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ABSTRACT Obesity is a risk factor for neurodegenerative disease and has been shown to adversely affect cognitive function. Professional athletes who participate in sports, which expose them

to repetitive concussions, may be at heightened risk for cognitive impairment. Here, we investigated the effects of body mass as measured by waist-to-height ratio (WHtR) on regional cerebral

blood flow using single-photon emission computed tomography imaging in 38 healthy weight (WHtR mean 49.34±2.8; age 58±9.6) and 38 overweight (WHtR mean 58.7±4.7; age 58±13.3) retired

National Football League football players. After matching for age and position, we used a two sample _t_-test to determine the differences in blood flow in healthy versus overweight

subjects. Statistical parametric mapping revealed a higher WHtR ratio is associated with decreased blood flow in Brodmann areas 8, 9 and 10, brain regions involved in attention, reasoning

and executive function (_P_<0.05, family-wise error) along with deficits in the temporal pole. Moreover, overweight athletes had significant decrease in attention (_P_=0.01326), general

cognitive proficiency (_P_=0.012; Microcog: Assessment of Cognitive Functioning) and memory (_P_=0.005; Mild Cognitive Impairment Screen). The association between elevated WHtR percentage

and decreased blood flow in the prefrontal cortex and temporal pole may be correlated with the decreased performance on tests of attention and memory. These findings suggest that a weight

management program may be critical to the health of athletes who have been exposed to mild brain trauma during their careers. SIMILAR CONTENT BEING VIEWED BY OTHERS BLOOD AND MRI BIOMARKERS

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EXPERIENCE AND COGNITIVE PERFORMANCE BY FNIRS Article Open access 28 June 2024 INTRODUCTION Obesity is a growing epidemic in youth,1 collegiate2 and professional football players,3 thus,

potentially escalating the risk for cognitive impairment in a group that is already at risk due to repetitive subconcussive and concussive brain trauma. Recent studies have highlighted the

impairments in executive cognitive function in overweight healthy adults,4 but no study to date has investigated the effects of weight on brain function in professional athletes. This is a

unique population of strength-trained individuals who are required to have a higher body mass for competitive purposes. Body mass index was found not to be a valid indicator of overweight

and obesity in a collegiate football population,5 suggesting that the waist-to-height ratio (WHtR) is a more appropriate assessment of the healthy weight of an amateur or professional

athlete. We have observed that retired football players are susceptible to weight gain.6 Therefore, it is important to evaluate if the combination of weight gain and brain trauma in football

players has an additive negative effect on brain function. Using single-photon emission computed tomography (SPECT) imaging, we have previously demonstrated significant global decreases in

blood flow in a study of 100 retired professional National Football League (NFL) football players.7 In addition, we recently found a decrease in blood flow in the prefrontal cortex of

normal, healthy individuals who have an elevated body mass.8 On the basis of our previous findings, we hypothesized that similar blood flow deficits and cognitive deficits are present in a

group of overweight athletes who have been exposed to repetitive subconcussive or concussive collisions as compared with normal-weight players. To test our hypothesis, we measured regional

cerebral blood flow (rCBF) in 38 normal-weight and 38 overweight retired NFL players who had previously visited our clinic to participate in a brain trauma study. We utilized SPECT imaging

as a measure of blood flow, and we administered the Microcog: Assessment of Cognitive Functioning (MACF) and Mild Cognitive Impairment Screen (MCIS) to assess mental performance and

attention. We hypothesized an inverse correlation between WHtR percentage and scores on attention, reasoning and general cognitive function in addition to significant deficits in blood flow

in the prefrontal cortex. MATERIALS AND METHODS SUBJECTS We recruited a total of 100 active and retired players, representing 27 teams and all positions to participate in a study measuring

the impact of playing professional American football on long-term brain function7 (see Table 1 for demographics). Players were recruited from retired NFL Players Association meetings and by

participants informing other players about the study. Of these 100 subjects, 76 were participants in this study, as we were able to attain their waist sizes. Each player met our inclusion

criteria of being on an active NFL roster for a minimum of 3 years. We excluded subjects who could not cease taking psychoactive medications (recreational or otherwise) for an appropriate

washout period before scanning. In all, 12% of the participants had a prior or current history of psychoactive medication use. All subjects received an explanation of the research study and

gave written informed consent in accordance with an Institutional Review Board-approved protocol. EVALUATION Each participant was interviewed by a physician and completed a detailed history.

Weight and height were obtained on all participants and a WHtR was calculated by dividing the waist circumference in inches by height in inches. NEUROPSYCHOLOGICAL EXAMS As part of the

evaluation the MACF was administered. This exam measures the following nine parameters: general cognitive functioning, general cognitive proficiency, information processing speed,

information processing accuracy, attention, reasoning, memory, spatial processing and reaction time. The MACF scores were compared with its own standardized sample (_n_=810) chosen to be

representative to the US population of adults with regard to education, gender and ethnicity between the ages of 18 and 89. Participants were also given the MCIS,9 a screening tool found to

be reliable in distinguishing mild cognitive impairment from normal.10 SPECT SCANS In addition, each subject underwent high-resolution brain SPECT imaging to measure rCBF. Each subject

received an age/weight-appropriate dose of Technetium-99m hexamethylpropyleneamine oxime (Tc-99m HMPAO) intravenously. Subjects were injected in normal lighting while they performed the

Conner's Continuous Performance Test II. The radiopharmaceutical was injected 3 min after starting the 15-min test. All subjects completed the task. Subjects were then scanned 30 min

later using a high-resolution Picker Prism 3000 triple-headed gamma camera (Picker Int. Inc., Ohio Nuclear Medicine Division, Bedford Hills, OH, USA) with fan beam collimators, acquiring

data in 128 × 128 matrices, yielding 120 images per scan with each image separated by 3° spanning 360°. SPECT data were processed and attenuation correction performed using general linear

(Chang) methods. All images were reconstructed and resliced using an oblique reformatting program, according to anterior–posterior commissure line so that the final images were similarly

aligned for analysis. IMAGE ANALYSIS Differences in HMPAO uptake were analyzed using Statistical Parametric Mapping 8 software (Wellcome Department of Cognitive Neurology, London, UK)

implemented on the Matlab platform (Math Works, Sherborn, MA, USA). Statistical parametric maps (SPMs) are spatially extended statistical processes that are constructed to test hypotheses

about regionally specific effects in neuroimaging data. SPM combines the general linear model and the theory of Gaussian random fields to make statistical inferences about regional

effects.11 The images were spatially normalized using a 12-parameter affine transformation followed by non-linear deformations12 to minimize the residual sum of squares between each scan and

a reference or template image conforming to the standard space defined by the Montreal Neurological Institute template. The original image matrix obtained at 128 × 128 × 29 with voxel sizes

of 2.16 × 2.16 × 6.48 mm were transformed and resliced to a 79 × 95 × 68 matrix with voxel sizes of 2 × 2 × 2 mm consistent with the Montreal Neurological Institute template. The normalized

images were smoothed using an 8-mm full-width half maximum isotropic Gaussian kernel. STATISTICAL ANALYSIS SPECT scans from age- and position-matched normal-weight players were compared

with overweight retired NFL players using statistical parametric mapping (SPM) with t-contrast modeling. The linear relationship between WHtR and blood flow was evaluated using the SPM

multiple regression model. The differences in general cognitive function, general cognitive proficiency, reasoning, attention and memory were evaluated using SPSS statistical software for

Windows (SPSS, Chicago, IL, USA) and _P_<0.05 was considered statistically significant. RESULTS ELEVATED WHTR DECREASES COGNITIVE PERFORMANCE AND RCBF Average WHtR in our overweight group

was 58.7±4.7 (range 53–72.97) and in our healthy weight group was 49.34±2.8 (range 41.03–52.9) with the means being statistically different (_t_ (2,74)=10.473, _P_<0.001). Those with a

WHtR percentage under 53% were categorized as healthy weight. We matched players by age and position based on findings from our previous work with this NFL group which demonstrated a

significant relationship between position and cognitive function.7 Initially, we examined results of the general cognitive proficiency and the general cognitive function as an assessment of

cognition in those with increased WHtR using the MACF. A between-group ANOVA demonstrated decreases in general cognitive proficiency (_P_=0.017) and general cognitive function (_P_=0.025) as

a main effect. The decrease in general cognitive proficiency remained significant after Bonferroni correction for the two comparisons (_P_<0.025). To discern which factors contributed to

decreased general cognitive proficiency, we evaluated attention, memory, reasoning, information processing speed, and information processing accuracy between the two groups. These variables

were previously demonstrated to be areas of deficit as well as sensitive to improvement in our previous study.6 Consistent with the decrease in general cognitive proficiency, information

processing accuracy was significantly decreased (_P_=0.024) but not information processing speed; general cognitive proficiency is more sensitive to processing accuracy than speed. Of the

three underlying domains that contribute to an overall decrease in cognitive proficiency, we found decreases in reasoning (_P_=0.023) and attention (_P_=0.023) but not memory in those with

elevated WHtR using the MCAF. An independent evaluation of memory function using the MCIS, which is sensitive to age-related memory impairment, revealed significant deficits with increased

body mass (_P_=0.003). Our initial SPM analysis on brain SPECT concentration scans revealed global diffuse decreases in blood flow in the frontal, temporal and parietal lobes of subjects in

the elevated WHtR group at _P_<0.001, uncorrected for family-wise error (FWE; Figure 1). We then refined our analysis to include regions associated with focus, impulsivity and attention

(Brodmann areas 8, 9, 10, 11 and 44 ) based on previous data demonstrating elevated body mass index results in decreased executive function4, 13 metabolic activity14 and blood flow8 in the

prefrontal cortex. This analysis emphasized the regions of significant decreases were specific to Brodmann areas 8, 9 and 10 in the elevated WHtR group at _P_<0.05 FWE. Figure 2

illustrates the three-dimensional cortical representation of these brain regions and Table 2 provides the regional areas of significant decrease with the largest cluster size as identified

through SPM and defined by the Automated Anatomical Labeling Atlas. These areas include the left and right superior and middle frontal gyrus. No significant increases were observed. AS BODY

MASS INCREASES FRONTAL AND TEMPORAL LOBE PERFUSION DECREASES Linear regression analysis at _P_<0.001 FWE measuring the effect of WHtR on blood flow while controlling for age, predicts the

most significant decreases as reported by voxel cluster size in the following five regions: Region 1 has an overall cluster size of 2666 voxels and includes the left superior temporal pole

(coordinates −40, 16, –20; _t_=6.91), left frontal medial orbital cortex (coordinates −2, 30, –14; _t_=6.79) and left insular cortex (coordinates −28, 18, –16; and _t_=6.78). Region 2 has an

overall cluster size of 207 voxels and includes the left frontal medial orbital cortex (coordinates −8, 56, –14; _t_=6.35) and right rectus (coordinates 8, 56, –18; _t_=6.35). Region 3 has

an overall cluster size of 342 voxels and includes the right superior temporal pole (coordinates 48, 10, –14; _t_=6.23 and coordinates 32, 12, –32; _t_=7.10). Region 4 has an overall cluster

size of 253 voxels at the left middle frontal cortex (coordinates −32, 54, 20; _t_=6.22). Region 5 has an overall cluster size of 90 voxels and includes the frontal superior right cortex

(coordinates 14, −42, 52; _t_=6.17 and coordinates 18, 54, 42; _t_=5.96). Figure 3 illustrates these decreased areas of perfusion through transverse, coronal and sagittal slices.

Furthermore, a plot of the regression slope of region 1 (left superior temporal pole and left frontal medial orbital cortex) demonstrates a negative correlation between WHtR and blood flow

at _P_<0.001 FWE (Figures 4 and 5). This suggests that as body mass increases, the blood flow to both temporal pole and prefrontal cortex decreases. DISCUSSION Obesity is a worldwide

epidemic and is becoming an issue of concern in certain contact sports like football.1, 3, 5, 15 Previously, we have demonstrated significant global decreases in blood flow in a population

of retired NFL players compared with healthy subjects,7 and we have observed decreases in blood flow to the prefrontal cortex in a group of healthy, cognitively normal individuals who were

overweight.8 Here, we show that retired, overweight NFL players have significantly more decreases in blood flow in the prefrontal cortex and temporal pole, and greater cognitive impairment

than those retired NFL players categorized as normal weight. It appears that both playing professional football and being overweight result in additive risk factors for decreasing blood flow

and cognition. The prefrontal cortex is the brain's executive processing center, allowing for cognitive flexibility, planning and forethought. This circuitry is involved in gathering

and consolidating input required for complex behavior, thus allowing for a top–down processing of information.16, 17 In essence, the prefrontal cortex functions as a highly tuned processing

center with projections to the sensory and motor cortical systems, ultimately allowing for the output of proper goal-oriented behavior. When this connectivity becomes disrupted, deficits in

cognitive flexibility, information processing speed, reasoning and attention ultimately result. In our cohort of overweight NFL players, we observed significant blood flow deficits

specifically in the dorsolateral prefrontal cortex (Brodmann areas 8, 9), regions involved with processing of visuospatial and motor information and the anterior prefrontal cortex (BA 10), a

region involved in memory retrieval and executive function. We also observed significant hypometabolism in the left temporal pole, which is associated with a variety of higher-order

cognitive processes including emotion, attention, behavior and memory. As the temporal pole has extensive connectivity with the hippocampus and the frontal lobes, the blood flow deficits

observed in the overweight players correlate well with the cognitive processing impairments present on the neuropsychiatric examinations. Mild traumatic brain injury results from repetitive

subconcussive impacts to the head and football players at the high school, collegiate and professional level are vulnerable to the cognitive deficits and long-term neurodegenerative

complications that may accompany it. It is without question that NFL players are at a heightened risk for cognitive impairment18 and dementia. Although the pathogenesis underlying traumatic

brain injury is not clearly understood, histological data demonstrate that the deposition of tau proteins, amyloid plaques and neurofibrillary tangles following repetitive head injury can

increase susceptibility to chronic traumatic encephalopathy, a progressive neurological disorder documented in the autopsied brains of professional athletes involved in contact sports.19,

20, 21 The mechanical forces from repetitive head trauma rupture delicate cell membranes and alter the fidelity of the electrical signal that has been observed by our group7 and others.22

These subtle neurobiological changes that can influence cognition may ultimately usher in the more chronic effects of traumatic brain injury, including diffuse axonal injury, ischemia,

synaptic loss and demyelination. The combined metabolic changes and alterations in neuronal integrity result in the global hypometabolism that we have previously reported in this population

of athletes.7 In addition to the obvious risk factors from playing contact sports, the additive impact of having excess body mass increases the propensity for further metabolic and

neurological complications. Anstey _et al._23 reported the results of a comprehensive meta-analysis on the association between body mass index and dementia, and found that categorization in

the overweight or obese range in midlife is a risk factor for dementia later in life. Obesity results in an upregulation of pro-inflammatory cytokines (C-reactive protein, tumor necrosis

factor α or interleukin-6) with a corresponding decrease in beneficial adipokines, triggering a cascade of apoptosis, neuroinflammation, microglia activation and blood–brain barrier damage

often observed with metabolic syndrome. Brain imaging studies have reported the deleterious effects of having a high body mass index being associated with lower brain volume24 and impaired

frontal lobe function.4, 8, 25 Therefore, it is clear that obesity has a role in compromised brain function, and we report here that retired NFL players who are overweight have greater

cognitive impairment and blood flow deficits in the prefrontal cortex and temporal pole as compared with their normal-weight cohorts. Obesity has been linked to executive dysfunction,4, 13,

25 and our cohort of overweight NFL players demonstrate decreased performance in the areas of attention and cognitive functioning upon neuropsychological evaluation. These observations may

correlate with the decrements in metabolic activity to the prefrontal cortex and temporal pole that we observe in our overweight athletes. Alternatively, the cognitive deficits may be

attributed to the elevated circulation of pro-inflammatory cytokines and biomarkers that result in myelin abnormalities, which have been documented in the frontal lobes of obese

individuals.26 With the heightened prevalence of obesity3 and cardiovascular disease risk factors27 in NFL players, our results suggest this trend will have negative, long-term consequences

on brain health and may lead to complications due to stoke or chronic traumatic encephalopathy. If this finding is replicated it indicates that proper weight education and management may be

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Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Amen Clinics, Newport Beach, CA, USA K Willeumier, D V Taylor & D G Amen Authors * K Willeumier View author publications

You can also search for this author inPubMed Google Scholar * D V Taylor View author publications You can also search for this author inPubMed Google Scholar * D G Amen View author

publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to D G Amen. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no

conflict of interest. ADDITIONAL INFORMATION AUTHOR CONTRIBUTIONS KW performed recruitment, testing and project management, and manuscript preparation. DT did the data analysis. DGA is the

primary investigator and evaluator of subjects. RIGHTS AND PERMISSIONS This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To

view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/ Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Willeumier, K., Taylor, D. & Amen, D.

Elevated body mass in National Football League players linked to cognitive impairment and decreased prefrontal cortex and temporal pole activity. _Transl Psychiatry_ 2, e68 (2012).

https://doi.org/10.1038/tp.2011.67 Download citation * Received: 27 September 2011 * Revised: 10 November 2011 * Accepted: 06 December 2011 * Published: 17 January 2012 * Issue Date: January

2012 * DOI: https://doi.org/10.1038/tp.2011.67 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is

not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * body mass index (BMI) * cognition * prefrontal

cortex * single photon computed tomography (SPECT) * temporal pole * waist-to-height ratio (WHtR)