Epigenetic signatures of chronic inflammation and their relation to brain structure and function across the lifecourse
Conole, Eleanor Lucy Shepherd
Chronic inflammation is considered a key contributor to individual differences in brain ageing. However, there remains conflicting evidence about the exact brain structural and functional consequences of chronic inflammation. Part of this ambiguity comes from the lack of robust biomarkers used to characterise chronic inflammation, with most studies conflating acute vs chronic inflammation and relying on single time point sampling of highly phasic inflammatory markers from blood. Recent research indicates the potential of epigenetics to circumvent this issue, in particular the use of DNA methylation (DNAm) to provide a biological archive of inflammatory burden. DNAm is an epigenetic mechanism that regulates gene expression and acts as an interface by which lifestyle and environment can influence phenotype; alterations in DNAm are increasingly investigated as proxies for certain exposures, traits, and conditions. This thesis explores chronic inflammation and its relation to brain health using a multi-omic approach, examining associations of proteomic and DNA methylation signatures of inflammation with brain measures from structural and diffusion MRI and cognitive ability at different stages of the lifecourse. Following introductory chapters presenting overviews of epigenetics, inflammation and neuroimaging and cognitive metrics, the empirical work of this thesis examines these interrelationships in three population cohorts covering the human lifespan: from infancy in Theirworld Edinburgh Birth cohort (TEBC; age < 1 year), to mid to late adulthood in Stratifying Longitudinal Resilience & Depression Longitudinally cohort (STRADL; age ~ 60 years, range 28 – 81 years), to older-age in the Lothian Birth Cohort 1936 (LBC1936; age ~ 73 years). First, neuroimaging and cognitive associations of chronic inflammation in older age are examined. In 521 individuals from the LBC 1936 cohort, associations between a DNA methylation predictor of C-Reactive Protein (DNAm CRP) and brain structure and cognition are shown to be consistently stronger (6.4-fold greater on average) than those with traditional serum CRP measures: with higher DNAm CRP levels significantly associated with global and regional brain atrophy (β range |0.200| to |0.150|), differences in white matter microstructure and white matter hyperintensity burden (β range |0.099| to |0.162|), and poorer global and domain- specific cognitive functioning (β range |0.095| to |0.158|). This paper also demonstrates that the association between inflammation and cognitive ability is partially mediated by brain structure (up to 29.7%), dependent on lifestyle and health factors. The second empirical chapter replicates this association of an epigenetic inflammatory signature with brain and postnatal health outcomes in early life. In a neonatal cohort of 258 infants, the relationship between DNAm CRP with perinatal health and neuroimaging outcomes is investigated. The results support the theory that DNAm may be leveraged to capture a more cumulative impact of inflammatory burden, with DNAm CRP being higher in preterms compared to term infants and higher DNAm CRP levels associating with perinatal inflammatory-related morbidities (such as late onset sepsis and histologic chorioamnionitis) both individually and in aggregate (OR range |2.00 | to |4.71|). The main finding – that elevated DNAm CRP associates with poorer measures of white matter, both globally and regionally (β range |0.206| to |0.371|) – is considered in the context of how early birth associates with an increase in immune-related risks, which coincide with windows of neurodevelopmental plasticity, highlighting the vulnerability of developing white matter to inflammatory insults. Finally, the brain health associations of signatures of inflammation in midlife are considered. In 709 participants from the STRADL cohort, DNAm signatures for CRP alongside a range of other inflammatory-immune mediators are constructed and compared against protein levels in relation to neuroimaging and cognitive metrics. 73 unique DNAm signatures associated with numerous aspects of global brain structure and cognitive ability (β range |0.097| to |0.200|), alongside regional atrophy across the brain's cortex (β range |0.087| to |0.260|) and focal vulnerability of specific white matter tract microstructure (β range |0.103| to |0.185|). Many of these DNAm-brain associations were larger than the analogous proteome-brain associations, broadly independent of immune-cell proportions, clinical risk factors, and had previously been linked to various age-related diseases, reinforcing the central role that inflammation plays in health trajectories. The results of this chapter suggest that associations with chronic inflammation and brain structure are apparent in mid to late adulthood and may precipitate and underlie changes in cognitive functioning seen in older-age. This PhD characterises the global and regional associations of chronic inflammation on brain structure at different stages of life, elucidating new perspectives on how these mechanisms may be contributing to individual differences in cognitive ability. I highlight the potential of the developing field of epigenetics to offer a solution to the traditional limitations of assessing inflammatory burden in human cohorts, and how this may be used to gain a better understanding of how inflammation relates to aberrant neurodevelopment and cognitive decline. These findings provide new insights about the extent of inflammation’s impact on brain health, as well as highlighting the utility of DNAm for risk prediction and stratification in relation to brain health outcomes.