Subclinical Cushing’s syndrome is a potential cause of metabolic dementia and rapidly progressive Alzheimer-type dementia
Introduction
Cushing’s syndrome (CS) is a clinical entity of the metabolic effects of glucocorticoid (GC) excess. The manifestations of CS involve many organ systems and metabolic disorders. Obesity, hypertension, diabetes mellitus, hirsutism, protein catabolism and hyperpigmentation are commonly seen in CS [1]. Additionally, inappropriate hypercortisolism can also cause several mental and mood changes such as impaired concentration, learning and memory (especially short term memory) deficits, delirium, psychosis, depression, euphoria and anxiety [2], [3].
Glucocorticoids have many neural functions that are mediated by the classic genomic effects via the intracellular GC receptors or nongenomic mechanisms. The effects of GCs in the brain are largely mediated through the interactions with two different receptors, named as type I (identical with mineralocorticoid receptors) and type II receptors (conventional GC receptors) [4]. GCs have the same affinity for both receptors in the brain because of the lack of the concomitant expression of 11ß OH steroid dehydrogenase. The type I receptors are expressed at highest levels in the limbic system, especially in the hippocampus. They have a higher affinity for GCs than the type II receptors [5]. The circadian rhythm of GC secretion is necessary for the normal functioning of different brain areas. Normal levels of GCs affect the limbic system by the type I receptors [6]. However, peak concentrations of GCs reduce the sensitivity of the hippocampus for the neural stimulations by type II receptors. In animal and human studies, it has been reported that the increased cortisol levels cause memory impairments and result in smaller hippocampal volumes [7], [8].
Dementia is a disorder that is characterized by the impairment of memory and at least one other cognitive function (aphasia, apraxia, agnosia and executive function) [9]. While loss of the short term memory is most prominent in the early stage, the disturbances in higher cortical functions and personality changes occur in late stages. Alzheimer’s disease, vascular dementia, dementia with Lewy bodies, dementia with Parkinson disease and frontotemporal dementia are the progressive and irreversible forms of dementia. Metabolic dementias are reversible forms of the dementia and are mostly caused by electrolyte imbalances, hypothyroidism, hypoglycemia, hyperparathyroidism, alcohol, vitamin B12 deficiency, hypoxemia and hepatic-renal failure [10]. Several risk factors, such as aging, family history, genetic factors and atherosclerotic risk factors (diabetes mellitus, hypertension, hypercholesterolemia and obesity), are accused in the development of dementia [11].
Section snippets
Hypothesis
Subclinical Cushing’s syndrome (SCS) causes autonomous GC over-production without the specific signs and symptoms of the CS which is much more common than classic CS [12]. The diagnosis of SCS is established by the GC secretion abnormalities in patients with incidentally discovered adrenal masses [13]. Various tests such as dexamethasone suppression, urinary free cortisol, ACTH levels, midnight serum or salivary cortisol concentrations and ACTH responses to CRH stimulation are used for the
Discussion
SCS is the most frequent (5–8%) hormonal abnormality detected in patients with adrenal incidentaloma which autonomously secrete cortisol [16]. Patients have mild hypercortisolism without the clinical manifestations of CS. However, it has been showed that patients with SCS may have cardiovascular risk factors such as obesity, hypertension, dyslipidemia and impaired glucose tolerance. The diagnosis of SCS is established by several laboratory studies (low baseline secretion of ACTH, lack of
References (23)
- et al.
Cushing’s syndrome
Endocrinol Metab Clin North Am
(2008) - et al.
The brain mineralocorticoid receptor: greedy for ligand, mysterious in function
Eur J Pharmacol
(2000) - et al.
The acute effects of corticosteroids on cognition: integration of animal and human model studies
Brain Res Brain Res Rev
(1997) - et al.
Essentials of the proper diagnoses of mild cognitive impairment, dementia, and major subtypes of dementia
Mayo Clin Proc
(2003) Subclinical Cushing’s syndrome
Endocrinol Metab Clin North Am
(2000)- et al.
The relation of cortisol levels with hippocampus volumes under baseline and challenge conditions
Brain Res
(2007) Psychiatric aspects of Cushing’s syndrome
QJM
(1996)- et al.
Cognitive decline in patients with Cushing’s syndrome
J Int Neuropsychol Soc
(2000) - et al.
Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation
Endocrinology
(1985) - et al.
Brain corticosteroid receptor balance in health and disease
Endocr Rev
(1998)
Corticosteroids: sculptors of the hippocampal formation
Rev Neurosci
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