Publications by authors named "Michael A Horan"

25 Publications

  • Page 1 of 1

Telephone Interview for Cognitive Status Scores Associate with Cognitive Impairment and Alzheimer's Disease Pathology at Death.

J Alzheimers Dis 2021 ;84(2):609-619

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: Early diagnosis of Alzheimer's disease (AD) provides an opportunity for early intervention. Cognitive testing has proven to be a reliable way to identify individuals who may be at risk of AD. The Telephone Assessment for Cognitive Screening (TICS) is proficient in screening for cognitive impairment. However, its ability to identify those at risk of developing AD pathology is unknown.

Objective: We aim to investigate associations between TICS scores, collected over a period of 13 years, and the cognitive status of participants at death. We also examine relationships between TICS scores and neuropathological indices of AD (CERAD score, Thal phase, and Braak stage).

Methods: Between 2004 and 2017, participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age underwent cognitive assessment using TICS. Scores from four time points were available for analysis. Cognitive impairment and AD pathology at death was evaluated in 101 participants.

Results: TICS scores at time points 2, 3, and 4 were significantly lower in those cognitively impaired at death compared to those considered cognitively normal. There were significant negative correlations between TICS scores and CERAD score and Braak stage at time points 2 and 4. No correlations between Thal phase and TICS were found.

Conclusion: Findings indicate that TICS could be used not only to screen for cognitive impairment, but also to identify individuals at risk of developing AD pathology, many years before any overt symptoms occur. Once identified, 'at risk' individuals could be targeted for early interventions which could attenuate the progression of the disease.
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http://dx.doi.org/10.3233/JAD-215102DOI Listing
January 2022

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

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

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

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

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

No association between head injury with loss of consciousness and Alzheimer disease pathology-Findings from the University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age.

Int J Geriatr Psychiatry 2019 08 10;34(8):1262-1266. Epub 2019 May 10.

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

Objectives: Head injury with loss of consciousness (HI-LOC) is a common occurrence. Some studies have linked such injuries with an increased risk of Alzheimer disease (AD). However, recent large clinicopathologic studies have failed to find a clear relationship between HI-LOC and the pathological changes associated with AD. The present study aims to further investigate the relationship between HI-LOC and AD pathology in the elderly.

Methods/design: History of HI-LOC in participants in the University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age was ascertained. The donated brains of 110 of these individuals were assessed for AD pathology using consensus guidelines. Analyses aimed to elucidate relationships between HI-LOC and AD pathology.

Results: No associations were found between incidence of HI-LOC and regional AD pathology or any of the three established measures of the neuropathology associated with AD: CERAD score, Thal phase, or Braak stage.

Conclusions: Single incidences of HI-LOC may not be sufficient to cause the pathology associated with late-stage AD. Other routes of damage, such as diffuse axonal injury or Lewy body pathology, may play a greater role in causing cognitive impairment associated with head injury.
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http://dx.doi.org/10.1002/gps.5129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767119PMC
August 2019

Pathological Correlates of Cognitive Impairment in The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age.

J Alzheimers Dis 2018 ;64(2):483-496

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

The neuropathological changes responsible for cognitive impairment and dementia remain incompletely understood. Longitudinal studies with a brain donation end point allow the opportunity to examine relationships between cognitive status and neuropathology. We report on the first 97 participants coming to autopsy with sufficient clinical information from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age. This study began in 1983 and recruited 6,542 healthy individuals between 1983 and 1994, 312 of whom consented to brain donation. Alzheimer-type pathology was common throughout the cohort and generally correlated well with cognitive status. However, there was some overlap between cognitive status and measures of Alzheimer pathology with 26% of cognitively intact participants reaching either CERAD B or C, 11% reaching Thal phase 4 or 5, and 29% reaching Braak stage III- VI. Cerebral amyloid angiopathy(CAA), α-synuclein, and TDP-43 pathology was less common, but when present correlated well with cognitive status. Possession of APOEɛ4 allele(s) was associated with more severe Alzheimer-type and CAA pathology and earlier death, whereas possession of APOEɛ2 allele(s) had no effect on pathology but was more common in cognitively intact individuals. The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort is pathologically representative when compared with similar studies. Cognitive impairment in life correlates strongly with all pathologies examined and the APOE status of an individual can affect pathology severity and longevity.
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http://dx.doi.org/10.3233/JAD-180171DOI Listing
July 2019

Scores Obtained from a Simple Cognitive Test of Visuospatial Episodic Memory Performed Decades before Death Are Associated with the Ultimate Presence of Alzheimer Disease Pathology.

Dement Geriatr Cogn Disord 2018 25;45(1-2):79-90. Epub 2018 Apr 25.

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

Background: Community- or population-based longitudinal studies of cognitive ability with a brain donation end point offer an opportunity to examine relationships between pathology and cognitive state prior to death. Discriminating the earliest signs of dementing disorders, such as Alzheimer disease (AD), is necessary to undertake early interventions and treatments.

Methods: The neuropathological profile of brains donated from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, including CERAD (Consortium to Establish a Registry for Alzheimer's Disease) and Braak stage, was assessed by immunohistochemistry. Cognitive test scores collected 20 years prior to death were correlated with the extent of AD pathology present at death.

Results: Baseline scores from the Memory Circle test had the ability to distinguish between individuals who developed substantial AD pathology and those with no, or low, AD pathology. Predicted test scores at the age of 65 years also discriminated between these pathology groups. The addition of APOE genotype further improved the discriminatory ability of the model.

Conclusions: The results raise the possibility of identifying individuals at future risk of the neuropathological changes associated with AD over 20 years before death using a simple cognitive test. This work may facilitate early interventions, therapeutics and treatments for AD by identifying at-risk and minimally affected (in pathological terms) individuals.
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http://dx.doi.org/10.1159/000486827DOI Listing
October 2018

Genome-wide association study identifies 74 loci associated with educational attainment.

Nature 2016 05 11;533(7604):539-42. Epub 2016 May 11.

Department of Neurology, General Hospital and Medical University Graz, Graz 8036, Austria.

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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http://dx.doi.org/10.1038/nature17671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4883595PMC
May 2016

The non-synonymous SNP, R1150W, in SCN9A is not associated with chronic widespread pain susceptibility.

Mol Pain 2012 Sep 24;8:72. Epub 2012 Sep 24.

Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

Background: Mutations in SCN9A, encoding the alpha subunit of the voltage-gated sodium channel (Nav1.7), have caused severe pain disorders and congenital insensitivity to pain. The aim of this study was to validate the previously reported association between a common non-synonymous polymorphism (R1150W, rs6746030) in SCN9A and chronic widespread pain (CWP), in independent population-based cohorts.

Findings: Genotype data for rs6746030 was available in four population-based cohorts (EPIFUND, the European Male Ageing Study (EMAS), the Framingham study and the Dyne Steel DNA Bank of Ageing and Cognition). Pain was assessed using body manikins and CWP was scored using American College of Rheumatology (ACR) criteria in all cohorts, except the Framingham study which assessed widespread pain (WP) using ACR criteria on a joint pain homunculus. Controls were subjects who reported no pain. Logistic regression (additive genetic model) was used to test for association between rs6746030 and CWP compared to controls, adjusting for study centre in EMAS. Generalised estimating equation regression was used to test for association between rs6746030 and WP, whilst accounting for relatedness between subjects in the Framingham study.Genotype data for rs6746030 was available for 1071 CWP cases and 3212 controls. There was no significant association between CWP and rs6476030 in individual cohorts or when combined in a fixed-effects meta-analysis (Odds Ratio = 0.96 (95% confidence interval 0.82, 1.11) p = 0.567).

Conclusions: In contrast to a previous study, no association between a non-synonymous polymorphism in SCN9A and CWP was observed in multiple population-based cohorts.
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http://dx.doi.org/10.1186/1744-8069-8-72DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3502104PMC
September 2012

Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region.

Ann Rheum Dis 2013 Mar 6;72(3):427-36. Epub 2012 Sep 6.

Department of Internal Medicine, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.

Background And Objectives: Chronic widespread pain (CWP) is a common disorder affecting ∼10% of the general population and has an estimated heritability of 48-52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP.

Methods: We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain.

Results: The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10(-8)). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10(-7)) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10(-8), I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10(-4)).

Conclusions: We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.
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http://dx.doi.org/10.1136/annrheumdis-2012-201742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691951PMC
March 2013

The role of ECE1 variants in cognitive ability in old age and Alzheimer's disease risk.

Am J Med Genet B Neuropsychiatr Genet 2012 Sep 12;159B(6):696-709. Epub 2012 Jun 12.

Medical Genetics, Molecular Medicine Centre, University of Edinburgh, Edinburgh, UK.

The β-amyloid peptide may play a central role in Alzheimer's disease (AD) pathogenesis. We have evaluated variants in seven Aβ-degrading genes (ACE, ECE1, ECE2, IDE, MME, PLAU, and TF) for association with AD risk in the Genetic and Environmental Risk in Alzheimer's Disease Consortium 1 (GERAD1) cohort, and with three cognitive phenotypes in the Lothian Birth Cohort 1936 (LBC1936), using 128 and 121 SNPs, respectively. In GERAD1, we identified a significant association between a four-SNP intragenic ECE1 haplotype and risk of AD in individuals that carried at least one APOE ε4 allele (P = 0.00035, odds ratio = 1.61). In LBC1936, we identified a significant association between a different two-SNP ECE1 intragenic haplotype and non-verbal reasoning in individuals lacking the APOE ε4 allele (P = 0.00036, β = -0.19). Both results showed a trend towards significance after permutation (0.05 < P < 0.10). A follow-up cognitive genetic study evaluated the association of ECE1 SNPs in three additional cohorts of non-demented older people. Meta-analysis of the four cohorts identified the significant association (Z < 0.05) of SNPs in the ECE-1b promoter with non-verbal reasoning scores, particularly in individuals lacking the APOE ε4 allele. Our genetic findings are not wholly consistent. Nonetheless, the AD associated intronic haplotype is linked to the 338A variant of known ECE1b promoter variant, 338C>A (rs213045). We observed significantly less expression from the 338A variant in two human neuroblastoma cell lines and speculate that this promoter may be subject to tissue-specific regulation.
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http://dx.doi.org/10.1002/ajmg.b.32073DOI Listing
September 2012

Genome-wide association uncovers shared genetic effects among personality traits and mood states.

Am J Med Genet B Neuropsychiatr Genet 2012 Sep 24;159B(6):684-95. Epub 2012 May 24.

Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.

Measures of personality and psychological distress are correlated and exhibit genetic covariance. We conducted univariate genome-wide SNP (~2.5 million) and gene-based association analyses of these traits and examined the overlap in results across traits, including a prediction analysis of mood states using genetic polygenic scores for personality. Measures of neuroticism, extraversion, and symptoms of anxiety, depression, and general psychological distress were collected in eight European cohorts (n ranged 546-1,338; maximum total n = 6,268) whose mean age ranged from 55 to 79 years. Meta-analysis of the cohort results was performed, with follow-up associations of the top SNPs and genes investigated in independent cohorts (n = 527-6,032). Suggestive association (P = 8 × 10(-8)) of rs1079196 in the FHIT gene was observed with symptoms of anxiety. Other notable associations (P < 6.09 × 10(-6)) included SNPs in five genes for neuroticism (LCE3C, POLR3A, LMAN1L, ULK3, SCAMP2), KIAA0802 for extraversion, and NOS1 for general psychological distress. An association between symptoms of depression and rs7582472 (near to MGAT5 and NCKAP5) was replicated in two independent samples, but other replication findings were less consistent. Gene-based tests identified a significant locus on chromosome 15 (spanning five genes) associated with neuroticism which replicated (P < 0.05) in an independent cohort. Support for common genetic effects among personality and mood (particularly neuroticism and depressive symptoms) was found in terms of SNP association overlap and polygenic score prediction. The variance explained by individual SNPs was very small (up to 1%) confirming that there are no moderate/large effects of common SNPs on personality and related traits.
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http://dx.doi.org/10.1002/ajmg.b.32072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795298PMC
September 2012

Evolutionary conserved longevity genes and human cognitive abilities in elderly cohorts.

Eur J Hum Genet 2012 Mar 2;20(3):341-7. Epub 2011 Nov 2.

Department of Psychology, The University of Edinburgh, Edinburgh, UK.

Genetic influences have an important role in the ageing process. The genetic factors that influence success in bodily ageing may also contribute to the successful ageing of cognitive abilities. A comparative genomics approach found longevity genes conserved between yeast Saccharomyces cerevisiae and nematode Caenorhabditis elegans. We hypothesised that these longevity genes influence variance in cognitive ability and age-related cognitive decline in humans. Here, we investigated six of these genes that have human orthologs and show expression in the brain. We tested AFG3L2 (MIM: 604581, AFG3 ATPase family gene 3-like 2 (yeast)), FRAP1 (MIM: 601231, a FK506 binding protein 12-rapamycin associated protein), MAT1A, MAT2A (MIM: 610550 and 601468, methionine adenosyltransferases I alpha and II alpha, respectively), SYNJ1 and SYNJ2 (MIM: 604297 and 609410, synaptojanin-1 and synaptojanin-2, respectively) in approximately 1000 healthy older Scots: the Lothian Birth Cohort 1936 (LBC1936). They were tested on general cognitive ability at age 11 years. At a mean age of 70 years, they re-sat the same general cognitive ability test and underwent an additional battery of diverse cognitive tests. In all, 70 tag and functional SNPs in the six longevity genes were genotyped and tested for association with cognition and cognitive ageing in LBC1936. Suggestive associations were detected between SNPs in SYNJ2, MAT1A, AFG3L2 and SYNJ1 and a general memory factor and general cognitive ability at age 11 and 70 years. Replication studies for cognitive ability associations were performed in 2506 samples from the Cognitive Ageing Genetics in England and Scotland consortium. A meta-analysis replicated the SYNJ2 association with cognitive abilities (lowest P=0.00077). SYNJ2 is a novel gene in which variation is potentially associated with cognitive abilities.
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http://dx.doi.org/10.1038/ejhg.2011.201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3283186PMC
March 2012

No association between Cholinergic Muscarinic Receptor 2 (CHRM2) genetic variation and cognitive abilities in three independent samples.

Behav Genet 2009 Sep 6;39(5):513-23. Epub 2009 May 6.

Genetic Epidemiology Unit, PO Royal Brisbane Hospital, Brisbane, QLD, 4029, Australia.

Cognitive ability has a substantial genetic component and more than 15 candidate genes have been identified over the past 8 years. One gene that has been associated with general cognitive ability is the cholinergic muscarinic 2 receptor (CHRM2). In an attempt to replicate this finding we typed marker rs8191992 (the originally reported CHRM2 SNP) in two population based cohorts-one Scottish aged over 50 years (N = 2,091) and the other English comprising non-demented elderly participants (N = 758)-and a family-based Australian adolescent sample (N = 1,537). An additional 29 SNPs in CHRM2 were typed in the Australian sample and a further seven in the English cohort. No significant association was found between CHRM2 and diverse measures of cognitive ability in any of the samples. In conclusion, this study does not support a role for CHRM2 in cognitive ability.
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http://dx.doi.org/10.1007/s10519-009-9274-zDOI Listing
September 2009

Type 2 diabetes whole-genome association study in four populations: the DiaGen consortium.

Am J Hum Genet 2007 Aug 26;81(2):338-45. Epub 2007 Jun 26.

Oy Jurilab, and Research Institute of Public Health, University of Kuopio, Kuopio, Finland, and Hope Hospital, Salford, UK.

Type 2 diabetes (T2D) is a common, polygenic chronic disease with high heritability. The purpose of this whole-genome association study was to discover novel T2D-associated genes. We genotyped 500 familial cases and 497 controls with >300,000 HapMap-derived tagging single-nucleotide-polymorphism (SNP) markers. When a stringent statistical correction for multiple testing was used, the only significant SNP was at TCF7L2, which has already been discovered and confirmed as a T2D-susceptibility gene. For a replication study, we selected 10 SNPs in six chromosomal regions with the strongest association (singly or as part of a haplotype) for retesting in an independent case-control set including 2,573 T2D cases and 2,776 controls. The most significant replicated result was found at the AHI1-LOC441171 gene region.
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http://dx.doi.org/10.1086/520599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1950819PMC
August 2007

Perceptions of risk and prevention of dementia in the healthy elderly.

Dement Geriatr Cogn Disord 2007 26;23(6):368-71. Epub 2007 Mar 26.

Department of Geriatric Medicine, Hope Hospital, Manchester, UK.

Objectives: (1) To determine the attitudes and perceptions of the elderly with regard to dementia. (2) To correlate these beliefs with demographic variables of age, sex, intelligence scores and social class.

Method: A postal questionnaire survey of a sample of 562 subjects of the Manchester University Age and Cognitive Performance longitudinal study group.

Results: The response rate was 95%. Most responders (69%) did not worry about dementia, although they were more likely to think about it if they had a family member with dementia (p < 0.005). There is no link between social class, sex, intelligence scores and age with regard to worries and concerns of dementia. The majority of responders (82%) took action to maintain their health but demonstrated poor awareness of risks or protective factors for dementia.

Conclusion: The elderly on the whole were not fearful of dementia or of acquiring it. There was poor awareness of risks or protective factors for dementia.
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http://dx.doi.org/10.1159/000101338DOI Listing
July 2007

Hoof beats.

Age Ageing 2007 May 14;36(3):356. Epub 2007 Mar 14.

North Western Region, UK.

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http://dx.doi.org/10.1093/ageing/afm018DOI Listing
May 2007

Apolipoprotein E epsilon4 allele frequency and age at onset of Alzheimer's disease.

Dement Geriatr Cogn Disord 2007 14;23(1):60-6. Epub 2006 Nov 14.

Clinical Neuroscience Research Group, Division of Medicine and Neuroscience, University of Manchester, Greater Manchester Neurosciences Centre, Hope Hospital, Salford, UK.

The age distribution of the epsilon4 allelic form of the apolipoprotein E gene (APOE) was investigated in 630 patients with Alzheimer's disease (AD) with onset age ranging from 35 to 90 years. Overall, mean age at onset in APOE epsilon4 allele bearers was significantly later than that in nonbearers. However, when stratified into early onset AD (EOAD) and late onset (LOAD) groups, mean age at onset in EOAD cases bearing APOE epsilon4 allele was later than that in those EOAD cases without epsilon4 allele, whereas in LOAD mean age at onset in cases bearing APOE epsilon4 allele was earlier than in those without epsilon4 allele. When analysed by decade, it was observed that 37% of the total number of APOE epsilon4 allele bearers, and 43% of total number of cases with APOE epsilon4/epsilon4 genotype fell into the 60-69 years age class. Hence, APOE epsilon4 allele frequency, at 0.44, was highest in the 60-69 years age class, progressively decreasing either side of this age group. APOE epsilon4 allele therefore has its maximum impact between onset ages of between 60 and 70 years.
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http://dx.doi.org/10.1159/000097038DOI Listing
February 2007

Concordance of Cornell medical index self-reports to structured clinical assessment for the identification of physical health status.

Arch Gerontol Geriatr 2004 May-Jun;38(3):261-9

Geriatric Medicine, University of Manchester, Salford, UK.

Self-reported questionnaires are frequently used to assess health status in epidemiological studies. The Cornell medical index is one such tool used to determine the presence of physical and psychiatric illness but its accuracy and value have been questioned. In this study we have assessed the ability of the CMI to predict health status in two separate patient populations (n = 101, 88) by comparison to a structured medical assessment based on the SENIEUR protocol by two physicians. There was good agreement between medication use reported on the CMI and on medical assessment (k = 0.79; CI: 0.70-0.88). Accuracy of prediction of the CMI for specific medical conditions was good 89-99%. A threshold score from the CMI was not predictive of health as determined by the SENIEUR protocol. In our older populations, we conclude that the CMI accurately predicted health status. The determination of normal health by a threshold score was poorly predictive of heath status. Self-reported medication use was the best predictor of health status.
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http://dx.doi.org/10.1016/j.archger.2003.10.005DOI Listing
September 2004

Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor.

J Clin Invest 2003 May;111(9):1309-18

School of Biological Sciences, University of Manchester, Manchester, United Kingdom.

Characteristic of both chronic wounds and acute wounds that fail to heal are excessive leukocytosis and reduced matrix deposition. Estrogen is a major regulator of wound repair that can reverse age-related impaired wound healing in human and animal models, characterized by a dampened inflammatory response and increased matrix deposited at the wound site. Macrophage migration inhibitory factor (MIF) is a candidate proinflammatory cytokine involved in the hormonal regulation of inflammation. We demonstrate that MIF is upregulated in a distinct spatial and temporal pattern during wound healing and its expression is markedly elevated in wounds of estrogen-deficient mice as compared with intact animals. Wound-healing studies in mice rendered null for the MIF gene have demonstrated that in the absence of MIF, the excessive inflammation and delayed-healing phenotype associated with reduced estrogen is reversed. Moreover, in vitro assays have shown a striking estrogen-mediated decrease in MIF production by activated murine macrophages, a process involving the estrogen receptor. We suggest that estrogen inhibits the local inflammatory response by downregulating MIF, suggesting a specific target for future therapeutic intervention in impaired wound-healing states.
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http://dx.doi.org/10.1172/JCI16288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC154440PMC
May 2003

Apolipoprotein E genotype does not predict decline in intelligence in healthy older adults.

Neurosci Lett 2002 May;324(1):74-6

Clinical Gerontology Group, Clinical Division I, University of Manchester, Hope Hospital, Stott Lane, Salford, M6 8HD, UK.

There is evidence of a genetic influence on the decline in cognitive performance of older adults, although the mechanisms responsible are unknown. A group of 767 subjects of the Manchester University Age and Cognitive Performance longitudinal study volunteer group, followed up from 1985 to the present, were genotyped for apolipoprotein E (APOE). The data from this were related to cross-sectional and longitudinal trends in the Heim intelligence test score (AH4-1) using previously reported random-effects models (Neuropsychologia 39 (2001) 532). There were no significant differences in mean scores for presence compared with absence of the APOE4 or APOE2 genotypes (P=0.48 and P=0.51, respectively). This research does not demonstrate a link between intelligence and APOE genotype in older adults.
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http://dx.doi.org/10.1016/s0304-3940(02)00135-0DOI Listing
May 2002

Predictors of outcome following hip fracture. Admission time predicts length of stay and in-hospital mortality.

Injury 2002 Jan;33(1):1-6

Clinical Division 1, University of Manchester, Manchester, UK.

Many factors may contribute to the mortality and morbidity following hip fracture, including the provision of care. We wished to examine the contribution of potential factors to in-hospital mortality, length of hospital stay and 90-day mortality by statistical analyses of an audit database of all hip fractures admitted to a teaching hospital following the introduction of a fast track admission system. In-hospital mortality was predicted by ASA grade, the presence of any complications, cardiovascular complications, grade of surgeon, operation type and shorter admission time, a measure of time taken to admit a patient to a hospital bed (P<0.001). Length of hospital stay was predicted by increased age, presence of chronic cognitive impairment/dementia, presence of an implant complication, operation type, fracture type and longer admission time, r=0.455, P<0.001. Ninety-day mortality was predicted by the presence of chronic cognitive impairment/dementia, cardiovascular complications, pulmonary complications, ASA grade, grade of surgeon and admission day, P<0.001. Rapid admission following a hip fracture may not be the ideal management approach for all patient groups. Further study is required to identify factors in the process of care which are associated with better outcomes.
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http://dx.doi.org/10.1016/s0020-1383(01)00142-5DOI Listing
January 2002
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