1. Coupled change in brain white matter integrity and fluid intelligence in later life Stuart J. Ritchie Centre for Cognitive Ageing and Cognitive Epidemiology The University of Edinburgh stuart.ritchie@ed.ac.uk @StuartJRitchie

2. Age-related cognitive decline Salthouse (2004) Curr Direct Psych Sci, p. 141

4. The disconnected mind Geschwind (1965), Brain (parts I and II) White matter lesions may cause agnosias, aphasias, apraxias What about age-related cognitive decline?

5. Regional volumes; white matter lesions; diffusion tensor imaging variables “…at the current time the evidence that these aspects of brain structure are neuroanatomical substrates of age- related cognitive decline is weak.” (p. 753)

6. Charlton et al. (2010) 84 adults aged 55-91 (M = 71) n = 73 with DTI variables across 2 years Measures of working memory, executive function, processing speed – Only working memory shows sig. decline Sig. decline in white matter integrity White matter change correlated with working memory change (r =.35, p =.004)

7. Lövdén et al. (2014) Sample of very old adults (aged 81-103) n = 40 with 2 waves of DTI and cognitive testing Strong change-change correlations found (but large 95% CIs)

8. Lothian Birth Cohort 1936 Born in 1936, tested in Scottish Mental Survey in 1947 Followed up from 2004 onwards as a study of ageing Follow-up testing: – n = 1,091 at mean age 70; – n = 866 at mean age 73; – n = 697 at mean age 76. DT-MRI scans (1.5T): – n = 731 at age 73; – n = 488 at age 76.

9. Cognitive Domains Tests completed at age 70, 73, & 76 Fluid intelligence ( g f ) – Matrix Reasoning, Block Design, Digit Span Backwards, Letter-Number Sequencing (all WAIS) Processing speed – Digit-Symbol Substitution (WAIS), Symbol Search (WAIS), Simple & Choice Reaction Time, Inspection Time Memory – Logical Memory, Verbal Paired Associates, Spatial Span (all WMS)

10. DT-MRI Fractional anisotropy (FA; non-randomness of water molecule movement) calculated using a diffusion tensor From Chanraud et al. (2010), Neuropsychol. Rev.

11. Tractography General FA calculated (age 73 and age 76) from 12 white matter tracts across the brain

12. Cross-sectional work Penke et al. (2010), J Neurosci n = 132 Penke et al. (2012), Mol Psych: 10% of variance in general intelligence explained by general factor of white matter integrity – FA + other variables (MD, MTR)

13. Age-related FA decline Kochunov et al. (2012) Neurobiol. Aging, p. 17

14. Hypotheses 1.(FA will correlate at baseline with performance in each of the cognitive domains) 2.FA and each of the cognitive domains will decline from age 73 to age 76 3.Decline in FA will correlate with decline in cognitive performance (fluid intelligence and processing speed, but not necessarily memory)

16. Latent Difference Score model y[1] = (1*y[0]) + (1*Δy)

18. Results: Level-Level.

19. Results: Level-Change

20. Results: Change-change *

21. Conclusions Decline in white matter integrity is associated with decline in fluid intelligence from age 73 to age 76 (p = 0.011) – Very large, narrow-age longitudinal sample – More complex & appropriate modeling technique than in previous work – But also higher-IQ and healthier than general population No such correlation for declines in memory (expected) or processing speed (unexpected) Longer time window needed for more power to detect change-change correlations? Best evidence to date for “the disconnected mind” underlying age-related cognitive decline?

22. Next up for diffusion MRI Covariates – APOE genotype; lifestyle factors; childhood IQ Other white matter integrity factors – And measures of white matter lesions And other DTI techniques (e.g. TBSS) In more detail: anterior vs. posterior tracts – which age faster? Connectomic/graph theory measures Wait 3 more years........

23. *Extra bonus stuff* New analysis: brain volumes Same LDS model, but for brain volume (total volume or grey/white matter volumes) Sig. vol. decline between 73 and 76 (all p <.001): – Total Brain Volume: -.07 SDs/year (-6.4ml/year) – Grey Matter: -.07 SDs/year – White Matter: -.10 SDs/year

29. Brain volume conclusions Grey and white matter do not decline together No predictions for subsequent decline in any cognitive domain Brain volume declines are correlated with speed decline Smaller, borderline correlations for g f No differences between grey and white matter coupled change

30. Thanks LBC1936 participants Ian Deary Mark Bastin Simon Cox Elliot Tucker-Drob Laura Engelhardt David Alexander Dickie Susana Muñoz Maniega Maria Valdés Hernández Joanna Wardlaw Funders: stuart.ritchie@ed.ac.uk