Review articleDepression related cerebral pathology and its relationship with cognitive functioning: A systematic review
Introduction
Mental illness, particularly depression, has a long documented and complex relationship with neurodegenerative disorders and cognitive decline (Fuchs, 2007, Herbert and Lucassen, 2016). While both depression and dementia have been associated with brain pathology alterations, research examining how depression related cerebral pathology affects cognition is lacking. Current reviews almost exclusively examine the association between major depressive disorder (MDD) and cognitive impairment (Epp et al., 2012, Monteiro et al., 2016, Roca et al., 2015, Thomas and T O'Brien, 2008, Weisenbach et al., 2012), or MDD and its associated neurobiological abnormalities (Nascimento et al., 2015, Weisenbach and Kumar, 2014). Consequently, underlying structural and functional abnormalities and the effect depression subtypes, have scarcely been investigated together as contributing factors to cognitive impairment and decline (Brevik et al., 2013).
Greater depressive symptom severity is commonly linked to worse cognitive performance on neuropsychological tests, with domain-specific deficits in: memory, attention, executive functioning and processing speed (Roca et al., 2015). Reviews examining clinical diagnosis of depression and dementia illustrate that individuals with a history of depression have double the risk of developing Alzheimer's disease (AD) (Ownby et al., 2006). Similarly, the presence of depression in the prodromal stages of dementia, including mild cognitive impairment (MCI), is associated with regional white matter atrophy and an increased risk of accelerated cognitive decline (Steffens, 2012). A decreased conversion duration to AD has also been revealed in those with depression and high amyloid-beta (Aβ) levels (Brendel et al., 2015), whilst individuals with late life depression (LLD) have significantly altered levels and metabolism of Aβ similar to that seen in AD (Nascimento et al., 2015). These findings support previously suggested underlying pathways that connect depression and dementia (Butters et al., 2008b). Despite this relationship remaining ill-defined, it is suggested that depression's relationship with dementia is dynamic, acting as a risk factor, prodromal symptom, and comorbid condition (Leggett et al., 2013). Although this research demonstrates that a reciprocal relationship exists, their reliance on clinical diagnosis limits their interpretation of the intricacies of this association.
This multidirectional relationship has previously been suggested to result from depression subtypes, in particular early and late-onset depression (LOD and EOD; Janssen et al., 2006, Koenig et al., 2014, Tittmann et al., 2014). This differentiation appears to be important both in terms of the etiological and clinical understanding of these symptoms and is likely to highlight that, despite the overlapping symptomatology and co-occurrence in LLD, mechanistically these two forms of the disease are distinct (Dols et al., 2017). While distinguishing these subtypes on clinical features has had minimal success (Grayson and Thomas, 2013), reviews focusing on cognitive ability and cerebral pathology as distinguishing factors have been more fruitful. These studies have depicted greater processing speed and executive functioning deficits, and greater and more frequent white matter hyperintensities (WMH) in those with LOD compared with EOD (Herrmann et al., 2007; Herrmann et al., 2008). EOD is thus proposed to result from predominantly psychosocial factors (although genetic and pathophysiological underpinnings are likely involved) and is comparable to typical MDD. Alternatively, LOD is characterised by greater overall levels of cognitive impairment, as well as greater subcortical atrophy, vascular and amyloid burden (Herrmann et al., 2008, Choi et al., 2017).
To date, current systematic reviews have only focused on singular aspects of either cognition or cerebral pathology, or relied on clinical endpoints and not cognitive assessment, thereby overlooking the complex and interrelated association between depression and these constructs (Abbasowa and Heegaard, 2014, Herbert and Lucassen, 2016). Therefore, this review will synthesise the available literature regarding depression related cerebral pathologies, and the associated neurocognitive impairment.
Section snippets
Methods
This systematic review was conducted in adherence to the guidelines stipulated in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Moher et al., 2009).
Study characteristics and selection
From the 1647 unique papers identified, following the independent review of titles by two investigators, 418 studies were selected due to their relevance to the review. After reviewing abstracts and then the entire paper, 97 of those were deemed to be of importance in exploring the effect of depressive symptoms on cognitive impairment and cerebral pathology, with an 87% consistency rating between investigators. These papers included 62 cross-sectional studies, 22 longitudinal studies, and 13
The association between depression, hippocampal volume and cognitive functioning
Most structural imaging studies demonstrated that in depression, smaller hippocampal volume was associated with related memory dysfunction (De Winter et al., 2017, Elcombe et al., 2015, Frodl et al., 2006, Jayaweera et al., 2016, Jayaweera et al., 2015, Khan et al., 2015, Turner et al., 2012, Werner et al., 2009, Young et al., 2015). Though some studies illustrated no difference in hippocampal volume between depressed and comparison groups, they nevertheless demonstrate the associated cognitive
5. Summary of findings
Whilst the interaction between depression, cerebral pathology and cognition is intricate and complex, review demonstrates that the relationship is modified by the type of depression present –LOD or EOD. In this review, EOD has been characterised by cognitive impairments, predominately in memory and processing speed, and is associated with reversible hippocampal abnormalities. Conversely, LOD appears indicative of early neurodegeneration, and stem from a vast array of cerebral abnormalities
6. Review limitations
The studies included within this review were only those concerning depression's effect on cognition and cerebral pathology, and consequently, any study examining the reverse relationship was not included. Of the brain volumes investigated, this review predominately focused on hippocampal alterations and therefore some studies investigating other brain regions may have been missed. The lack of longer duration studies limited the ability of this review to accurately explore how this relationship
7. Conclusion and future directions
Recent literature indicates that the differences in symptomatology between EOD and LOD may be crucial to both understanding outcomes and providing efficacious treatment for individuals experiencing LLD. Therefore, and despite discrepancies within the literature, the differentiation between these categories is critical in the future examination of this question. Greater emphasis on the contributing factors for depression, the different subtypes, and the progression of this relationship in
Disclosure statement
Professor Szoeke has provided clinical consultancy and been on scientific advisory committees for the Australian Commonwealth Scientific and Industrial Research Organisation, Alzheimer's Australia, University of Melbourne and other relationships which are subject to confidentiality clauses. She has been a named Chief Investigator on investigator driven collaborative research projects in partnership with Pfizer, Merck, Bayer and GE. She may accrue revenues from patent in pharmacogenomics
Contributors
A.J, A.M.G, M.T, S.C and C.S all provided scientific input into the paper.
Study design and protocol: SC and CS provided list of potential projects for incoming students to the program. Systematic review methodology design: A.M.G, S.C and C.S
Results collection: A.J searched PsycINFO, EMBASE, MEDLINE, and Scopus for all relevant literature. A.J and M.T screened titles, abstracts and full texts for included articles, any disputes were then investigated further to determine their acceptability.
Funding details
Funding for the Healthy Ageing Program (HAP) has been provided by the National Health and Medical Research Council (NHMRC Grants 547600, 1032350 & 1062133), Ramaciotti Foundation, Australian Healthy Ageing Organisation, the Brain Foundation, the Alzheimer's Association (NIA320312), Australian Menopausal Society, Bayer Healthcare, Shepherd Foundation, Scobie and Claire Mackinnon Foundation, Collier Trust Fund, J.O. & J.R. Wicking Trust, Mason Foundation and the Alzheimer's Association of
Acknowledgements
We thank Melanie Formica for her valuable assistance and comments which greatly improved the quality of this manuscript.
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