Post-mortem brain analyses of the Lothian Birth Cohort 1936

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Non-pathological, age-related cognitive decline varies markedly between individuals & places significant financial & emotional strain on people, their families & society as a whole. Understanding the differential age-related decline in brain function is critical not only for the development of therapeutics to prolong cognitive health into old age, but also to gain insight into pathological ageing such as Alzheimer’s disease.

The Lothian Birth Cohort of 1936 (LBC1936) comprises a rare group of people for whom there are childhood cognitive test scores & longitudinal cognitive data during older age, detailed structural brain MRI, genome-wide genotyping, & a multitude of other biological, psycho-social, & epidemiological data. Synaptic integrity is a strong indicator of cognitive health in the human brain; however, until recently, it was prohibitively difficult to perform detailed analyses of synaptic & axonal structure in human tissue sections.

We have adapted a novel method of tissue preparation at autopsy to allow the study of human synapses from the LBC1936 cohort in unprecedented morphological & molecular detail, using the high-resolution imaging techniques of array tomography & electron microscopy. This allows us to analyze the brain at sub-micron resolution to assess density, protein composition & health of synapses. Here we present data from the first donated LBC1936 brain & compare our findings to Alzheimer’s diseased tissue to highlight the differences between healthy & pathological brain ageing.

Our data indicates that compared to an Alzheimer’s disease patient, the cognitively normal LBC1936 participant had a remarkable degree of preservation of synaptic structures. However, morphological & molecular markers of degeneration in areas of the brain associated with cognition (prefrontal cortex, anterior cingulate cortex, & superior temporal gyrus) were observed. Our novel post-mortem protocol facilitates high- resolution neuropathological analysis of the well-characterized LBC1936 cohort, extending phenotyping beyond cognition & in vivo imaging to now include neuropathological changes, at the level of single synapses. This approach offers an unprecedented opportunity to study synaptic & axonal integrity during ageing & how it contributes to differences in age-related cognitive change.

• Authors: Christopher M. Henstridge; Rosemary J. Jackson; JeeSoo M. Kim; Abigail G. Herrmann; Ann K. Wright; Sarah Harris; Mark E. Bastin; John M. Starr; Joanna Wardlaw; Thomas H. Gillingwater; Colin Smith; Chris-Anne McKenzie; Simon R. Cox; Ian J. Deary; Tara L. Spires-Jones.

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