Are APOE ɛ genotype and TOMM40 poly-T repeat length associations with cognitive ageing mediated by brain white matter tract integrity?

Genetic polymorphisms in the APOE ε and TOMM40 ‘523’ poly-T repeat gene loci have been associated with significantly increased risk of Alzheimer’s disease. This study investigated the independent effects of these polymorphisms on human cognitive ageing, and the extent to which nominally significant associations with cognitive ageing were mediated by previously reported genetic associations with brain white matter tract integrity in this sample. Most participants in the Lothian Birth Cohort 1936 completed a reasoning-type intelligence test at age 11 years, and detailed cognitive/physical assessments and structural diffusion tensor brain magnetic resonance imaging at a mean age of 72.70 years (s.d.=0.74). Participants were genotyped for APOE ε2/ε3/ε4 status and TOMM40 523 poly-T repeat length. Data were available from 758–814 subjects for cognitive analysis, and 522–543 for mediation analysis with brain imaging data. APOE genotype was significantly associated with performance on several different tests of cognitive ability, including general factors of intelligence, information processing speed and memory (raw P-values all<0.05), independently of childhood IQ and vascular disease history. Formal tests of mediation showed that several significant APOE-cognitive ageing associations—particularly those related to tests of information processing speed—were partially mediated by white matter tract integrity. TOMM40 523 genotype was not associated with cognitive ageing. A range of brain phenotypes are likely to form the anatomical basis for significant associations between APOE genotype and cognitive ageing, including white matter tract microstructural integrity

Processing speed and the relationship between Trail Making Test-B performance, cortical thinning and white matter microstructure in older adults

Part B of the Trail Making Test (TMT-B) is widely used as a quick and easy to administer measure of executive dysfunction. The current study investigated the relationships between TMT-B performance, brain volumes, cortical thickness and white matter water diffusion characteristics in a large sample of older participants, before and after controlling for processing speed. Four hundred and eleven healthy, community-dwelling older adults who were all born in 1936 were assessed on TMT-B, 5 tests of processing speed, and provided contemporaneous structural and diffusion MRI data. Significant relationships were found between slower TMT-B completion times and thinner cortex in the frontal, temporal and inferior parietal regions as well as the Sylvian fissure/insula. Slower TMT-B completion time was also significantly associated with poorer white matter microstructure of the left anterior thalamic radiation, and the right uncinate fasciculus. The majority of these associations were markedly attenuated when additionally controlling for processing speed. These data suggest that individual differences in processing speed contribute to the associations between TMT-B completion time and the grey and white matter structure of older adults

Brain structural differences between 73- and 92-year olds matched for childhood intelligence, social background, and intracranial volume

Fully characterizing age differences in the brain is a key task for combating aging-related cognitive decline. Using propensity score matching on 2 independent, narrow-age cohorts, we used data on childhood cognitive ability, socioeconomic background, and intracranial volume to match participants at mean age of 92 years (n = 42) to very similar participants at mean age of 73 years (n = 126). Examining a variety of global and regional structural neuroimaging variables, there were large differences in gray and white matter volumes, cortical surface area, cortical thickness, and white matter hyperintensity volume and spatial extent. In a mediation analysis, the total volume of white matter hyperintensities and total cortical surface area jointly mediated 24.9% of the relation between age and general cognitive ability (tissue volumes and cortical thickness were not significant mediators in this analysis). These findings provide an unusual and valuable perspective on neurostructural aging, in which brains from the 8th and 10th decades of life differ widely despite the same cognitive, socioeconomic, and brain-volumetric starting points

Statistics teaching in medical school: opinions of practising doctors

Background: The General Medical Council expects UK medical graduates to gain some statistical knowledge during their undergraduate education; but provides no specific guidance as to amount, content or teaching method. Published work on statistics teaching for medical undergraduates has been dominated by medical statisticians, with little input from the doctors who will actually be using this knowledge and these skills after graduation. Furthermore, doctor's statistical training needs may have changed due to advances in information technology and the increasing importance of evidence-based medicine. Thus there exists a need to investigate the views of practising medical doctors as to the statistical training required for undergraduate medical students, based on their own use of these skills in daily practice. Methods: A questionnaire was designed to investigate doctors' views about undergraduate training in statistics and the need for these skills in daily practice, with a view to informing future teaching. The questionnaire was emailed to all clinicians with a link to the University of East Anglia Medical School. Open ended questions were included to elicit doctors' opinions about both their own undergraduate training in statistics and recommendations for the training of current medical students. Content analysis was performed by two of the authors to systematically categorise and describe all the responses provided by participants. Results: 130 doctors responded, including both hospital consultants and general practitioners. The findings indicated that most had not recognised the value of their undergraduate teaching in statistics and probability at the time, but had subsequently found the skills relevant to their career. Suggestions for improving undergraduate teaching in these areas included referring to actual research and ensuring relevance to, and integration with, clinical practice. Conclusions: Grounding the teaching of statistics in the context of real research studies and including examples of typical clinical work may better prepare medical students for their subsequent career