Introduction

Performance on tasks of executive function has been observed to decline with age. A better understanding of what may influence these changes could contribute towards our understanding of what promotes healthy ageing or direct research in patient cohorts. The role of cortical and subcortical grey matter structures is recognised, but white matter correlates are less well understood. This study aimed to examine the relationship between changes in microstructure of frontal white matter pathways and age-related decline of three key cognitive processes associated with executive function (attention, working memory and planning). We predicted that the cingulum (CB) would play a mediatory role in the age- related decline of selective attention and that the CB, inferior fronto-occipital fasciculus (IFOF) and superior longitudinal fasciculus (SLF) I, II and III would play mediatory roles in age-related decline of spatial working memory and planning performance (Fig. 3). We then conducted exploratory analysis including other white matter pathways the frontal lobe (anterior segments of the corpus callosum (CC), frontal aslant tract (FAT) and uncinate fasciculus (UF).

Methods

104 healthy participants (18 – 79 years) took part in this cross-sectional observational study. Diffusion weighted images were acquired through a spin-echo single-shot echo planar imaging (EPI) sequence on a 3T General Electric Signa HDx Twin Speed system MRI scanner with an 8-channel head coil (64 directions, b=3000 s/mm2, 2.4x2.4x2.4 mm3). Corrections for head motion and eddy current distortion were applied using exploreDTI. A HARDI based method using Spherical Deconvolution (SD) was applied to reconstruct the white matter tracts (Dell’acqua et al., 2010; Flavio Dell’Acqua et al, 2013). Behavioural measures were selected from the Cambridge Brain Sciences battery (Hampshire, Highfield, Parkin, & Owen, 2012). A subset of 18 participants was used to establish reliability of manual and semi-automated tractography protocols for measures of volume and Hindrance Modulated Orientation Anisotropy (HMOA), an index of white matter diffusion properties, across all tracts in young and older adults. Semi-automated tractography was conducted using MegaTrack, a method that extracts volume and microstructure measures by mapping a single manual dissection across a combined ‘Mega’ data set of multiple subjects. (Dell’Acqua et al., 2015). Data from a separate group of 86 participants were then analysed to test for age-related changes to tract microstructure and task performance and correlations between microstructure and task performance. We then performed mediation analysis to identify indirect effects of tract microstructure on age-related cognitive decline.

Results

Overall volume and microstructure measures from manual and semi-automated dissection protocols demonstrated good to excellent reliability (whole group tract volume ICC: 0.66 – 0.92, whole group HMOA ICC: 0.60 – 0.99) in both young and older adult age groups except for the third segment (rostral body) of the CC, the right FAT and right IFOF. Significant age-related declines were observed across all behavioural measures and all tracts except for the right CB, bilateral SLFI, and left SLF II (Fig. 1 & 2). Significant tract - task correlations were identified across several different pathways and behavioural measures. For example, the left IFOF HMOA was associated with behavioural measures of attention and spatial working memory (Fig. 3). Contrary to our predictions, no mediation effects were found within the proposed tract - task groupings shown in Fig. 3. Instead, during exploratory analysis, HMOA of the left UF demonstrated a small to medium indirect effect on age-related decline in planning performance in healthy adults (Fig. 4).

Discussion

The results from this study have established that manual and semi-automated dissection protocols are reliable for both young and older adults in a number of white matter pathways. This study also replicated age-related decline of all behavioural measures and described for the first-time ageing trajectories of the FAT and SLFI - III. The tracts observed to align to different facets of executive function were not those that we predicted. For example, while there are reports regarding the role of the SLF system in attention and motor processes (Howells et al., 2018; Thiebaut de Schotten et al., 2011), this group of pathways did not align themselves to the measures of attention used in this study. It could be speculated that the SLF system operates as part of a wider network and as such does not present as the primary tract system for these functions. Of note was the appearance of the IFOF in association with two of the behavioural measures, which could be indicative of the predominantly visual presentation of these tasks, emphasising the important link between visual attention and executive function previously postulated (Furey, et al, 2000). The observation of a mediatory role of the left uncinate in age-related decline of planning provokes questions of whether this tract’s role in inhibitory processing or verbal mediation may contribute towards the completion of this planning task.

Conclusion

These results provide promising support for the use of semi-automated methods in diffusion tractography across the adult lifespan. The tract – task associations provide new evidence of both common and different white matter pathways supporting different facets of executive function. Lastly, the role of the left uncinate may indicate a new target for future research in identifying anatomical vulnerabilities associated with either executive decline during normal aging or executive dysfunction in patient groups.

Acknowledgements

This abstract represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

References

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