX-FRAIL CKD trial aims to inform the design of a definitive randomised controlled trial (RCT) that investigates the effectiveness of a progressive, multicomponent home-based exercise programme in prefrail and frail older adults with CKD.

Methods And Analysis: The EX-FRAIL CKD trial is a two-arm parallel group pilot RCT. Participants categorised as prefrail or frail, following Frailty Phenotype (FP) assessment, will be randomised to receive exercise or usual care. Participants randomised to the intervention arm will receive a tailored 12-week exercise programme, which includes weekly telephone calls to advise on exercise progression. Primary feasibility outcome measures include rate of recruitment, intervention adherence, outcome measure completion and participant attrition. Semistructured interviews with a purposively selected group of participants will inform the feasibility of the randomisation procedures, outcome measures and intervention. Secondary outcome measures include physical function (walking speed and Short Physical Performance Battery), frailty status (FP), fall concern (Falls Efficacy Scale-International tool), activities of daily living (Barthel Index), symptom burden (Palliative care Outcome Scale-Symptoms RENAL) and HRQOL (Short Form-12v2).

Ethics And Dissemination: Ethical approval was granted by a National Health Service (NHS) Regional Ethics Committee and the NHS Health Research Authority. The study team aims to publish findings in a peer-reviewed journal and presents the results at relevant national and international conferences. A summary of findings will be provided to participants, a local kidney patient charity and the funding body.

Trial Registration Number: ISRCTN87708989.
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http://dx.doi.org/10.1136/bmjopen-2019-035344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311028PMC
June 2020

Trajectories of recall memory as predictive of hearing impairment: A longitudinal cohort study.

PLoS One 2020 18;15(6):e0234623. Epub 2020 Jun 18.

Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.

Objectives: Accumulating evidence points to a relationship between hearing function and cognitive ability in later life. However, the exact mechanisms of this relationship are still unclear. This study aimed to characterise latent cognitive trajectories in recall memory and identify their association with subsequent risk of hearing impairment.

Methods: We analysed data from the English Longitudinal Study of Ageing Wave 1 (2002/03) until Wave 7 (2014/15). The study population consisted of 3,615 adults aged 50+ who participated in the first wave of the English Longitudinal Study of Ageing, who had no self-reported hearing impairment in Wave 1, and who underwent a hearing test in Wave 7. Respondents were classified as having hearing impairment if they failed to hear tones quieter than 35 dB HL in the better ear.

Results: The trajectories of recall memory scores were grouped using latent class growth mixture modelling and were related to the presence of hearing impairment in Wave 7. Models estimating 1-class through 5-class recall memory trajectories were compared and the best-fitting models were 4-class trajectories. The different recall memory trajectories represent different starting points and mean of the memory scores. Compared to respondents with the highest recall memory trajectory, other trajectories were increasingly likely to develop later hearing impairment.

Conclusions: Long-term changes in cognitive ability predict hearing impairment. Further research is required to identify the mechanisms explaining the association between cognitive trajectories and hearing impairment, as well as to determine whether intervention for maintenance of cognitive function also give benefit on hearing function among older adults.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234623PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302912PMC
August 2020

Regulation of interleukin 6 by a polymorphic CpG within the frontal cortex in Alzheimer's disease.

Neurobiol Aging 2020 08 15;92:75-81. Epub 2020 Apr 15.

Department of Life Sciences, Bioscience Research Centre, Manchester Metropolitan University, Manchester, UK. Electronic address:

The cytokine interleukin 6 (IL-6) has been linked to the pathogenesis of Alzheimer's disease (AD). This is the first study to investigate the genetic and epigenetic interactions in the control of IL-6 in human brain and its relation to AD neuropathology in prefrontal cortex tissues from AD and controls genotyped for the SNP -174 C/G rs1800795, a polymorphic CpG in which the G allele creates a CpG site. Within CC homozygotes there were significantly higher brain levels of IL-6 protein compared to G allele carriers. The C allele that resulted in an absence of methylation at a CpG was also associated with significant changes in methylation at neighboring CpGs. Furthermore, there were significant differences in methylation between CC and CG/GG at CpG sites in the AD and control groups. That DNA methylation was altered in the brains by the presence of rs1800795, which further correlated with protein levels suggests the presence of a polymorphic CpG and genetic-epigenetic interactions in the regulation of IL-6 in the prefrontal cortex within AD brains.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.04.008DOI Listing
August 2020

Interactions between season of birth, chronological age and genetic polymorphisms in determining later-life chronotype.

Mech Ageing Dev 2020 06 1;188:111253. Epub 2020 May 1.

Division of Informatics, Imaging & Data Sciences, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK.

Human chronotype, the temporal pattern of daily behaviors, is influenced by postnatal seasonal programming and ageing. The aim of this study was to investigate genetic variants that are associated with season of birth programming and longitudinal chronotype change. Longitudinal sleep timing and genotype data from 1449 participants were collected for up to 27 years. Gene-environment interaction analysis was performed for 445 candidate single nucleotide polymorphisms that have previously been associated with chronotype. Associations were tested using linear mixed model. We identified 67 suggestively significant genomic loci that have genotype-ageing interaction and 25 genomic loci that may have genotype-season of birth interaction in determining chronotype. We attempted to replicate the results using longitudinal data of the UK Biobank from approximately 30,000 participants. Biological functions of these genes suggest that epigenetic regulation of gene expression and neural development may have roles in these processes. The strongest associated gene for sleep trajectories was ALKBH5, which has functions of DNA repair and epigenetic regulation. A potential candidate gene for postnatal seasonal programming was SIRT1, which has previously been implicated in postnatal programming, ageing and longevity. Genetic diversity may explain the heterogeneity in ageing-related change of sleep timing and postnatal environmental programming of later-life chronotype.
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http://dx.doi.org/10.1016/j.mad.2020.111253DOI Listing
June 2020

Study protocol for a cluster randomised controlled feasibility trial evaluating personalised care planning for older people with frailty: PROSPER V2 27/11/18.

Pilot Feasibility Stud 2020 28;6:56. Epub 2020 Apr 28.

1Academic Unit for Ageing and Stroke Research, University of Leeds, Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, BD9 6RJ UK.

Background: Frailty is characterised by increased vulnerability to falls, disability, hospitalisation and care home admission. However, it is relatively reversible in the early stages. Older people living with frailty often have multiple health and social issues which are difficult to address but could benefit from proactive, person-centred care. Personalised care planning aims to improve outcomes through better self-management, care coordination and access to community resources.

Methods: This feasibility cluster randomised controlled trial aims to recruit 400 participants from 11 general practice clusters across Bradford and Leeds in the north of England. Eligible patients will be aged over 65 with an electronic frailty index score of 0.21 (identified via their electronic health record), living in their own homes, without severe cognitive impairment and not in receipt of end of life care. After screening for eligible patients, a restricted 1:1 cluster-level randomisation will be used to allocate practices to the PROSPER intervention, which will be delivered over 12 weeks by a personal independence co-ordinator worker, or usual care. Following initial consent, participants will complete a baseline questionnaire in their own home including measures of health-related quality of life, activities of daily living, depression and health and social care resource use. Follow-up will be at six and 12 months. Feasibility outcomes relate to progression criteria based around recruitment, intervention delivery, retention and follow-up. An embedded process evaluation will contribute to iterative intervention optimisation and logic model development by examining staff training, intervention implementation and contextual factors influencing delivery and uptake of the intervention.

Discussion: Whilst personalised care planning can improve outcomes in long-term conditions, implementation in routine settings is poor. We will evaluate the feasibility of conducting a cluster randomised controlled trial of personalised care planning in a community population based on frailty status. Key objectives will be to test fidelity of trial design, gather data to refine sample size calculation for the planned definitive trial, optimise data collection processes and optimise the intervention including training and delivery.

Trial Registration: ISRCTN12363970 - 08/11/18.
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http://dx.doi.org/10.1186/s40814-020-00598-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187486PMC
April 2020

Seasonality and season of birth effect in the UK Biobank cohort.

Am J Hum Biol 2020 11 28;32(6):e23417. Epub 2020 Mar 28.

Division of Informatics, Imaging & Data Sciences, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.

Objectives: Humans live in environments that reduce the impact of seasonal cues. However, studies suggest that many aspects of human biology, such as birth, metabolism, health, and death are still annually rhythmic.

Methods: Using UK Biobank, a large (N = 502 536) population-based resource, we investigated the influence of seasonality on birth rate, basal metabolic rate, health, reaction speed, and sleep. We also investigated the association between season of birth and regional brain volumes, basal metabolic rate, health, reaction speed, and sleep.

Results: Our results showed that annual birth rate peaks in April and May. Individuals had the highest basal metabolic rate in December and January. Poorer subjective general health and slower reaction time were observed in May. Susceptibility to insomnia showed an opposite trend that peaked in autumn and winter. People reported shorter periods of sleep, easier waking, earlier chronotype, more daytime dozing, and napping in summer compared with winter. Our results suggest that season of birth may influence later-life characteristics. We also observed that the effect of season of birth is in the opposite direction of the seasonal rhythm for basal metabolic rate, reaction time, and insomnia. Moreover, our analysis showed that prevalence of allergy is higher among people born in spring compared to autumn.

Conclusions: Overall, our findings indicate a significant effect of seasonality on a range of human traits and that early-life seasons appear to have an effect on health and behaviors in adulthood.
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http://dx.doi.org/10.1002/ajhb.23417DOI Listing
November 2020

Frailty is independently associated with worse health-related quality of life in chronic kidney disease: a secondary analysis of the Frailty Assessment in Chronic Kidney Disease study.

Clin Kidney J 2020 02 30;13(1):85-94. Epub 2019 Apr 30.

Department of Renal Medicine, Lancashire Teaching Hospitals NHS Foundation Trust, Preston,UK.

Background: Understanding how frailty affects health-related quality of life (HRQOL) in those with chronic kidney disease (CKD) could assist in the development of management strategies to improve outcomes for this vulnerable patient group. This study aimed to evaluate the relationship between frailty and HRQOL in patients with CKD Stages 4 and 5 (G4–5) and those established on haemodialysis (G5D).

Methods: Ninety participants with chronic kidney disease (CKD G4–5D) were recruited between December 2016 and December 2017. Frailty was assessed using the Frailty Phenotype, which included assessments of unintentional weight loss, weakness (handgrip strength), slowness (walking speed), physical activity and self-perceived exhaustion. HRQOL was assessed using the RAND 36-Item Health Survey Version 1.0 (SF-36).

Results: Nineteen (21%) patients were categorized as frail. Frailty, when adjusted for age, gender, dialysis dependence and comorbidity, had a significant effect on five of the eight SF-36 domains: physical functioning, role limitations due to emotional problems, energy/fatigue, social functioning and pain. Regression modelling best explained the variation in the physical functioning domain (adj. R2 = 0.27, P < 0.001), with frailty leading to a 26-point lower score. Exhaustion was the only Frailty Phenotype component that had a significant effect on scores across all SF-36 domains.

Conclusions: Frailty is independently associated with worse HRQOL in patients with CKD G4–5D, with self-perceived exhaustion being the most significant Frailty Phenotype component contributing to HRQOL. Efforts should be made to identify frail patients with CKD so that management strategies can be offered that aim to improve morbidity, mortality and patient-reported outcomes, including HRQOL and fatigue.
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http://dx.doi.org/10.1093/ckj/sfz038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025341PMC
February 2020

A Comparative Study of Pathological Outcomes in The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age and Brains for Dementia Research Cohorts.

J Alzheimers Dis 2020 ;73(2):619-632

Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Neuroscience & Experimental Psychology, The University of Manchester, Salford Royal Hospital, Salford, UK.

In the present study, we have characterized and compared individuals whose brains were donated as part of The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age (UoM) with those donated through the Manchester arm of the UK Brains for Dementia Research (BDR) program. The aim of this study was to investigate how differences in study recruitment may affect final pathological composition of cohort studies. The UoM cohort was established as a longitudinal study of aging and cognition whereas the BDR program was established, prima facie, to collect brains from both demented and non-demented individuals for the purpose of building a tissue research resource. Consequently, the differences in recruitment patterns generated differences in demographic, clinical, and neuropathological characteristics. There was a higher proportion of recruits with dementia [mostly Alzheimer's disease (AD)] within the BDR cohort than in the UoM cohort. In pathological terms, the BDR cohort was more 'polarized', being more composed of demented cases with high Braak pathology scores and non-demented cases with low Braak scores, and fewer non-AD pathology cases, than the UoM cohort. In both cohorts, cerebral amyloid angiopathy tended to be greater in demented than non-demented individuals. Such observations partly reflect the recruitment of demented and non-demented individuals into the BDR cohort, and also that insufficient study time may have elapsed for disease onset and development in non-demented individuals to take place. Conversely, in the UoM cohort, where there had been nearly 30 years of study time, a broader spread of AD-type pathological changes had 'naturally' evolved in the brains of both demented and non-demented participants.
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http://dx.doi.org/10.3233/JAD-190580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029329PMC
November 2020

Metabolic dysregulation in vitamin E and carnitine shuttle energy mechanisms associate with human frailty.

Nat Commun 2019 11 5;10(1):5027. Epub 2019 Nov 5.

School of Chemistry, Manchester Institute for Biotechnology, University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK.

Global ageing poses a substantial economic burden on health and social care costs. Enabling a greater proportion of older people to stay healthy for longer is key to the future sustainability of health, social and economic policy. Frailty and associated decrease in resilience plays a central role in poor health in later life. In this study, we present a population level assessment of the metabolic phenotype associated with frailty. Analysis of serum from 1191 older individuals (aged between 56 and 84 years old) and subsequent longitudinal validation (on 786 subjects) was carried out using liquid and gas chromatography-mass spectrometry metabolomics and stratified across a frailty index designed to quantitatively summarize vulnerability. Through multivariate regression and network modelling and mROC modeling we identified 12 significant metabolites (including three tocotrienols and six carnitines) that differentiate frail and non-frail phenotypes. Our study provides evidence that the dysregulation of carnitine shuttle and vitamin E pathways play a role in the risk of frailty.
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http://dx.doi.org/10.1038/s41467-019-12716-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831565PMC
November 2019
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