Smaller grey matter volumes in the anterior cingulate cortex and greater cerebellar volumes in patients with long-term remission of Cushing's disease: a case–control study

Abstract

Objective: Patients with long-term remission of Cushing's disease (CD) have persistent psychological and cognitive impairments. It is unknown whether, and to what extent, these impairments are accompanied by structural abnormalities in the brain. We aim to investigate structural changes in the brain in patients with predominantly long-term remission of CD and to examine whether these changes are associated with psychological and cognitive dysfunction and clinical severity. Design: A cross-sectional, case-control study. Methods: In 25 patients with predominantly long-term remission of CD and 25 matched healthy controls, grey matter volumes in the regions of interest (hippocampus, amygdala, and anterior cingulate cortex (ACC)) and in the whole brain were examined, using 3T magnetic resonance imaging and a voxel-based morphometry approach. Psychological and cognitive functioning were assessed using validated questionnaires and clinical severity was assessed using the Cushing's syndrome severity index. Results: Compared with controls, patients had smaller grey matter volumes of areas in the ACC (on average 14%, P!0.05) and greater volume of the left posterior lobe of the cerebellum (on average 34%, P!0.05). As expected, patients with remitted CD reported more depressive symptoms (PZ0.005), more anxiety (PZ0.003), more social phobia (PZ0.034), more apathy (PZ0.002), and more cognitive failure (PZ0.023) compared with controls, but the differences in grey matter volumes were not associated with psychological or cognitive measures, nor with clinical severity. Conclusion: Patients with predominantly long-term remission of CD showed specific structural brain abnormalities, in the presence of psychological dysfunction. Our data form a basis for future work aimed at elucidating the relation of the structural brain abnormalities and the sustained psychological deficits after long-term exposure to high cortisol levels.

Hippocampal and cerebellar atrophy in patients with Cushing’s disease

“…Decreasing glucose uptake and the toxic effect of excitatory amino acids on nervous cells are discussed, along with the theory of declining synthesis of neurotrophic factors and the hypothesis that excess glucocorticoids could suppress neurogenesis in the dentate gyrus, leading to hippocampal volume loss. 30 To date only 1 study can be identified that used a similar technique in patients in long-term remission of CD, 3 but not in those with untreated disease. In their study, Andela et al found a significant reduction of volume of the gyrus cinguli in patients after long-term remission of CD, and they hypothesized that these changes play a role in the long-term psychological dysfunction found in patients in whom CD has been cured.…”

“…Changes in cerebellar volume are also known to be caused by elevated cortisol levels and stress, 3,28 which may also facilitate changes in cognitive function and emotional control. 5 Whereas Andela et al found an increase in cerebellar volume in their patients 6 months after cure, our data show a lower cerebellar volume, supporting the results published by Santos et al in 2014, 31 who also found a significant reduction of cerebellar volume in patients with active CS.…”

“…34,38 In CD these changes have been linked to atrophy of the brain in general, 26,32 and different subregions of the brain, 3,6,28,32 caused by excess glucocorticoids and their neurotoxic effects. 19,24 Structures of the limbic system-the hippocampus, the anterior cingulate gyrus, and the amygdala-are affected by long-term exposure to glucocorticoids because these areas are part of the stress response system and are rich in mineralocorticoid receptors and glucocorticoid receptors.…”

“…For all analyses, we used the default settings of the unified segmentation engine. The unified segmentation approach yielded 3 stereotactically normalized tissue maps (GM, WM, and CSF) with a voxel volume of 1 mm 3 and intensities between 0 and 1. The determinant of the Jacobian matrix of the transformation field was applied locally to ensure that the volume was preserved after stereotactic normalization (modulation).…”

MECHANISMS IN ENDOCRINOLOGY: Cushing's syndrome causes irreversible effects on the human brain: a systematic review of structural and functional magnetic resonance imaging studies

“…One study did neither describe diagnostic nor remission criteria (20). Described diagnostic criteria were clinical features (truncal obesity, skin and muscle arthophy, moon facies) (11,12,13,21), elevated urinary free cortisol (UFC) (11,12,13,21,22,23,24,25,26,27,28,29), elevated cortisol secretion rates (11,12,13,21,23,24,25,30), elevated midnight salivary cortisol (29,31), absence of blunted circadian rhythm of cortisol secretion (11,12,13,21,26,27,30,32,33), elevated ACTH levels (in CD only) (12,13,21,23,24), lack of suppression after low dose dexamethasone ((1 mg) (22,25,29,33), (2 mg) (12,13,21...…”