Exercising against the depressing side of ‘inflammageing’: something to remember for dementia prevention

Abstract

Dementia is a leading global health challenge. Undoubtably, prevention strategies are urgently required to address the exponential growth in dementia prevalence. It has been estimated that up to a 30% decrease in dementia prevalence can be achieved via the reduction of modifiable risk factors through lifestyle and medical management [4]. In order to attenuate or delay dementia onset, it is essential to understand the prodromal phases of the disorder and how certain risk factors may individually or cumulatively contribute to dementia pathology and cognitive decline. Mild Cognitive Impairment (MCI) is commonly known as the prodromal stage of dementia. During this stage, not only are clinical signs of cognitive decline apparent, but also neurobiological changes in cortical and subcortical structures of the brain [5]. One of the earliest affected and most vulnerable subcortical structures, is the hippocampus. Indeed, hippocampal atrophy is a hallmark of Alzheimer’s disease (AD), which accounts for up to 70% of all people with dementia [6]. Importantly, although those with MCI are at high risk for developing dementia, a proportion of these individuals’ cognition may remain stable or even revert back to normal functioning. It is estimated that there is a reversion rate of between 8% (clinical-based studies) and 25% (population-based studies) [7]. This difference in trajectory between MCI and insidious dementia onset, and MCI and reversion back to normal cognitive functioning sheds light on important research rationales. Firstly, this difference in clinical trajectory may be due to variation in comorbidities of ageing disorders with MCI that may exacerbate or accelerate the disease progression. Simultaneously, those who revert back to normal cognition may be benefiting from lifestyle activities and practices that may reduce, manage or resolve some dementia modifiable risk factors. Without adequate sensitive and specific detection of clinical biomarkers for MCI and even dementia, however, a third reasoning behind reversion rates is undeniable. That is, the potential of false positive diagnoses of MCI at baseline measures which may also lead to misattribution error in the cause or benefits of certain treatments in reverting cognitive deficits. Therefore, until more sensitive and specific diagnostic tools are available for MCI, results from intervention and current longitudinal studies investigating the reversion of cognitive decline in MCI must be interpreted with caution. Regardless, studies are should examine common comorbid disorders that predispose individuals to dementia risk, and how they differ to those without comorbidity. Further, exploration into the neurobiological underpinnings associated with the differences (if any) are required in order to develop targeted treatment strategies. Finally, the investigation into the effects of lifestyle interventions on neurobiological differences are recommended to determine whether or not it is capable of reducing dementia risk. Depression acts as both an independent risk factor for dementia as well as a factor shown to significantly heighten the risk of MC-to-dementia conversion. Previous studies have shown that those with comorbid depression and MCI are more than twice as likely to develop AD than those with MCI alone [8]. The hippocampus is implicated in dementia studies as well as studies in MCI and depression. However, studies comparing those with and without a history of depression in MCI are lacking, with the majority of current literature focusing on current major depression. This is a particularly important area to study as cognitive deficits often remain and manifests despite clinical remission [9]. Nevertheless, there have been numerous studies suggesting that inflammation may be driving mechanism by which depression and MCI may progress into dementia. Although, these studies have conflicting results with regards to which inflammatory markers are involved since most studies only include one to three inflammatory markers. In order to address the above-mentioned gaps in the current literature, this thesis commences with a review of the literature characterising MCI as a prodromal stage for dementia, and exploring depression as a comorbid disorder that has the potential to accelerate or exacerbate the neurodegenerative processes. In particular, this thesis investigates the implications of a lifetime depression history on hippocampal volumes from transversely segmented subfields as well as longitudinal head/body/tail (H/B/T) segmentations, and memory encoding and retention. Importantly, MCI can be further categorised into amnestic MCI (aMCI) and non-amnestic MCI (naMCI) subtypes. Prior studies have shown that hippocampal changes in aMCI are likely to be driven by accumulating amyloid beta and tau pathology, and these individuals are at greatest risk for progression to Alzheimer’s disease (AD) [10-14]. By contrast, the neuropathology underpinning hippocampal changes in depression and naMCI, remains unclear [15, 16]. Whilst there has been evidence to suggest that inflammation may be a key link with depression, naMCI and dementia, the current body of literature is conflicting with regards to which inflammatory markers may be involved and studies of inflammation in remitted or subthreshold depression are lacking. Therefore, more focus of this thesis has been placed on older adults with naMCI, comparing those with and without a history of depression to elucidate possible differences between the two groups. Further, we explored the potential role of common systemic inflammatory marker C-Reactive Protein (CRP), in differentiating those with and without depression history through relationships with hippocampal subfields and H/B/T subregions. Finally, this thesis investigated, in a pilot randomised controlled trial, the effects the CogStep combined home-based exercise and psychoeducation program on a broad range of inflammatory markers, hippocampal subfields and H/B/T subregions, mood and cognitive outcomes in older adults with cognitive difficulties. In the first empirical study, presented in Chapter 3, we examined whether a history of depression affects the subiculum, CA1, DG subfields and H/B/T subregion volumes bilaterally in older adults with naMCI and whether the relationships between our hippocampal regions of interest and memory encoding and retention differed in those with and without a history of depression. We found in this cross-sectional study, that volumetric change was circumscribed to the right CA1 in those with a history of depression. Contrary to our hypothesis, we found that those with a history of depression had significantly larger right CA1 volumes. Importantly, the relationship between the right CA1 and both memory encoding and retention measures differed significantly between those with and without a depression history. Hence, for the first time in the literature, we have demonstrated that a lifetime history of depression significantly affects the relationship between hippocampal volume and memory encoding and retention in individuals with naMCI. This in turn, suggests that there may be different neuropathological underpinnings between those with and without a depression history that are unlikely due to the deposition of amyloid beta and tau pathology. In Chapter 4, Study 2 is presented, where the potential role of CRP in differentiating between those with and without a depression history was explored in older adults ‘at risk’ for dementia, namely those with naMCI or subjective cognitive complaints (SCC). Interestingly, when examining the clinical and imaging data cross-sectionally, data showed that a history of depression was associated with lower levels of CRP in blood. This is a contrasting result compared to other studies that have demonstrated higher levels of inflammation in patients with major depression. However, our results may be reflective of the acute and non-specific nature of CRP and therefore future studies should examine a broad range of inflammatory markers, comparing acute, chronic, or remitted depressive states. In addition, we found that elevated levels of CRP were significantly associated with smaller right hippocampal head and right CA1 volumes in those who have never experienced a depressive episode in their lifetime. The results from this study provides the basis for future studies investigating the aetiology behind reduced right CA1 volume and greater CRP concentration in those without a depression history and explore how this affects the clinical trajectory towards dementia onset. Of significance, as part of this study, we also validated the transversely segmented subfields by comparing T1 MPRAGE outputs to data obtained from high-resolution T2-weighted imaging of the hippocampus. Notably, we showed high concordance between the segmentation, thereby validating the use of T1 data in Studies 1-3 of this thesis. Finally, Study 3, presented in Chapter 5, provides findings from the ‘CogStep 2.0’ randomised controlled clinical pilot study. This study investigated the effects of a 12-week combined exercise and psychoeducation CogStep intervention on a broad range of inflammatory markers, hippocampal subfield volumes, cognition and mood in older adults with cognitive difficulties. Specifically, we examined the levels of CRP, IL-1, IL-6, IL-8, IL10, IL-12p70, and TNF-, which have been previously implicated in depression and dementia studies [17-19]. In this study, our results showed that our CogStep intervention produced significant reductions in TNF and IL-levels and increased upper body strength at 12-week follow-up. There were no significant differences in hippocampal volumes, verbal memory and mood in the group by time analyses. Despite this, when we compared those with and without a history of depression in exploratory analyses, we observed that there were moderate-large effects of depression history on change over time for CRP, TNF- and right hippocampal head volumes. Therefore, our findings warrant future investigations in larger studies with longitudinal follow-up periods to explore the relationship between change in inflammatory markers and hippocampal head volumes, and comparing the effects of exercise on those with and without a history if depression. In conclusion, this series of studies provides preliminary evidence that there may be aetiological differences and neuropathological underpinnings of cognitive impairment for those with and without a lifetime history of depression. Of note, this thesis has shown that acute-phase inflammatory markers have an inverse relationship with hippocampal subfield and subregion volumes in the context of depression history. Importantly, we have explored a wide range of inflammatory markers and have demonstrated that our combined exercise and psychoeducation program may specifically reduce TNFand IL- levels. The synthesised findings of this thesis provide valuable clinical insight into the role of systemic inflammation and depression history in individuals who are at risk for developing non-AD types of dementia. Additionally, this thesis supports the implementation of lifestyle changes aiming to address modifiable risk factors of dementia. Large population studies with longitudinal tracking are now required to confirm whether a depression history and associated inflammatory markers affects clinical trajectories, and how lifestyle changes are able to delay or attenuate dementia onset.