Cognitive ability is a heritable trait with a polygenic architecture, for which several associated variants have been identified using genotype-based and candidate gene approaches. Haplotype-based analyses are a complementary technique that take phased genotype data into account, and potentially provide greater statistical power to detect lower frequency variants.In the present analysis, three cohort studies (n total = 48,002) were utilised: Generation Scotland: Scottish Family Health Study (GS:SFHS), the English Longitudinal Study of Ageing (ELSA), and the UK Biobank. A genome-wide haplotype-based meta-analysis of cognitive ability was performed, as well as a targeted meta-analysis of several gene coding regions.None of the assessed haplotypes provided evidence of a statistically significant association with cognitive ability in either the individual cohorts or the meta-analysis. Within the meta-analysis, the haplotype with the lowest observed P-value overlapped with the D-amino acid oxidase activator ( DAOA) gene coding region. This coding region has previously been associated with bipolar disorder, schizophrenia and Alzheimer's disease, which have all been shown to impact upon cognitive ability. Another potentially interesting region highlighted within the current genome-wide association analysis (GS:SFHS: P = 4.09 x 10 -7), was the butyrylcholinesterase ( BCHE) gene coding region. The protein encoded by BCHE has been shown to influence the progression of Alzheimer's disease and its role in cognitive ability merits further investigation.Although no evidence was found for any haplotypes with a statistically significant association with cognitive ability, our results did provide further evidence that the genetic variants contributing to the variance of cognitive ability are likely to be of small effect.
Abstract INTRODUCTION The ‘epigenetic clock’ is a DNA methylation-based estimate of biological age and is correlated with chronological age – the greatest risk factor for Alzheimer’s disease (AD). Genetic and environmental risk factors exist for AD, several of which are potentially modifiable. Here, we assess the relationship associations between the epigenetic clock and AD risk factors. METHODS Linear mixed modelling was used to assess the relationship between age acceleration (the residual of biological age regressed onto chronological age) and AD risk factors relating to cognitive reserve, lifestyle, disease, and genetics in the Generation Scotland study (n=5,100). RESULTS We report significant associations between the epigenetic clock and BMI, total:HDL cholesterol ratios, socioeconomic status, and smoking behaviour (Bonferroni-adjusted P<0.05). DISCUSSION Associations are present between environmental risk factors for AD and age acceleration. Measures to modify such risk factors might improve the risk profile for AD and the rate of biological ageing. Future longitudinal analyses are therefore warranted.
Department of Nuclear Medicine, Aberdeen Royal Infirmary, UK Abstracts of the 34th Annual Meeting of the British Nuclear Medicine Society Manchester International Conference Centre, UK, 27–29 March 2006
The underlying mechanisms leading to dementia and Alzheimer's disease (AD) are unclear. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, may be associated with cognitive decline, but population-based evidence is lacking.Change in cognitive performance was assessed in participants of the Aberdeen Birth Cohort of 1936 using longitudinal Raven's progressive matrices (RPM) between 2000 and 2004. Multiple linear regression was used to estimate the association between ADMA concentrations in 2000 and change in cognitive performance after adjustment for potential confounders.A total of 93 participants had complete information on cognitive performance between 2000 and 2004. Mean plasma ADMA concentrations were approximately 0.4 μmol/L lower in those participants with stable or improved RPM scores over follow-up compared with participants whose cognitive performance worsened. In confounder-adjusted analysis, one SD (0.06 μmol/L) increase in ADMA at 63 years of age was associated with an average reduction in RPM of 1.26 points (95% CI 0.14-2.26) after 4 years.Raised plasma ADMA concentrations predicted worsening cognitive performance after approximately 4 years in this cohort of adults in late-middle age. These findings have implications for future research, including presymptomatic diagnosis or novel therapeutic targets for dementia and AD.
• Structural brain imaging is recommended in patients with dementia by all current guidelines. • Brain imaging cannot diagnose dementia but can suggest the most likely underlying neuropathology in a demented patient. • Alzheimer's disease is the commonest cause of dementia and usually co-exists with other pathologies, most often cerebrovascular disease. • Frontotemporal dementias are a heterogeneous group of neuropathologies that typically cause asymmetric frontal, anterior temporal and/or insular atrophy. • Dementia with Lewy bodies is caused by the same pathology as Parkinson's disease, and there is clinical overlap. • Cerebrovascular disease is associated with vascular risk factors, increases linearly with age and, typically, is manifest as white matter ischaemic change and/or lacunar infarcts. • There are no currently available disease-modifying treatments for dementia. • The prevalence of dementia is doubling every 20 years, as people live longer and health and social care resources will soon become insufficient. The worldwide prevalence of dementia is estimated to be 36.5 million with an additional 7.7 million new cases every year. In the UK alone, the prevalence is close to a million. Dementia continues to have huge implications for health and social care. Even in affluent societies like the UK, the needs will soon outstrip available resources. Dementia, defined as a syndrome of progressive memory and cognitive decline that affects the individual in activities of daily life is still fundamentally a clinical diagnosis. However, neuroimaging has increasingly come to play a major role not only in clinical practice but also in research and clinical trials. Current guidelines in the UK recommend structural brain imaging in all patients with a new diagnosis of dementia. Largely, this is to exclude treatable causes like subdural haematoma. However, imaging can also assist in further characterization of certain types of dementia. This article is an update on the various imaging modalities available in current clinical practice in the work-up of dementia in the UK and briefly touches on the newer technologies being explored in dementia research.
Fatigue is a major burden among patients with RA, yet is poorly understood. We sought to conduct the first imaging study to investigate the neurobiological correlates of fatigue in RA and to improve upon the methodological limitations of previous neuroimaging studies that have investigated this symptom in other populations.Chronically fatigued RA patients were clinically characterized before undertaking a combined functional and structural mode MRI brain scan. The functional sequences were acquired during a fatigue-evoking task, then network-to-whole-brain analyses were undertaken. The structural analyses employed voxel-based morphometry in order to quantify regional grey matter volume. The scan was repeated 6 months later to test reproducibility.Fifty-four participants attended both scans [n = 41 female; baseline mean (s.d.) age 54.94 (11.41) years]. A number of significant functional and structural neural imaging correlates of fatigue were identified. Notably, patients who reported higher levels of fatigue demonstrated higher levels of functional connectivity between the Dorsal Attention Network and medial prefrontal gyri, a finding that was reproduced in the repeat scans. Structurally, greater putamen grey matter volumes significantly correlated with greater levels of fatigue.Fatigue in RA is associated with functional and structural MRI changes in the brain. The newly identified and reproduced neural imaging correlates provide a basis for future targeting and stratification of this key patient priority.
Genomic imprinting is important for normal brain development and aberrant imprinting has been associated with impaired cognition. We studied the imprinting status in selected imprints (H19, IGF2, SNRPN, PEG3, MEST1, NESPAS, KvDMR, IG-DMR and ZAC1) by pyrosequencing in blood samples from longitudinal cohorts born in 1936 (n = 485) and 1921 (n = 223), and anterior hippocampus, posterior hippocampus, periventricular white matter, and thalamus from brains donated to the Aberdeen Brain Bank (n = 4). MEST1 imprint methylation was related to childhood cognitive ability score (-0.416 95% CI -0.792,-0.041; p = 0.030), with the strongest effect evident in males (-0.929 95% CI -1.531,-0.326; p = 0.003). SNRPN imprint methylation was also related to childhood cognitive ability (+0.335 95%CI 0.008,0.663; p = 0.045). A significant association was also observed for SNRPN methylation and adult crystallised cognitive ability (+0.262 95%CI 0.007,0.517; p = 0.044). Further testing of significant findings in a second cohort from the same region, but born in 1921, resulted in similar effect sizes and greater significance when the cohorts were combined (MEST1; -0.371 95% CI -0.677,-0.065; p = 0.017; SNRPN; +0.361 95% CI 0.079,0.643; p = 0.012). For SNRPN and MEST1 and four other imprints the methylation levels in blood and in the five brain regions were similar. Methylation of the paternally expressed, maternally methylated genes SNRPN and MEST1 in adult blood was associated with cognitive ability in childhood. This is consistent with the known importance of the SNRPN containing 15q11-q13 and the MEST1 containing 7q31-34 regions in cognitive function. These findings, and their sex specific nature in MEST1, point to new mechanisms through which complex phenotypes such as cognitive ability may be inherited. These mechanisms are potentially relevant to both the heritable and non-heritable components of cognitive ability. The process of epigenetic imprinting—within SNRPN and MEST1 in particular—and the factors that influence it, are worthy of further study in relation to the determinants of cognitive ability.
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