Post-mortem brain analyses of the Lothian Birth Cohort 1936: extending lifetime cognitive and brain phenotyping to the level of the synapse.
BACKGROUND
Non-pathological, age-related cognitive decline varies markedly between individuals andplaces significant financial and emotional strain on people, their families and society as a whole.Understanding the differential age-related decline in brain function is critical not only for the development oftherapeutics to prolong cognitive health into old age, but also to gain insight into pathological ageing suchas Alzheimer's disease. The Lothian Birth Cohort of 1936 (LBC1936) comprises a rare group of people forwhom there are childhood cognitive test scores and longitudinal cognitive data during older age, detailedstructural brain MRI, genome-wide genotyping, and a multitude of other biological, psycho-social, andepidemiological 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 and axonalstructure in human tissue sections. We have adapted a novel method of tissue preparation at autopsy toallow the study of human synapses from the LBC1936 cohort in unprecedented morphological andmolecular detail, using the high-resolution imaging techniques of array tomography and electronmicroscopy. This allows us to analyze the brain at sub-micron resolution to assess density, proteincomposition and health of synapses. Here we present data from the first donated LBC1936 brain andcompare our findings to Alzheimer's diseased tissue to highlight the differences between healthy andpathological brain ageing.


RESULTS
Our data indicates that compared to an Alzheimer's disease patient, the cognitively normalLBC1936 participant had a remarkable degree of preservation of synaptic structures. However,morphological and molecular markers of degeneration in areas of the brain associated with cognition(prefrontal cortex, anterior cingulate cortex, and superior temporal gyrus) were observed.


CONCLUSIONS
Our novel post-mortem protocol facilitates high-resolution neuropathological analysis of the well-characterized LBC1936 cohort, extending phenotyping beyond cognition and in vivo imaging to nowinclude neuropathological changes, at the level of single synapses. This approach offers an unprecedentedopportunity to study synaptic and axonal integrity during ageing and how it contributes to differences in agerelatedcognitive change.
Centre for Cognitive and Neural Systems, University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK.
Christopher M
CM
Henstridge
Centre for Cognitive and Neural Systems, University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK.
Rosemary J
RJ
Jackson
Centre for Cognitive and Neural Systems, University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK.
JeeSoo M
JM
Kim
Centre for Cognitive and Neural Systems, University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK.
Abigail G
AG
Herrmann
Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.
Ann K
AK
Wright
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.|Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine and MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK.
Sarah E
SE
Harris
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.|Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
Mark E
ME
Bastin
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.|Geriatric Medicine Unit, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
John M
JM
Starr
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.|Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
Joanna
J
Wardlaw
Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.
Thomas H
TH
Gillingwater
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.|Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.|Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
Colin
C
Smith
Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
Chris-Anne
CA
McKenzie
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.|Department of Psychology, CCACE, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.
Simon R
SR
Cox
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK. I.Deary@ed.ac.uk.|Department of Psychology, CCACE, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK. I.Deary@ed.ac.uk.
Ian J
IJ
Deary
Centre for Cognitive and Neural Systems, University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK. Tara.spires-jones@ed.ac.uk.|Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK. Tara.spires-jones@ed.ac.uk.
Tara L
TL
Spires-Jones
D000368:Aged; D000375:Aging / Q000473:pathology*; D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D003071:Cognition; D015331:Cohort Studies; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D017628:Microglia / Q000473:pathology; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure; D011180:Postmortem Changes; D013569:Synapses / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D000097382:CD68 Molecule
D016229:Amyloid beta-Peptides; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D006657:Histones; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C067980:CD68 antigen, human; D000097382:CD68 Molecule