Abstract
Background: N-acetylaspartate (NAA) is synthesized only by neurons and is involved in neuronal metabolism and axonal myelination. NAA is the strongest signal on brain magnetic resonance spectroscopy, and its concentration have been associated with cognitive dysfunction in neurodegenerative diseases, obesity, and type 2 diabetes (T2D).Materials and Methods: We explored the impact of obesity and T2D on circulating NAA as well as the impact of bariatric surgery and antidiabetic treatments. We developed an LC-MS method for the accurate measurements of fasting plasma NAA levels in 505 subjects (156 subjects with normal glucose tolerance, 24 subjects with impaired glucose tolerance, and 325 patients with T2D) to examine the associations of NAA with obesity and dysglycemia. To validate cross-sectional findings, plasma NAA was measured 6 months after Roux-en-Y Gastric Bypass (RYGB) in 55 morbidly obese subjects, and after 1 year of antidiabetic treatment (with dapagliflozin, exenatide, or dapagliflozin plus exenatide) in 192 T2D patients.Results: In the whole population, NAA was associated with age (r = 0.31, p <0.0001) and BMI (r = −0.20, p <0.0001). Independently of age and BMI, NAA was reciprocally related to HbA1c and fasting plasma glucose (partial r = −0.13, both p = 0.01). Surgically-induced weight loss raised NAA (by 18 nmol/L on average, p <0.02). Glucose lowering treatment increased NAA in proportion to the drop in HbA1c (r = 0.31, p <0.0001) regardless of the agent used.Conclusions: Circulating NAA concentrations are modulated by age, obesity, and glycemic control. Whether they may mark for the corresponding metabolic effects on brain function remains to be established by joint measurements of spectroscopic signal and cognitive function.
Highlights
Type 2 diabetes (T2D) and obesity increase the risk of serious complications in multiple organs, including the brain [1]
Obesity and T2D are associated with a higher prevalence of cognitive dysfunction, dementia, and neurodegenerative diseases, including Alzheimer and Parkinson diseases [2–5]
Microvascular disease induced by hyperglycemia is responsible for disruption of the blood-brain barrier (BBB) through pericyte depletion, possibly caused by excess superoxide produced during enhanced mitochondrial respiration [6, 7]
Summary
Type 2 diabetes (T2D) and obesity increase the risk of serious complications in multiple organs, including the brain [1]. Obesity and T2D are associated with a higher prevalence of cognitive dysfunction, dementia, and neurodegenerative diseases, including Alzheimer and Parkinson diseases [2–5]. Magnetic resonance spectroscopy (MRS) has provided details regarding metabolite changes in the brain that might be related to functional and structural alterations. Recent MRS-based analyses carried out in humans have suggested that N-acetylaspartate (NAA), the most concentrated metabolite in the brain (∼10 mM) [12– 14], is significantly reduced in several diseases including Alzheimer [15, 16], Huntington disease [17], bipolar disorder [18], schizophrenia [19], multiple sclerosis [20], and T2D [21–25]. NAA is the strongest signal on brain magnetic resonance spectroscopy, and its concentration have been associated with cognitive dysfunction in neurodegenerative diseases, obesity, and type 2 diabetes (T2D)
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