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

in European Journal of Endocrinology

Background

Cushing's syndrome (CS) is characterized by excessive exposure to cortisol, and is associated with both metabolic and behavioral abnormalities. Symptoms improve substantially after biochemical cure, but may persist during long-term remission. The causes for persistent morbidity are probably multi-factorial, including a profound effect of cortisol excess on the brain, a major target area for glucocorticoids.

Objective

To review publications evaluating brain characteristics in patients with CS using magnetic resonance imaging (MRI).

Methods

Systematic review of literature published in PubMed, Embase, Web of Knowledge, and Cochrane databases.

Results

Nineteen studies using MRI in patients with CS were selected, including studies in patients with active disease, patients in long-term remission, and longitudinal studies, covering a total of 339 unique patients. Patients with active disease showed smaller hippocampal volumes, enlarged ventricles, and cerebral atrophy as well as alterations in neurochemical concentrations and functional activity. After abrogation of cortisol excess, the reversibility of structural and neurochemical alterations was incomplete after long-term remission. MRI findings were related to clinical characteristics (i.e., cortisol levels, duration of exposure to hypercortisolism, current age, age at diagnosis, and triglyceride levels) and behavioral outcome (i.e., cognitive and emotional functioning, mood, and quality of life).

Conclusion

Patients with active CS demonstrate brain abnormalities, which only partly recover after biochemical cure, because these still occur even after long-term remission. CS might be considered as a human model of nature that provides a keyhole perspective of the neurotoxic effects of exogenous glucocorticoids on the brain.

Abstract

Background

Cushing's syndrome (CS) is characterized by excessive exposure to cortisol, and is associated with both metabolic and behavioral abnormalities. Symptoms improve substantially after biochemical cure, but may persist during long-term remission. The causes for persistent morbidity are probably multi-factorial, including a profound effect of cortisol excess on the brain, a major target area for glucocorticoids.

Objective

To review publications evaluating brain characteristics in patients with CS using magnetic resonance imaging (MRI).

Methods

Systematic review of literature published in PubMed, Embase, Web of Knowledge, and Cochrane databases.

Results

Nineteen studies using MRI in patients with CS were selected, including studies in patients with active disease, patients in long-term remission, and longitudinal studies, covering a total of 339 unique patients. Patients with active disease showed smaller hippocampal volumes, enlarged ventricles, and cerebral atrophy as well as alterations in neurochemical concentrations and functional activity. After abrogation of cortisol excess, the reversibility of structural and neurochemical alterations was incomplete after long-term remission. MRI findings were related to clinical characteristics (i.e., cortisol levels, duration of exposure to hypercortisolism, current age, age at diagnosis, and triglyceride levels) and behavioral outcome (i.e., cognitive and emotional functioning, mood, and quality of life).

Conclusion

Patients with active CS demonstrate brain abnormalities, which only partly recover after biochemical cure, because these still occur even after long-term remission. CS might be considered as a human model of nature that provides a keyhole perspective of the neurotoxic effects of exogenous glucocorticoids on the brain.

Introduction

Cushing's syndrome (CS) is a rare clinical syndrome characterized by excessive endogenous exposure to cortisol due to various etiologies. The majority of patients have adrenocorticotropin (ACTH)-producing pituitary tumors (i.e., Cushing's disease (CD)); other causes include adrenal tumors or ectopic ACTH-secreting tumors. CS manifests all characteristic features of excessive stress hormone exposure, i.e. psychopathology, gonadal dysfunction, hirsutism, abnormal (central) fat distribution, thin skin with easy bruisability, hypertension, muscle weakness, and osteoporosis (1). Patients are treated with surgery, and in case surgical remission is not obtained, radiotherapy and/or with medical treatment (2). Although symptoms improve substantially after biochemical cure, cardiovascular morbidity and mortality remained elevated (3, 4, 5). Furthermore, despite long-term remission, patients with CS report impaired quality of life (6), higher prevalence of psychopathology, and demonstrated impairments in cognitive functioning (7, 8). It is likely that the causes for persistent morbidity are multi-factorial, including intrinsic imperfections of surgical or endocrine replacement therapy; the impact of living with a chronic disease in addition to the irreversible effects of cortisol excess on the CNS during remission may affect personality, behavior, and metabolism, which cannot be neglected. Although the attention for the presence of psychopathology and impairments in cognitive functioning in patients with active, as well as remitted CS is self-evident, the number of studies evaluating brain structures and activity in patients with CS has been rather limited.

The detrimental effects of hypercortisolism, such as in CS, on the human brain were first highlighted in autopsy reports, describing a lighter brain and enlarged ventricles in deceased CS patients (9). The first in vivo studies in the human evaluating these brain characteristics were performed in patients with CS using pneumoencephalography. Momose et al. (10) used pneumoencephalography in 31 patients with CD, and demonstrated cerebral cortical atrophy in 90% of the patients and cerebellar cortical atrophy in 74% of the patients compared with normal references derived from the literature. The introduction of the magnetic resonance imaging (MRI) scanner in 1977 enabled the assessment of brain volumes and brain structures more accurately and in more detail. Starkman et al. (11) were the first to report on hippocampal volumes obtained from routine pituitary MRI diagnostics of patients with active CS, and compared these with healthy control data derived from the literature. Hippocampal volume was decreased during active CS, but a partial recovery could be observed after successful treatment (12, 13). However, new imaging techniques are emerging that enable to better evaluate brain structures and functioning.

The aim of this study was to systematically review the literature on structural and functional changes in the brain identified with (MRI) in patients with CS. The secondary aim was to review potential associations between brain characteristics and disease status, cognitive functioning, psychopathology, and general well-being.

Methods

Search strategy and data extraction

The following electronic databases were searched: PubMed, Embase, Web of Knowledge, and Cochrane. The search was performed on August 5, 2014. We composed a search strategy focusing on MRI studies in patients with CD and CS (see Supplement 1 for the complete search strategy, see section on supplementary data given at the end of this article). Studies on patients with CS due to the use of exogenous corticosteroids were excluded. Data extraction and eligibility were assessed by two independent investigators (C D Andela and A M Pereira). Inconsistencies were resolved by consensus. All references were checked for additional papers. The following data were extracted: i) sample size, ii) gender distribution, iii) mean age of included patients, iv) disease status (active/remission), v) estimated duration of exposure to hypercortisolism, vi) methods used, and vii) results.

Quality assessment

Due to different designs and methods in the studies that were identified, it was not possible to use a pre-existing quality assessment tool. Therefore, we formulated a quality assessment list adapted from the list used in a systematic review on neuroimaging studies in patients with multiple sclerosis (14). Sixteen items were defined: clear study objective, inclusion/exclusion criteria, population demographics, diagnostic criteria and/or remission criteria, estimation of disease duration, composition of patient group (i.e., heterogeneous or homogenous regarding to origin of CS (pituitary–adrenal) and disease status (active-remission)), sample size, design (retrospective assessment based on scans obtained from routine pituitary evaluation, or prospective or cross-sectional), inclusion of a control group assessed in the same manner as the patient group, assessment of cognitive and psychological functioning, imaging protocol, scanner type (1T, 1.5T or 3T), strength of effect reported, multivariate analysis, and discussion of limitations. Total individual quality scores ranged from 0 to 20 points (see Table 1). The quality of each study was assessed by two independent reviewers (C D Andela and A M Pereira) and discrepancies were discussed and resolved by consensus. Total scores were calculated as percentages (‘individual total score’/20×100%). The median of the quality scores was 75% and was used as cut-off point, with papers with quality scores ≥75% being considered as high quality papers. Given the low number of studies, studies were not excluded based on the quality assessment (Table 2).

Table 1

List of criteria used for the quality assessment.

1Research objectiveYes=1/no=0
2Inclusion/exclusion criteriaYes=1/no=0
3Population demographics (at least gender, age, and educationa)Yes=1/no=0
4Diagnostic criteria and/or remission criteriaYes=1/no=0
5Estimation of disease durationYes=1/no=0
6Composition of patient groupsHeterogeneous (CS/CD)=0
Homogenous CS-CD=1
7Heterogeneous (active/remission)=0
Homogenous (active–remission)=1
8Sample sizen<20=0
n>20=1
9DesignRetrospective=0
Prospective=1
Cross-sectional=1
10Control group includedNo control group=0
Control group=1
Matched control group=2
11Cognitive measures (including cognitive tasks during fMRI)Yes=1/no=0
12Psychological measuresYes=1/no=0
13Imaging protocolYes=1/no=0
14Scanner1T=1/1.5T=2/3T=3
15Strength of effectYes=1/no=0
16Multivariate analysisYes=1/no=0
17Limitations discussedYes=1/no=0

Or IQ in case of studies in children.

Table 2

Quality assessment.

1234567891011121314151617Individual scoreQuality score (%)
(11)111110100010121011260
(12)110111111000121111470
(23)110100101100121011155
(24)110100101100121001050
(20)10000111010000100630
(15)110101111100121011365
(13)110111111011121101575
(27)111110101211121011680
(30)111111111011121111785
(21)110111111001121111575
(26)111110101110131111680
(17)111110011210131111785
(33)111111101000111111365
(25)111110111101131111785
(22)1111111112111311120100
(18)111110101200131011575
(16)111110011210131111785
(19)111110111211131011890
(29)1111111112111311120100

The 17 quality items were scored following the criteria listed in Table 1. Bold, quality score≥75%.

Results

Literature overview

The literature search identified 142 publications, of which 16 were eligible for inclusion. By scanning references of included articles, three articles were added to the selection. Therefore, the final selection consisted of 19 articles including a total number of 339 unique patients (Table 3 and Fig. 1). This selection consisted of six longitudinal studies, 11 cross-sectional studies, and two studies using both designs. The majority of the studies used structural MRI (n=14), three studies used proton magnetic resonance spectroscopy (H-MRS), and two studies used functional MRI (fMRI). Nine studies combined MRI outcome with the assessment of cognitive functioning. Further information on the MRI techniques, neuropsychological tests, and behavioral measures are provided in the Supplementary file 2, see section on supplementary data given at the end of this article.

Table 3

Study characteristics of MRI studies in patients with CS.

ReferencesnGender (m/f)Age (mean±s.d.)Active/treatedEstimated duration of hypercortisolismProcedure and methodEvaluated brain areasOutcomes
Cross-sectional
(11)122/1037.3±13.959 active CD

3 active CS

1 healthy control
Range 1–4 years1.5T MRI scans obtained from routine pituitary MRI

Volumes were manually traced and digitally calculated

Neuropsychological tests: WMS, WAIS
Dentate gyrus.

Hippocampus proper, subiculum
HFV of 27% of the patients fell outside the 95% CI for normal subjects. An association was found between reduced HFV and verbal learning and memory tasks. HFV was negatively correlated with plasma cortisol levels.
(23)130/13Mean: 42.0 (range 21–64)6 active CD

7 active CS

40 healthy controls
NA1.5T MRI

H-MRS

Metabolites were quantified
2 cm3 localized in the thalamic, frontal and temporal area of the left hemispherePatients demonstrated a decrease in Cho/Cr ration in frontal and thalamic areas. Patients with CS demonstrated a larger reduction, compared with patients with CD.
(20)6348/15NA63 active CD

63 controls with non-ACTH producing sellar pathology, age and gender matched
NACT/MRI obtained during treatment period

Atrophy was rated
Whole brainCD patients demonstrated more atrophy than controls. After stratifying for age and years of disease, no differences were found between patients and control when they were older than 60 years, or when disease duration was shorter than 1 years or between 4 and 5 years.
(15)a36/2b9/2941.3±12.021 active CD

17 active CS

18 controls with non-ACTH producing sellar tumors

20 controls with no sellar tumors
NACT and/or MRI obtained from routine pituitary evaluation

Measurement of diameters and subjective estimation of degree of cerebral atrophy
Third ventricle

Bicaudate

Whole brain
Third ventricle diameter, bicaudate diameter, and the subjective evaluation of brain atrophy were increased in patients compared with controls.
(27)a115/612.1±3.410 active CD

1 active CS

10 healthy age- and gender-matched controls
4.4±1.2 1.5T MRI

Volumes were manually traced and quantified

Total cerebral volume was quantified automatically

Neuropsychological tests: PANESS, WISC, WAIS, CVLT-C, Woodstock-Johnson Psychoeducational Battery-R: test achievement

Psychological assessment: BASC
Cerebrum, ventricles, temporal lobe, hippocampus

amygdala
CS had smaller total cerebral volumes, lager ventricles and smaller amygdala volumes, HV was smaller, but not significant compared with controls.
(26)124/813.5±2.910 active CD

2 active CS

22 healthy controls
Mean 2.6 years (range 1–4.5)3T fMRI

Face Memory Task

BOLD signal
Amygdala

Anterior hippocampus
Patients demonstrated increased activation in the left amygdala and right anterior hippocampus in response to successful encoding compared to controls.
(25)214/1734.4±14.920 active CD

1 active CS

21 healthy controls
32.4±23.7 months3T fMRI

Facial emotion perception test

BOLD signal
Hippocampus

Amygdala

Whole brain
Patients had less activation in the left anterior superior temporal gyrus, and higher activation in the frontal, medial, and subcortical regions. Elevated activation of the left middle frontal and lateral posterior pulvinar areas was positively correlated with accuracy in emotion identification.
(17)336/2744.8±11.87 active CD

4 active CS

18 remission CD

4 remission CS

Average duration of remission: 7.3±2.4 years

34 healthy age-, gender-, education-matched controls
5.5±3.7 years3T MRI

Volumes were automatically segmented and measured

Neuropsychological tests: RAVLT, ROCF
Hippocampus

Cortical GM Subcortical GM
No differences in HV between CS and controls. Patients with severe memory impairment showed smaller HV than controls. Total GM and cortical GM were decreased in CS patients. Subcortical GM was only reduced in patients with severe memory impairment.
(22)254/2145±825 CD remission, Average duration of remission: 11.2±8.2 year

25 healthy age-, gender-, education-matched controls
7.9±7.9 years3T MRI

Harvard-oxford cortical and subcortical structural atlases were used to create a mask

Psychological and cognitive measures: MADRS, IDS, BAI, FQ, AS, IS, CFQ

Physical questionnaire: CSI
Hippocampus, amygdala, ACC

Whole brain
Patients demonstrated smaller GM volumes of the ACC and greater GM volumes of the left posterior lobe, compared with controls. Differences in GM were not associated psychological-, cognitive-, or clinical measures.
(18)18c3/1544.8±12.515 remission CD

3 remission CS

Average duration of remission: 8.5±3.2 years

18 age-, education matched healthy controls
4.7±2.6 years3T MRI

H-MRS

Measurement of metabolic peaks
Hippocampus headPatients showed decreased NAA levels in the hippocampi, and increased levels of Glx.
(29)22d4/1842.42±7.3322 remission CD

Average duration of remission: 11.9±8.5 year

22 healthy age-, gender, education matched controls
6.73±5.39 years3T MRI

Johns Hopkins University WM atlas was used to create a mask

Psychological and cognitive measures: MADRS, IDS, BAI, FQ, AS, IS, CFQ

Physical questionnaire: CSI
Bilateral cingulate cingulum Bilateral hippocampal cingulum

Bilateral uncinated fasciculus

Corpus callosum Whole brain
Patients demonstrated widespread changes in WM integrity of the whole brain. Reduced WM integrity in the uncinated fasciculus was associated with severity of depressive symptoms.
(19)366/30Active 44.2±9.3

Remission 41.9±10.4
10 active CD

5 active CS

18 remission CD

3 remission CS

Average duration of remission: NA

36 healthy controls matched for age, gender, and education
Active 62.2±59.1 months

Remission 61.8±32.2 months
3T MRI

Volumes were automatically segmented and measured

Neuropsychological tests: Animals, WAIS, BNT, FAS, Grooved Pegboard, ROCF, SDMT, TMT, WCST

QoL: CushingQoL
CerebellumPatients had smaller GM volumes of the bilateral cerebellum, compared with controls. GM of the cerebellum negatively correlated with triglyceride levels and age at diagnosis. Left GM volumes correlated positively with visual memory performance, and right GM volume was positively correlated with QoL.
(16)355/30Medically treated: 41.4±12.3

Cured: 44.5±10
4 medically treated CD

4 medically treated CS

24 remission CD

3 remission CS

Average duration of remission: 41 months (6–288)

35 healthy controls
Medically treated: 46.5±32.5 months

Cured: 57.6±34.5 months
3T MRI

GM/WM boundary was constructed by classifying all white matter voxels in a MRI volume

Cortical thickness estimates were obtained with the shortest distance between the WM and the pial surfaces at each location of the cortex

Neuropsychological tests: IGT, RAVLT
Whole brainPatients showed decreased cortical thickness. Decision making did not correlate with cortical thickness.
Longitudinal
(24)10e0/10Mean: 41.3 (range 21–64)5 active CD

5 active CS
NA1.5T MRI

H-MRS

Metabolites in ROI were quantified

Before and 6 months after correction of hypercortisolism
2 cm3 localized in the thalamic, frontal and temporal area of the left hemispherePatients demonstrated recovery of Cho levels in thalamic and frontal areas after correction of hypercortisolism.
(12)18/4b5/1738.7±14.8 22 active CD2.6±2.3 years1.5T MRI

Manually tracing, volumes within tracing were digitally calculated

Before and after surgery (16±9.3 months)
Hippocampus

Caudate head

ICV
With remission of CD, HFV increased in individual patients up to 10%. This percentage is correlated with the change in UFC.
(15)a22NA40.9±10.714 active CD

8 active CS
NACT and/or MRI obtained from routine pituitary evaluation

Measurement of diameters and subjective estimation of degree of cerebral atrophy

Before correction of hypercortisolism and after correction (39.7±34.1 months)
Third ventricle

Bicaudate

Whole brain
After correction of hypercortisolism patients showed a decrease in third ventricle diameter, bicaudate diameter, and subjective evaluation of brain atrophy.
(13)5/19f4/2033.7±13.124 active CD2.7±2.1 years1.5T MRI

Manually tracing, volumes within tracing were digitally calculated

Neuropsychological tests: WMS, SRT

Psychological assessment: SCL-90-R

Before and after surgery (15.7±8.8 months)
Hippocampus

Caudate head
Decrease in UFC was correlated with increase in HFV, which was associated with improvement in af learning task.
(30)5/22f4/2338.74±13.2427 active CD3.64±3.09 years1.5T MRI

Manually tracing, volumes within tracing were digitally calculated

Volumes were corrected for intracranial volume and controlled for age

Neuropsychological tests: SRT, WAIS, Verbal fluency (D)

Psychological measures: SCL-90-R

Before successful surgical treatment and after (3–5, 6–12, 13–18 months)
Hippocampus

Caudate head
Controlling for age, HFV increased from baseline to one-year after treatment, whereas CHV did not increased.

Increase in HFV was associated with a decrease in cortisol levels up to 1 year after treatment.
(27)a115/612.1±3.410 active CD

1 active CS
4.4±1.2 years1.5T MRI

Manually tracing, volumes were quantified by two independent raters

Total cerebral volume was quantified automatically

Neuropsychological tests: WISC

Psychological assessment: KSADS-PL

Before and 1 year after surgery
Cerebrum, ventricles, temporal lobe, hippocampus

Amygdala
After surgery patients demonstrated an increase in total cerebral brain volume and a decrease in ventricular size. No significant changes were observed in amygdala size or HV.
(21)4/19f4/1934.0±13.323 active CD2.7±2.1 years1.5T MRI

Manually tracing, volumes within tracing were digitally calculated

Volumes were corrected for intracranial volume

Psychological assessment: SCL-90-R

Before and ∼1 year after surgery
Hippocampus

caudate head
Increased HFV and right CHV were associated with lower UFC. Change in right CHV was associated with mood and ideation.
(33)102/838.2±13.1Ten active CD3.5±1.1 years1T MRI

Manually outlined, volumes were automatically calculated

Before and 12 months after surgery
Hippocampus

whole brain
Patients demonstrated an increase in right and left hippocampus head volumes after surgery.

HV, hippocampal volume; HFV, hippocampal formation volume; CHV, caudate head volume; ICV, intracranial volume; GM, grey matter; WM, white matter; VBM, Voxel-based morphometry; ACC, anterior cingulate cortex; H-MRS, Proton magnetic resonance spectroscopy; Cr, creatine and phosphocreatine; Cho, choline-containing compounds; NAA, N-Acetyl-Aspartate; Glx, Glutamate+Glutamine; QoL, quality of life.

Cross-sectional and longitudinal design.

Patients from study of (11).

Patients from study of (17).

Patients from study of (22).

Patients from study of (23).

Patients from study of (12).

Figure 1

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Figure 1

Flow diagram of selection and exclusion stages.

Citation: European Journal of Endocrinology 173, 1; 10.1530/EJE-14-1101

Quality assessment

The individual quality scores of the studies ranged from 30 to 100%, with a median of 75%. Overall, the more recent articles had higher quality scores, which can partly be explained by the transition from using 1.5T scanners to 3T scanners, and the absence of applying multivariate analysis in the earlier studies. Furthermore, 53% of the studies (n=10) included patients with CS of both pituitary and adrenal origin, and approximately half of the studies did not include psychological (n=11) and/or cognitive measures (n=9).

Endocrine evaluation

Diagnostic criteria for CS were clearly defined in 13 studies (68%). Five studies (26%) did not describe diagnostic criteria, but mentioned criteria of remission (15, 16, 17, 18, 19). 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), dose not mentioned (23, 24)) or 50% suppression after high dose (8 mg) (12, 13, 21), and abnormal response to corticotropin releasing hormone (CRH) (30).

Described remission criteria were normal UFC (15, 16, 17, 18, 19), adrenal insufficiency, morning cortisol suppression after low dose dexamethasone overnight (1 mg) (17, 18, 19), or <30 mg hydrocortisone/day (15).

All studies (except four (15, 20, 23, 24)) reported on the estimated duration of hypercortisolism, which was based on patient's history and old photographs. In studies that included pediatric patients with CS, the onset of decreased growth velocity was used (26, 27). The mean estimated duration of hypercortisolism ranged from 2.6 to 7.9 years.

MRI outcome in patients with active CS

The first studies evaluating brain volume with MRI in patients with active CS used MRI scans obtained from routine pituitary evaluation. In 1992, Starkman et al. (11) reported hippocampal volume to be outside the 95% CI of healthy control data derived from the literature in 27% of the patients (total sample size n=12). In a larger cohort (n=63), patients with CS were reported to have more brain atrophy compared with controls (Fig. 2) (20). In agreement, Bourdeau et al. (15) demonstrated that patients with active CS had increased third ventricle diameter, bicaudate diameter, and cerebral atrophy, compared with control patients with no sellar tumors. A recent study has found smaller grey matter volumes of the bilateral cerebellum in patients with active CS compared with controls (19). When investigating the effect of CS on the developing brain, children with CS were found to have smaller cerebral volumes, larger ventricles and smaller amygdala than controls (27).

Figure 2

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Figure 2

Brain atrophy in a patient with active CD vs healthy control. (A) T1-weighted sagittal MRIs of a 32-year-old patient with CD and (B) age- and sex-matched control (20).

Citation: European Journal of Endocrinology 173, 1; 10.1530/EJE-14-1101

Khiat et al. (23) used H-MRS, a non-invasive tool that can be used to evaluate changes in cerebral metabolites. The patients with active CS had decreased ratios of creatine and phosphocreatine ratios (markers of energy metabolism) and decreased choline-containing compounds (a membrane marker) in frontal and thalamic areas, indicating persistent alterations in the cholinergic system (23).

Only two studies have investigated patients with active CS with fMRI. Using an emotional faces task, adult patients demonstrated less activation in the left anterior superior temporal gyrus, and higher activation in the frontal, medial, and subcortical regions during the identification of emotional faces. These findings indicated alterations in brain activity in regions used for emotion processing (25). Furthermore, adolescents with active CS demonstrated increased activation in the left amygdala and right anterior hippocampus in response to successful encoding during the performance of a facial memory task. These results point toward alterations in brain activity in substrates related to depressive symptoms and emotional memory. Interestingly, none of the adolescents suffered from psychiatric disease, therefore the authors postulated that the exaggerated amygdala activity and exposure to elevated cortisol levels are not sufficient for initiating depression in adolescents (26).

Longitudinal studies assessing the potential reversibility of brain abnormalities

Eight studies evaluated the potential reversibility of alterations in the brain after correction of hypercortisolism (mean duration of follow-up between 6 and 40 months).

Correction of hypercortisolism increased hippocampal volume (12), and decreased third ventricle- and bicaudate diameter, and regressed brain atrophy (15). Toffanin et al. (33) reported a significant increase in right and left hippocampus head volumes in CD patients after transsphenoidal surgery, with no significant increase in the body and tail of the hippocampus, suggesting that the head of the hippocampus is more sensitive to excessive cortisol exposure. Recovery in metabolite concentrations was also accompanied by an increase in thalamic and frontal choline levels up to 6 months after correction of hypercortisolism, indicating improvement in cholinergic system function (23). Children with CS demonstrated an increase in cerebral volumes and a decrease in ventricular volumes after surgery, and total cerebral volume and ventricular size after 1-year follow-up were comparable with age-matched controls (27).

MRI outcome in patients in long-term remission of CS

Six studies evaluated patients in remission of CS using a cross-sectional design and identified structural, functional, and biochemical abnormalities. The average duration of remission ranged from 3.4 to 11.9 years.

Resmini et al. (17) found no differences between patients with active disease and patients in remission, and therefore analyzed these patients as one group. They found no differences in hippocampal volume between patients and healthy-matched controls, but total grey matter (cortical and subcortical) and cortical grey matter were smaller in patients compared with controls. Andela et al. (22) found smaller grey matter volumes of the anterior cingulate cortex (ACC) and larger grey matter volumes of the left posterior lobe of the cerebellum in CD patients in long-term remission compared with healthy-matched controls (Fig. 3), whereas Santos et al. (19) found no differences in cerebellar volumes between patients in remission and controls. Recently, Crespo et al. (16) have evaluated cortical thickness in medically treated eucortisolemic patients and patients in remission and demonstrated that patients with CS had decreased cortical thickness when compared with controls.

Figure 3

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Figure 3

Grey matter volumes in patients after long-term remission of CD. (A) Results of regions of interest analysis, with lesser grey matter volumes in patients than that in controls (P<0.05; 617 voxels, 2-mm isotropic). (B) Results of whole brain analysis with lesser grey matter volumes in patients than that in controls (P<0.05; 37 voxels, 2-mm isotropic). (C) Results of whole brain analysis with greater grey matter volumes in patients than that in controls (P<0.05; 323 voxels, 2-mm isotropic). The left hemisphere corresponds with the right side of the image (22).

Citation: European Journal of Endocrinology 173, 1; 10.1530/EJE-14-1101

At present, only one study has evaluated white matter integrity in patients with long-term remission of CD and demonstrated widespread reductions of integrity in white matter tracts throughout the brain (29).

Finally, using H-MRS, Resmini et al. demonstrated lower N-acetyl-aspartate (NAA) ratios (marker of neuronal density, integrity, and variability) in the bilateral hippocampus in patients in remission of CS compared with controls, reflecting neuronal damage. Furthermore, patients demonstrated higher glutamate (excitatory neurotransmitter) and glutamine (glial marker) levels in both hippocampi, indicating proliferation as a repair mechanism. The authors postulated that these persisted alteration in biochemical markers in the brain could be related to glucocorticoid neurotoxicity (18).

Associations between brain abnormalities and clinical characteristics

Several studies found associations between structural and functional brain abnormalities and clinical and laboratory characteristics in patients with CS.

In patients with active disease, hippocampal volumes were negatively correlated with plasma cortisol levels, but not with UFC, current age, and cortisol levels multiplied by the estimated duration of disease (11). In fMRI studies in active disease, dorsal anterior cingulate activation during emotional task was positively associated with percent decline in ACTH from morning peak to afternoon nadir, but not with percent cortisol decline from morning peak to afternoon nadir (25). On the other hand, in adolescents with active disease left amygdala activation and right anterior hippocampal activation during a facial memory task was not correlated with 24-h UFC levels (26). Bicaudate diameter was correlated with UFC in patients with active CD, whereas no associations were found with degree of cerebral atrophy. In patients with adrenal CS, UFC did correlate with the degree of cerebral atrophy (15). Duration of hypercortisolism was negatively associated with subcortical grey matter volume (17), and significant differences in brain atrophy were found between subsets of patients with a long disease duration compared with patients with shorter disease duration (20). Furthermore, grey matter volume of the bilateral cerebellum was negatively associated with age at diagnosis and triglyceride levels, but not with current age, level of cholesterol, glucose, UFC, duration of exposure to hypercortisolism (19). Furthermore, cortical thickness was not associated with duration of eucortisolism, duration of prior hypercortisolism, and UFC (16).

Increase in hippocampal volume after correction of hypercortisolism was negatively associated with current age (12), and significant differences in the degree of brain atrophy were found between subsets of patients of different age (20). In contrast, Bourdeau et al. (15) found no correlation between brain volume and current age, although this could be related to the relatively young sample of patients included. An increase in hippocampal volume was associated with a decrease in UFC after treatment (12, 13, 21), but not with reduction in plasma cortisol, duration of disease, or the number of months relapsed since treatment (21, 30). Increase in right caudate head volume (CHV) was also associated with decrease in UFC, while increase in left CHV and right and left CHV together were not associated with change in UFC (13, 21).

In patients with long-term remission, no correlations were found between grey matter volumes of the ACC and cerebellum and white matter integrity, and estimated duration of hypercortisolism, duration of remission and clinical severity (22, 29), nor between NAA and GLX ratios and duration of hypercortisolism and duration of remission (18).

Associations between brain abnormalities and behavioral outcome/measures

In several studies, associations between structural and functional brain abnormalities and behavioral measures, especially in memory and mood domains, were found.

In patients with active disease, hippocampal volumes were positively associated with verbal learning and verbal recall (11). Increased activation of the left lateral posterior/pulvinar nuclei of the thalamus and the left middle frontal gyrus was positively correlated with accuracy of emotion identification in patients with active disease, whereas activation in the left superior parietal lobule was not significantly correlated with accuracy of emotion identification (25). In adolescents with active CS, left amygdala activation and right anterior hippocampal activation did not correlate with the performance of a facial memory task (26). Increase in hippocampal volume after correction of hypercortisolism was positively associated with improvement in learning (13, 30), but change in CHV was not (13, 30). An increase in right caudate volume was associated with improvement in mood (depression and anxiety) and related ideation (obsessive–compulsive and paranoid ideation), whereas change in left CHV and hippocampal volume were not correlated with mood or ideation (21).

Recently, Crespo et al. have demonstrated that cortical thickness was not associated with decision-making in medically treated eucortisolemic patients and patients in remission (16). Furthermore, in a group of patients with active disease, as well as patients in remission, patients with severe memory impairment showed smaller hippocampal volumes than controls (17), and grey matter volumes of the left lobe of the cerebellum were positively associated with visual memory and grey matter volumes of the right lobe of the cerebellum were positively associated with reported disease-specific quality of life (19).

In patients with long-term remission, reductions in white matter integrity in the left uncinate fasciculus were associated with severity of depressive symptoms, whereas no correlations were found between white matter integrity in other brain regions, grey matter volumes in the ACC and cerebellum, and behavioral outcome (i.e., depressive symptoms, anxiety, apathy, irritability, and cognitive failure) (22, 29).

Discussion

This systematic review shows that endogenous glucocorticoid excess in CS has profound effects on the human brain. This includes structural grey matter, possibly white matter abnormalities and neurochemical and functional alterations. After correction of hypercortisolism, the structural and neurochemical alterations improve substantially and correlate with improvements in clinical and behavioral outcomes. Nevertheless, abnormalities in both grey- and white matter are not completely reversible at long-term remission and are accompanied by psychological symptoms and impairments in cognitive functioning (7, 22, 29, 34).

The brain, and in particular the limbic system, is a major target area for cortisol, considering the high density of both the mineralocorticoid and glucocorticoid receptors (35). The neurotoxic effects of corticosteroid excess on the CNS are well-recognized in experimental animal studies: i.e. reduction in apical dendrites of hippocampal pyramidal neurons (36), hippocampal volume reduction (37), and reduction volume of the left anterior cingulate gyrus (38). Furthermore, experimental models of chronic stress have clearly shown neurotoxic effects that appeared to be reversible by anti-glucocorticoid treatment (39). However, long-term experimental histopathological data after abrogation of corticosteroid overexposure are not available to our knowledge. It is tempting to speculate that the observed psychological morbidity and cognitive impairment in patients with active CS (40, 41) could be explained, at least in part, by the findings of MRI studies. In support of this, brain abnormalities and behavioral outcomes are clearly correlated. The ACC, hippocampus, and amygdala together constitute the neurocircuitry of stress (42). Therefore, psychopathology and cognitive impairment in patients with active CS might be related to structural alterations within this circuitry, in addition to alterations in functional activity and connectivity within it. In accordance, changes in functional activity were reported during a facial emotion task in adult patients (25) and a facial memory task in adolescents (26). FMRI studies on other emotional and cognitive tasks (e.g., executive function, and memory) in adult patients with CS, or studies assessing functional connectivity during rest have not been reported. Also, there were no fMRI studies in patients in remission of CS published in the time window of our literature search.

At present, brain characteristics in CS patients who are in long-term remission have been reported in only six cross-sectional MRI studies, with an average duration of remission ranging from 3.4 to 11.9 years. These studies showed smaller grey matter volumes in the ACC, larger grey matter volumes in the cerebellum, widespread reductions in white matter integrity (22, 29), and alterations in specific neuronal metabolites in the hippocampus (18). The behavioral phenotype of patients in remission of CS (7, 34) might also be, at least in part, explained by these findings. This is supported by the observed correlations between reductions in white matter integrity in the left uncinate fasciculus and severity of depressive symptoms in one diffusion tensor imaging (DTI) study. However, no other correlations were identified between the structural brain abnormalities and behavioral outcomes in patients in remission of CS, which might be due to a limited power or to the fact that behavioral outcomes may show stronger associations with functional brain abnormalities (22, 29).

The actual course of the residual alterations in patients in long-term remission is hard to capture, because longitudinal studies with long-term follow-up are lacking (i.e., mean duration of follow-up in available studies ranging from 6 to 40 months). Furthermore, previous studies in patients with active CS mainly evaluated the hippocampus, and the first MRI studies in patients with CS did not have access to modern and more sophisticated analytical tools. Therefore, it is plausible to assume that previous studies have been unable to document abnormalities at least in active patients. For instance, white matter integrity as assessed with diffusion tensor imaging (29) has not been evaluated in patients with active disease, which retains us from drawing conclusions about the development of these reductions in white matter integrity.

It is tempting to speculate that the brain abnormalities found in patients with CS during active disease, as well as during remission, also apply for patients with iatrogenic CS due to glucocorticoid treatment. This is supported by findings of similar brain abnormalities in patients while on long-term corticosteroid therapy as in patients with CS (smaller hippocampal, amygdala volumes, cerebral atrophy, and alterations in neurochemical concentrations) (43, 44, 45, 46).

A considerable amount of between-study heterogeneity was observed. First of all, heterogeneity was present regarding sample composition, with some studies analyzing homogenous groups of patients with pituitary CD or patients with adrenal CS, whereas other studies analyzed a more heterogeneous group of patients with pituitary as well adrenal CS. In addition, some studies analyzed homogenous groups of patients with active disease or patients in remission, whereas other studies analyzed patients with active, as well as with remitted disease. Secondly, studies demonstrated a great variety in analyzed brain regions of interest and in the methodology used. Consequently, no meta-analysis could be performed. Furthermore, it should be acknowledged that CS is associated with multisystem morbidity (5) and pituitary hormone deficiencies, which all can affect the brain (47, 48, 49, 50, 51).

In conclusion, patients with CS demonstrate structural brain abnormalities, as well as neurochemical and functional abnormalities, which only partly recover during long-term remission, because these still occur even after long-term remission. CS might be considered as a human model of nature that provides a keyhole perspective of the neurotoxic effects of exogenous glucocorticoids on the brain.

Supplementary data

This is linked to the online version of the paper at http://dx.doi.org/10.1530/EJE-14-1101.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.

Funding

This review did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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    Flow diagram of selection and exclusion stages.

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    Brain atrophy in a patient with active CD vs healthy control. (A) T1-weighted sagittal MRIs of a 32-year-old patient with CD and (B) age- and sex-matched control (20).

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    Grey matter volumes in patients after long-term remission of CD. (A) Results of regions of interest analysis, with lesser grey matter volumes in patients than that in controls (P<0.05; 617 voxels, 2-mm isotropic). (B) Results of whole brain analysis with lesser grey matter volumes in patients than that in controls (P<0.05; 37 voxels, 2-mm isotropic). (C) Results of whole brain analysis with greater grey matter volumes in patients than that in controls (P<0.05; 323 voxels, 2-mm isotropic). The left hemisphere corresponds with the right side of the image (22).

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