Computerized Analysis of Brain MRI Parameter Dynamics in Young Patients With Cushing Syndrome—A Case-Control Study

Tirosh, Amit; RaviPrakash, Harish; Papadakis, Georgios Z.; Tatsi, Christina; Belyavskaya, Elena; Lyssikatos, Charalampos; Lodish, Maya; Bağcı, Ulaş; Stratakis, Constantine A.

doi:10.1210/clinem/dgz303

Cited by 10 publications

(8 citation statements)

References 33 publications

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“…In the AdKO 2.0 brains, volumetric decreases were prominent in white matter areas, such as the corpus callosum and cingulate cingulum. In human studies, patients show smaller absolute volumes of white matter ( Jiang et al, 2019 ; Tirosh et al, 2020 ), as well as reduced fractional anisotropy and increased mean diffusivity, which indicate white matter deterioration ( Pires et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Effects of Long-Term Endogenous Corticosteroid Exposure on Brain Volume and Glial Cells in the AdKO Mouse

et al. 2021

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Chronic exposure to high circulating levels of glucocorticoids has detrimental effects on health, including metabolic abnormalities, as exemplified in Cushing’s syndrome (CS). Magnetic resonance imaging (MRI) studies have found volumetric changes in gray and white matter of the brain in CS patients during the course of active disease, but also in remission. In order to explore this further, we performed MRI-based brain volumetric analyses in the AdKO mouse model for CS, which presents its key traits. AdKO mice had reduced relative volumes in several brain regions, including the corpus callosum and cortical areas. The medial amygdala, bed nucleus of the stria terminalis, and hypothalamus were increased in relative volume. Furthermore, we found a lower immunoreactivity of myelin basic protein (MBP, an oligodendrocyte marker) in several brain regions but a paradoxically increased MBP signal in the male cingulate cortex. We also observed a decrease in the expression of glial fibrillary acidic protein (GFAP, a marker for reactive astrocytes) and ionized calcium-binding adapter molecule 1 (IBA1, a marker for activated microglia) in the cingulate regions of the anterior corpus callosum and the hippocampus. We conclude that long-term hypercorticosteronemia induced brain region-specific changes that might include aberrant myelination and a degree of white matter damage, as both repair (GFAP) and immune (IBA1) responses are decreased. These findings suggest a cause for the changes observed in the brains of human patients and serve as a background for further exploration of their subcellular and molecular mechanisms.

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Section: Discussionmentioning

confidence: 99%

Effects of Long-Term Endogenous Corticosteroid Exposure on Brain Volume and Glial Cells in the AdKO Mouse

et al. 2021

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“…In addition, significant and positive correlations were observed between GMVs in these subregions and remission time in short-term-remitted CD patients. Previous studies demonstrated not only partially reversible GMV reductions in particular brain subregions, such as the hippocampus ( 8 , 28 ), but also similar partial reversibility in other brain subregions and in the whole brain ( 17 , 29 ). Thus, it is reasonable to assume that partial reversibility of GMVs could be found, not only in particular brain subregions but also in most brain subregions of remitted CD patients.…”

Section: Discussionmentioning

confidence: 85%

Trends in regional morphological changes in the brain after the resolution of hypercortisolism in Cushing’s disease: a complex phenomenon, not mere partial reversibility

Jiang

Yang

Sun

et al. 2021

Endocrine Connections

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The adverse effects of hypercortisolism on the human brain have been highlighted in previous studies of Cushing’s disease (CD). However, the relative alterations in regional hypercortisolism in the brain remain unclear. Thus, we investigated regional volumetric alterations in CD patients. We also analyzed the associations between these volumetric changes and clinical characteristics. The study participants comprised of active CD (n = 60), short-term-remitted CD (n = 28), and long-term-remitted CD (n = 32) patients as well as healthy control subjects (n = 66). Gray matter volumes (GMVs) were measured via voxel-based morphometry. The GMVs of substructures were defined using the automated anatomical labeling (AAL) atlas. Trends for partial reversibility of GMVs were found in 87 brain substructures of CD patients. However, significantly different trends, including enlarged, irreversible, and unburden trends, were observed in the rest of the brain substructures. Trends toward normalization in GMV were found in most brain substructures of CD patients. Different trends, including enlarged, irreversible, and unburden GMVs, were observed in the other subregions, such as the amygdala, thalamus, and caudate. Morphological changes in GMVs after the resolution of hypercortisolism are a complex phenomenon; the characteristics of these changes significantly differ within the brain substructures.

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“…Previous studies have reported a reduction in cortical thickness in patients with stress-related disorders such as generalized and social anxiety disorder 25 , 26 bipolar disorder 27 , 28 , and major depressive disorder 29 , 30 . Two earlier studies investigated cortical thickness in CS patients and HCs: the first found no differences in cortical thickness 31 and the second reported increased cortical thickness in the lateral orbitofrontal and superior frontal cortex in children with CS in compared to HCs, however this study did not adjust for multiple comparisons 32 .…”

Section: Introductionmentioning

confidence: 82%

“…These findings are not in line with two previous studies investigating cortical thickness in CS patients. One study did not identify any differences in cortical thickness 31 , and the second study identified increased cortical thickness in the lateral orbitofrontal-and superior frontal cortex in children with CS in compared to HCs but did not adjust for multiple comparisons 32 . As the differences found in these areas appear to be marginal, it is unlikely that these effects would have persisted after correction.…”

Section: Discussionmentioning

confidence: 99%

“…A possible explanation why these earlier studies did not find results in line with ours could be due to the differences between the CS patient populations included in the studies (i.e., our study consisted solely of patients with remitted CD and the other studies also included patients with other causes of CS), or perhaps due to differences in FreeSurfer versions (e.g., the current study used a newer version than that denoted in the Crespo et al 31 paper (v5.3.0 versus v4.3.1). Unfortunately, the Tirosh et al 32 paper did not indicate the version of FreeSurfer they used. Using the more recent releases has been posited to provide a more accurate segmentation, although differences may also be caused due to different software builds 60 .…”

Section: Discussionmentioning

confidence: 99%

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Cortical thickness abnormalities in long-term remitted Cushing’s disease

et al. 2020

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Long-term remitted Cushing’s disease (LTRCD) patients commonly continue to present persistent psychological and cognitive deficits, and alterations in brain function and structure. Although previous studies have conducted gray matter volume analyses, assessing cortical thickness and surface area of LTRCD patients may offer further insight into the neuroanatomical substrates of Cushing’s disease. Structural 3T magnetic resonance images were obtained from 25 LTRCD patients, and 25 age-, gender-, and education-matched healthy controls (HCs). T1-weighted images were segmented using FreeSurfer software to extract mean cortical thickness and surface area values of 68 cortical gray matter regions and two whole hemispheres. Paired sample t tests explored differences between the anterior cingulate cortex (ACC; region of interest), and the whole brain. Validated scales assessed psychiatric symptomatology, self-reported cognitive functioning, and disease severity. After correction for multiple comparisons, ROI analyses indicated that LTRCD-patients showed reduced cortical thickness of the left caudal ACC and the right rostral ACC compared to HCs. Whole-brain analyses indicated thinner cortices of the left caudal ACC, left cuneus, left posterior cingulate cortex, right rostral ACC, and bilateral precuneus compared to HCs. No cortical surface area differences were identified. Cortical thickness of the left caudal ACC and left cuneus were inversely associated with anxiety symptoms, depressive symptoms, and disease duration, although certain associations did not persist after correction for multiple testing. In six of 68 regions examined, LTRCD patients had reduced cortical thickness in comparison to HCs. Cortical thickness of the left caudal ACC was inversely associated with disease duration. This suggests that prolonged and excessive exposure to glucocorticoids may be related to cortical thinning of brain structures involved in emotional and cognitive processing.

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Computerized Analysis of Brain MRI Parameter Dynamics in Young Patients With Cushing Syndrome—A Case-Control Study

Cited by 10 publications

References 33 publications

Effects of Long-Term Endogenous Corticosteroid Exposure on Brain Volume and Glial Cells in the AdKO Mouse

Effects of Long-Term Endogenous Corticosteroid Exposure on Brain Volume and Glial Cells in the AdKO Mouse

Trends in regional morphological changes in the brain after the resolution of hypercortisolism in Cushing’s disease: a complex phenomenon, not mere partial reversibility

Cortical thickness abnormalities in long-term remitted Cushing’s disease

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