Increased Total Urinary Cortisol (tUC) and Serum Brain-derived Neurotrophic Factor (BDNF) Ratio in Alzheimer Disease (AD)-affected Patients

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Stress and stress-induced glucocorticoids have been involved in many neuropsychiatric disorders, including Alzheimer disease (AD).1 The “glucocorticoids cascade hypothesis” has been proposed as one of the pathogenic mechanisms of AD. This theory arose from the initial observation of high cerebrospinal fluid cortisol levels in AD patients, together with experimental evidence that increased glucocorticoids levels could damage the hippocampus.2 According to the glucocorticoid cascade hypothesis, a hyperactive hypothalamic-pituitary-adrenal (HPA) axis results in hippocampal damage, which causes disinhibition of the glucocorticoid-negative feedback, leading to a subsequent increase in glucocorticoids levels.2 In AD patients, increased plasma cortisol levels were associated with a more rapid disease and cognitive deficit progression and also positively correlated with brain Aβ burden measured by Pittsburgh Compound B-positron emission tomography studies.3 Stress-induced activation of the HPA axis has been reported to accelerate the neuropathogenic mechanisms underlying AD. Both clinical and experimental studies identified chronic stress as a risk factor for developing AD.4 One of the main factors mediating stress-related changes in hippocampal neuroplasticity is represented by the neurotrophin brain-derived neurotrophic factor (BDNF). In fact, excessive glucocorticoids have been linked to a decrease in BDNF expression and, consequently, of the dendritic arborization in hippocampal pyramidal neurons.5 Glucocorticoids have been involved in central BDNF regulation through glucocorticoid receptors,6 and the HPA-axis hyperactivity has been demonstrated to reduce hippocampal BDNF expression in mice.7 However, in AD patients, the relationship between cortisol, BDNF, and decline in cognitive functions remains unclear. Therefore, this study aimed to evaluate the relationship between serum BDNF levels, the total (24 h) urinary cortisol (tUC), their ratio (tUC/BDNF), and cognitive functions in drug-naive AD patients and age-matched healthy controls (HC).

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