Children experience cognitive decline despite reversal of brain atrophy one year after resolution of Cushing syndrome

Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1932, USA.
Journal of Clinical Endocrinology &amp Metabolism (Impact Factor: 6.31). 05/2005; 90(5):2531-6. DOI: 10.1210/jc.2004-2488
Source: PubMed

ABSTRACT Adults with Cushing syndrome frequently develop brain atrophy, memory impairment, and depression, with partial to complete resolution after cure. The effect of excess glucocorticoid exposure on the brain of children has not been systematically studied. Eleven children (six girls, five boys; ages, 8-16 yr) with endogenous Cushing syndrome seen at the National Institutes of Health Clinical Center from 1999-2000 and 10 healthy age- and sex-matched control subjects were studied. Cognitive and psychological evaluations and magnetic resonance imaging of the brain were done before and 1 yr after cure for patients with Cushing syndrome and once for controls. The estimated duration of Cushing syndrome was 4.4 +/- 1.2 yr. When compared with control subjects, children with Cushing syndrome had significantly smaller cerebral volumes (P < 0.001), larger ventricles (P = 0.02), and smaller amygdala (P = 0.004). At baseline, there were no significant differences in IQ between the two groups, and no psychopathology was identified. Despite reversal of cerebral atrophy 1 yr after surgical cure (total cerebral volume, 947 +/- 94 vs.1050 +/- 74 ml, P < 0.001; ventricular volume, 21.4 +/- 12.5 vs. 14.5 +/- 11.6 ml, P < 0.001), children with Cushing syndrome experienced a significant (P < 0.05) decline in Wechsler IQ scores (Full Scale, 112 +/- 19 vs. 98 +/- 14) and a decline in school performance, without any associated psychopathology. The effect of glucocorticoid excess on the brain of children appears to be different from adults. Despite rapid reversibility of cerebral atrophy, children experience a significant decline in cognitive function 1 yr after correction of hypercortisolism.

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Available from: Jay N Giedd, Aug 21, 2015
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    • "Notably, studies on hippocampal cell cultures showed that supraphysiological doses of glucocorticoids lead to a reversible phase of atrophy of the apical dendrites of pyramidal neurons [24]. In addition, glucocorticoids have been shown to increase the synaptic accumulation of glutamate and to stimulate the N-methyl-D-aspartate (NDMA) receptors with a subsequent increase in intracellular cytosolic Ca + in postsynaptic neurons, which activate several processes leading to neuron cell death [19] [22]. Of note, the partial reversibility of brain atrophy after a return to eucortisolism would indicate that the abovediscussed MRI abnormalities are not exclusively related to neuronal death. "
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    ABSTRACT: Various neurological and psychiatric manifestations have been recorded in children with adrenal disorders. Based on literature review and on personal case-studies and case-series we focused on the pathophysiological and clinical implications of glucocorticoid-related, mineralcorticoid-related, and catecholamine-related paediatric nervous system involvement. Childhood Cushing syndrome can be associated with long-lasting cognitive deficits and abnormal behaviour, even after resolution of the hypercortisolism. Exposure to excessive replacement of exogenous glucocorticoids in the paediatric age group (e.g., during treatments for adrenal insufficiency) has been reported with neurological and magnetic resonance imaging (MRI) abnormalities (e.g., delayed myelination and brain atrophy) due to potential corticosteroid-related myelin damage in the developing brain and the possible impairment of limbic system ontogenesis. Idiopathic intracranial hypertension (IIH), a disorder of unclear pathophysiology characterised by increased cerebrospinal fluid (CSF) pressure, has been described in children with hypercortisolism, adrenal insufficiency, and hyperaldosteronism, reflecting the potential underlying involvement of the adrenal-brain axis in the regulation of CSF pressure homeostasis. Arterial hypertension caused by paediatric adenomas or tumours of the adrenal cortex or medulla has been associated with various hypertension-related neurological manifestations. The development and maturation of the central nervous system (CNS) through childhood is tightly regulated by intrinsic, paracrine, endocrine, and external modulators, and perturbations in any of these factors, including those related to adrenal hormone imbalance, could result in consequences that affect the structure and function of the paediatric brain. Animal experiments and clinical studies demonstrated that the developing (i.e., paediatric) CNS seems to be particularly vulnerable to alterations induced by adrenal disorders and/or supraphysiological doses of corticosteroids. Physicians should be aware of potential neurological manifestations in children with adrenal dysfunction to achieve better prevention and timely diagnosis and treatment of these disorders. Further studies are needed to explore the potential neurological, cognitive, and psychiatric long-term consequences of high doses of prolonged corticosteroid administration in childhood.
    International Journal of Endocrinology 09/2014; 2014:282489. DOI:10.1155/2014/282489 · 1.52 Impact Factor
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    • "The hippocampus is the most studied brain structure showing neuronal degeneration associated to stress and high glucocorticoid levels [4], followed by the prefrontal cortex as observed in Cushing's disease, major depression and PTSD [1;17;18]. Smaller amygdaloid nucleus [19] and an overall brain atrophy were also reported by magnetic resonance imaging in Cushing's patients [5;17]. Another clinical study showed that the reduced volume of the cingulate gyrus correlated to an increase in plasma adrenocorticotropic hormone levels in humans [20]. "
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    ABSTRACT: Chronic stress and persistently high glucocorticoid levels can induce brain atrophy. Corticotropin-releasing factor (CRF)-overexpressing (OE) mice are a genetic model of chronic stress with elevated brain CRF and plasma corticosterone levels and Cushing's syndrome. The brain structural alterations in the CRF-OE mice, however, are not well known. We found that adult male and female CRF-OE mice had significantly lower whole brain and cerebellum weights than their wild type (WT) littermates (347.7+/-3.6mg vs. 460.1+/-4.3mg and 36.3+/-0.8mg vs. 50.0+/-1.3mg, respectively) without sex-related difference. The epididymal/parametrial fat mass was significantly higher in CRF-OE mice. The brain weight was inversely correlated to epididymal/parametrial fat weight, but not to body weight. Computerized image analysis system in Nissl-stained brain sections of female mice showed that the anterior cingulate and sensorimotor cortexes of CRF-OE mice were significantly thinner, and the volumes of the hippocampus, hypothalamic paraventricular nucleus and amygdala were significantly reduced compared to WT, while the locus coeruleus showed a non-significant increase. Motor functions determined by beam crossing and gait analysis showed that CRF-OE mice took longer time and more steps to traverse a beam with more errors, and displayed reduced stride length compared to their WT littermates. These data show that CRF-OE mice display brain size reduction associated with alterations of motor coordination and an increase in visceral fat mass providing a novel animal model to study mechanisms involved in brain atrophy under conditions of sustained elevation of brain CRF and circulating glucocorticoid levels.
    Neuroscience Letters 03/2010; 473(1):11-5. DOI:10.1016/j.neulet.2010.01.068 · 2.06 Impact Factor
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    • "In humans, similar findings of hippocampal atrophy associated with memory and anxiety problems have been reported in adults who suffered a chronic stress (Bourdeau et al., 2005; de Kloet et al., 2005; Lupien et al., 2005). The only study that examined the behavioral and brain structural consequences of chronically elevated corticosteroids in 11 children and adolescents with Cushing syndrome reported reduced amygdala volume, no hippocampal size alterations, and, similar to the present findings, no affective symptoms or memory deficits (Merke et al., 2005). Here, we report for the first time the presence of functional neural abnormalities in these structures associated with hypercortisolemia. "
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    ABSTRACT: Chronic elevations of endogenous cortisol levels have been shown to alter medial temporal cortical structures and to be accompanied by declarative memory impairments and depressive symptoms in human adults. These effects of elevated endogenous levels of cortisol have not been directly studied in adolescents. Because adolescents with Cushing syndrome show endogenous elevations in cortisol, they represent a unique natural model to study the effects of prolonged hypercortisolemia on brain function, and memory and affective processes during this developmental stage. Using functional magnetic resonance imaging (fMRI), we compared 12 adolescents with Cushing syndrome with 22 healthy control adolescents on amygdala and anterior hippocampus activation during an emotional faces encoding task. None of these adolescents manifested depressive symptoms. Encoding success was assessed using a memory recognition test performed after the scan. The fMRI analyses followed an event-related design and were conducted using the SPM99 platform. Compared to healthy adolescents, patients with Cushing syndrome showed greater left amygdala and right anterior hippocampus activation during successful face encoding. Memory performance for faces recognition did not differ between groups. This first study of cerebral function in adolescents with chronic endogenous hypercortisolemia due to Cushing syndrome demonstrates the presence of functional alterations in amygdala and hippocampus, which are not associated with affective or memory impairments. Such findings need to be followed by work examining the role of age and related brain maturational stage on these effects, as well as the identification of possible protective factors conferring resilience to affective and cognitive consequences in this disease and/or during this stage of cerebral development.
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