Research paperCumulative Cardiovascular Disease Risk and Triglycerides Differentially Relate to Subdomains of Executive Function in Bipolar Disorder; preliminary findings
Introduction
It is well-recognized that individuals with bipolar disorder (BD) are at an increased risk of cardiovascular disease (CVD) (Goldstein, 2017). Indeed, medical morbidity rates in BD are elevated relative to the general population, by virtue of a heightened prevalence of diabetes, obesity, dyslipidaemia, hypertension and a clustering of these CVD risk factors called the metabolic syndrome (Goldstein, 2017; Goldstein et al., 2009a; McIntyre et al., 2010). Not only do CVD risk factors contribute to increased mortality, but they may predispose to adverse brain health via vascular and/or immune and metabolic pathways. For example, available evidence in BD patients and those at-risk for the disorder, indicates that the anatomical structure of the brain is affected by body mass, with reductions in brain volume, thickness and white matter microstructure reported in overweight/obese individuals compared to those of normal weight (Bora et al., 2019; Kuswanto et al., 2014; Mansur et al., 2018).
It is previously documented that CVD risk factors associate particularly consistently with frontal lobe systems and the cognitive domain of executive function (Nishtala et al., 2014; Oveisgharan and Hachinski, 2010; Rostamian et al., 2015; Wiberg et al., 2010; Wolfe et al., 1990). This is thought to relate to an association of CVD-risk and white matter lesions in cortico-subcortical neural circuits that mediate executive processes rather than other neural circuitry, such as the medial temporal lobe, which governs memory (Prins et al., 2005; Pugh and Lipsitz, 2002; Rostamian et al., 2015; Tullberg et al., 2004). Relevantly, executive dysfunction in BD has been linked to deep white matter hypointensities (Rolstad et al., 2016), and while there is substantial evidence of cognitive impairment in BD across a range of domains, executive function is of key interest given meta-analytic evidence of large case-control effects and its relevance as an endophenotype (Balanzá-Martínez et al., 2008; Miskowiak et al., 2017; Van Rheenen et al., 2017; Van Rheenen and Rossell, 2014a). More pertinently, despite the sparse longitudinal cognitive literature in BD generally suggesting that the cognitive trajectory is set early on and remains stable across time (Van Rheenen et al., 2019), there is some preliminary longitudinal data suggesting that executive impairments specifically, may decline as a function of illness duration (Torrent et al., 2012). This raises the possibility that, in comparison to other cognitive domains, impairment in executive function in BD is more closely linked to CVD risk and morbidity; which is itself known to increase with age and has been associated with a more severe BD disease course (Calkin et al., 2015; Fiedorowicz et al., 2009; Rizzo et al., 2014).
The majority of studies in the burgeoning literature examining associations between CVD risk factors and cognitive function in BD have examined Body Mass Index (BMI) or the presence of obesity, defined categorically (Bora et al., 2019). A recent BD meta-analysis indicated that the most robust association between obesity/overweight and cognitive dysfunction was for the executive domain of cognition, consistent with prior work documenting a CVD risk - executive function association (Bora et al., 2019). To date, few BD studies of cognition have explicitly examined central obesity - indexed by waist circumference or waist-hip-ratio. There is evidence that central adiposity more strongly predicts health risk and mortality than BMI, and it therefore may have more relevance to cognitive function (Janssen et al., 2004; Staiano et al., 2012). Associations between waist circumference and increased impulsivity (Naiberg et al., 2016a), and between waist-hip-ratio and cognitive inhibition, immediate, and delayed verbal memory (Lackner et al., 2016), have been reported in preliminary BD studies. Worse executive function has also been found in BD patients with comorbid metabolic syndrome (Bai et al., 2016), with three studies showing associations between cognition and individual metabolic syndrome components (Hubenak et al., 2015; Hui et al., 2019; Naiberg et al., 2016a). In these studies, negative associations between high density lipoprotein (HDL) and language and memory (Hui et al., 2019), hypertension and global cognition (Hubenak et al., 2015) and triglycerides and executive function were reported (Naiberg et al., 2016a).
Identifying factors that may influence and/or be influenced by cognition in BD is relevant insofar as cognitive function is a critical mediator of psychosocial function (Mora et al., 2013; Solé et al., 2012; Van Rheenen and Rossell, 2014b). Available studies have generally not evaluated central-adiposity or dyslipidaemia with respect to cognitive performance in BD, nor the impact of dietary fat consumption despite its known implications for incident diabetes and mental well-being (Firth et al., 2019; Francis and Stevenson, 2013). Similarly, to our knowledge, no BD studies have examined the extent to which cumulative CVD risk impacts cognition in the disorder using the Framingham Heart Risk Score (FRS; Pencina et al., 2009). This sex-specific multivariable weighted score is elevated in BD and is strongly associated with cognitive decline in the ageing population (Coello et al., 2019; Kaffashian et al., 2013). It has been shown to be a better indicator of CVD events than the convergence of multiple risks factors subsumed within a diagnosis of the metabolic syndrome (Wannamethee et al., 2005).
Herein we aimed to evaluate the association between executive function and a composite risk score calculated using the Framingham Heart Study formula. We further aimed to evaluate the association of executive function and other CVD risk factors including BMI, waist circumference, serum triglycerides and dietary fat intake. Based on previous literature, we hypothesised that CVD risk factors would be higher in the BD group compared to controls, and that these risk factors would be associated with poor executive performance in the BD group.
Section snippets
Methods
All procedures contributing to this work comply with the ethical standards of the Alfred Hospital Human Ethics Review Board and with the Declaration of Helsinki Declaration.
Results
Group comparisons of the demographic and clinical characteristics of the sample are summarized in Table 1. Group comparisons of CVD risk factors and cognitive performance are reported in Table 2. BD patients were significantly older than controls (p=.011) but there were no differences in sex distribution (p=.627), or premorbid IQ (p=.207). Antipsychotics were used by 35% of the BD group, while mood stabilisers were used by 70%.
Numerically, BD participants had worse SCWT-I scores than controls
Discussion
In this study in the BD group only, higher CVD risk using the 30-year FRS was associated with worse cognitive inhibition, while higher triglyceride levels were associated with worse cognitive flexibility. The FRS and triglycerides explained around a third of the variance (29%) in cognitive inhibition and cognitive flexibility (35%) respectively. These correlations are consistent with existing research broadly linking CVD risk factors including BMI/obesity and the presence of metabolic syndrome
Author contributions
TVR conceived of the project, collected the data, conducted the data analyses, and prepared the first draft of the manuscript. All authors provided intellectual and editorial input and agreed to its final form.
Ethical Standards
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.
Declaration of Competing Interest
The authors have no potential conflicts of interest with respect to the research, authorship, and publication of this article.
Acknowledgements
The National Health and Medical Research Council (NHMRC) provided salary support to TVR (Early Career Fellowship 1088785), SR (Senior Research Fellowship 1154651) and MB (Senior Principal Research Fellowships 1059660 and 1156072). VBM acknowledges the support from Instituto de Salud Carlos III (PI16/1770, PROBILIFE study). The authors would also like to acknowledge the project specific financial support of the Helen McPherson Smith Trust and Australian Rotary Health/Bipolar Expedition. Finally,
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