Elevated body-mass index is associated with reduced white matter integrity in two large independent cohorts
Introduction
Obesity is a major challenge for public health especially in developed countries with an estimated worldwide prevalence of 13% (World Health Organization, 2014). To avoid further spreading of this preventable condition, a better understanding of the etiological mechanisms leading to excessive weight gain appears crucial.
In this regard, genetic and neuroimaging research has cumulated evidence for neurobiological correlates of obesity pointing to a key role of altered brain structure and function in the development of excessive weight gain (Batterink et al., 2010; Bobb et al., 2014; Burger and Berner, 2014; Locke et al., 2015; Opel et al., 2015a, Opel et al., 2015b; Raji et al., 2010). More specifically, gray matter volume reduction in the medial prefrontal cortex and the striatum are among the most replicated findings in neuroimaging studies in obesity research (Opel et al., 2015b; Pannacciulli et al., 2006; Shott et al., 2014). Moreover, results from a recent study carried out by our group suggest that these prefrontal brain structural alterations might be an intermediate phenotype that mediates the genetic risk for obesity (Opel et al., 2017).
However, while the relevance of gray matter atrophy in obesity has recently been confirmed by a number of highly powered studies including replication in several independent cohorts, large scale evidence for altered white matter integrity in obesity and replication of such findings is widely lacking up to now. Lack of statistical power in many studies as well as diverging methodological aspects (region-of-interest (ROI) vs. whole brain approaches, tract-based spatial statistics (TBSS) vs. tractography approaches) have prevented comparability and replication among diffusion tensor imaging (DTI) research in obesity.
Among the available studies that addressed white matter abnormalities in obesity, reduced white matter integrity in a variety of fiber tracts was frequently demonstrated in rather small samples (Karlsson et al., 2013; Mueller et al., 2014; Stanek et al., 2011; Xu et al., 2013). Up to now, evidence from the largest available study population of 268 healthy subjects comes from a TBSS study carried out by Papageorgiou et al. and suggests widespread reduced fractional anisotropy (FA) to be associated with higher body mass index (BMI) values in the thalamic radiation, the inferior fronto-occipital fasciculus and the inferior longitudinal fasciculus (Papageorgiou et al., 2017). Findings from a ROI based DTI study investigating white matter differences in the corpus callosum and the fornix support this association between higher BMI and reduced FA (Stanek et al., 2011). Fractional anisotropy (FA), which can be seen as a quantitative index of white matter coherence (Soares et al., 2013), has become the most common DTI measure in voxel-based analysis (Teipel et al., 2014). The current belief is that high FA values represent highly organized and normally myelinated axon structure. Thus, reduced FA can be interpreted as a loss of coherence in the main preferred diffusion direction and therefore points to deficits in white matter microstructure and integrity (Soares et al., 2013).
Interestingly, altered white matter integrity has also been associated with several obesity related conditions such as metabolic syndrome and hypertension (Alfaro et al., 2017; Maillard et al., 2012). Yet, to the best of our knowledge no previous DTI study investigating obesity related white matter alterations controlled for the presence of further cardiovascular risk factors such as hypertension or metabolic disorders.
Since reduced integrity of white matter tracts has been described for a variety of neurological (Kern et al., 2011; Melzer et al., 2013) and psychiatric diseases (Benedetti et al., 2015; Kochunov et al., 2017; Repple et al., 2017), large-scale investigation and replication of white matter microstructure alterations in obesity appears to be of great importance to provide a reliable basis for a better understanding of potential neurobiological overlaps between obesity and psychiatric disorders.
Therefore, with the present study we aimed to investigate whole brain white matter alterations associated with obesity in two large independent samples of healthy adults. Based on the previous findings of reduced FA in obesity in diverse white matter tracts, we hypothesized that elevated BMI values would be associated with significantly reduced FA in several, widespread white matter tracts including the thalamic radiation, the inferior fronto-occipital fasciculus, the inferior longitudinal fasciculus, the fornix, and the corpus callosum and that these findings could be replicated in an independent sample. Regarding the previous evidence for associations between white matter alterations and hypertension as well as metabolic syndrome, we furthermore investigated whether the association between FA reductions and BMI would occur independently of further cardiovascular risk factors by controlling for Hemoglobin A1c (HbA1c) and systolic blood pressure in our analyses.
Section snippets
Participants
373 subjects participated in the present study as part of the Münster Neuroimaging Cohort (MNC). Subjects of the MNC study were recruited via newspaper advertisement with no apparent link to obesity. Exclusion criteria were any history of severe neurological (e.g., concussion, stroke, tumor, neuro-inflammatory diseases) and medical (e.g. cancer, chronic inflammatory or autoimmune diseases, diabetes mellitus, infections) conditions as well as any presence or history of psychiatric disorders
Results
Both cohorts significantly differed with regard to age as assessed using a two-sample t-test (MNC: mean age = 39.39, SD = 11.24; HCP: mean age = 28.75, SD = 3.68; p < .001). Moreover, as could be expected, BMI was significantly positively correlated with age in both samples with a more pronounced association in the MNC sample which included participants with a wider age range (MNC: r = 0.283, p < .001; HCP: r = 0.080, p = .009). In the HCP sample, again as expected, we also found significant
Discussion
The present study demonstrates robust and widespread associations between BMI and reduced white matter integrity in two independent cohorts of healthy adults. The present work represents the currently largest effort to investigate obesity related alterations in white matter and provides direct replication in an independent cohort underlining the relevance of impaired white matter integrity in the neurobiology of obesity.
Our results are in line with previous DTI research indicating reduced FA in
Conflict of interest
Arolt is a member of the advisory board of, or has given presentations on behalf of, the following companies: Astra-Zeneca, Janssen-Organon, Lilly, Lundbeck, Servier, Pfizer, Otsuka, and Trommsdorff. These affiliations are of no relevance to the work described in the manuscript. H. Kugel has received consultation fees from MR:comp GmbH, Testing Services for MR Safety. This cooperation has no relevance to the work that is covered in the manuscript. The other authors declare no conflict of
Acknowledgments
This work was funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 to UD; SFB-TRR58, Projects C09 and Z02 to UD), the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD) and was supported by the deanery of the medical faculty of Münster.
Data were provided [in part] by the Human Connectome Project, WU-Minn Consortium (Principal Investigators: David Van Van Essen and Kamil Ugurbil; 1U54MH091657) funded
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2021, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Most of the studies using FA found a loss of WM integrity with impaired cognitive function in obese individuals (Alfaro et al., 2018; Karlsson et al., 2013; Kullmann et al., 2015; Stillman et al., 2017; Verstynen et al., 2013; Zhang et al., 2018). More specifically, increasing obesity measurements such as body mass index (BMI) appear to be associated with lower FA values in the corpus callosum (Karlsson et al., 2013; Papageorgiou et al., 2017; Repple et al., 2018; Stanek et al., 2011; Xu et al., 2013; Zhang et al., 2018), the cingulum (He et al., 2015; Papageorgiou et al., 2017), the corona radiata (Dennis et al., 2014; Shott et al., 2015; Verstynen et al., 2013; Zhang et al., 2018), the corticospinal tract (Karlsson et al., 2013; Papageorgiou et al., 2017; Repple et al., 2018; Ryan and Walther, 2014), the cerebellar peduncle (Kullmann et al., 2016; Repple et al., 2018; Verstynen et al., 2013; Zhang et al., 2018) and many other tracts. Higher accumulation of visceral adipose tissue, a measure of body fat distribution, is also associated with lower FA values in several tracts (Cárdenas et al., 2020).
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This is to indicate that JR and NO contributed equally to the present work and should therefore both be regarded as first authors.