The proposed study will delineate mechanism underlying the effects of chronic obesity on brain functioning and determine if cognitive benefits of bariatric surgery and weight loss contribute to enhanced cerebral metabolic or hemodynamic function assessed using multimodal neuroimaging methods. The contribution of post-surgical improvements in diabetes-associated insulin-glucose disturbances will be tested. Obesity has reached epidemic proportions and is now a major public health problem, contributing to various comorbid medical conditions, including brain disturbances. There is increasing evidence that chronic obesity may adversely affect the brain, even in the absence of comorbid diseases, such as diabetes, cardiovascular disease, and stroke. We have previously shown that elevated body mass index (BMI) is associated with reduced cognitive function. Increasingly, bariatric surgery is being used as a treatment for chronic morbid obesity. Besides causing dramatic weight loss in many patients, bariatric surgery alters systemic metabolic and vascular function, including altering insulin and glucose metabolism. Our initial findings from a multicenter longitudinal study of bariatric surgery indicated that people experience improvements in neurocognitive functioning, including memory recall, by 12 weeks post-surgery. These benefits continue over 12 months and are related not only to the amount of weight lost, but also changes in underlying risk factors, such as improved metabolic function, and remission of type-2 diabetes Neuroimaging provides a potentially powerful biomarker of alterations in brain structure and function (e.g., FMRI), as well as cerebral pathophysiology. To date no published studies have examined neuronal, metabolic and vascular brain changes following bariatric surgery as proposed in this study. Our preliminary neuroimaging data indicates enhanced functional brain response on FMRI, increased regional cerebral blood flow on arterial spin labeling (ASL), and changes in cerebral metabolite levels on magnetic resonance spectroscopy (MRS). We hypothesize that: 1) Cerebral metabolic and hemodynamic disturbances linked to obesity adversely affect brain function (evident from cognitive testing and FMRI);2) Weight loss and associated metabolic changes post-bariatric surgery improve brain functions;and 3) Enhanced neurocognitive and neuronal function (FMRI) are due to improved cerebral metabolic (MRS) and vascular (ASL) function. Remission of diabetes is expected to be one factor accounting for these effects, though this effect will also be tied to improved cerebral (MRS) and systemic (e.g., serum cytokines) metabolic health and cerebral perfusion (ASL). A prospective longitudinal cohort matched design will be used to assess changes in these neuroimaging indices, pre- and post-surgery and relative non-surgical obese controls. The groups will have equal proportions of diabetics and non-diabetics with obesity, enabling us to test its influence. By examining obesity and weight loss in the context of bariatric surgery, this study capitalizes on a powerful natural experimental manipulation that can provide a unique window into the effects of obesity and weight loss on the brain.
Obesity is a major public health problem that not only underlies many medical conditions, including diabetes and vascular disease;it also contributes to brain dysfunction. We have previously shown elevated body mass to be associated with mild neurocognitive dysfunction, in the absence of comorbid disease and we have also shown improvements in cognitive functioning following bariatric surgery. The proposed longitudinal study will examine whether cerebral metabolic and vascular dysfunction, including glucose/insulin disturbances (co- morbid diabetes) underlie obesity-associated cognitive dysfunction, and whether significant weight loss and diabetes remission following bariatric surgery reduces these disturbances.
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