MESTRADO INTEGRADO EM MEDICINA – TRABALHO FINAL
CAROLINA MIGUEL FERREIRA GONÇALVES
Cushing's Syndrome: the effects on the central nervous system
ARTIGO DE REVISÃO
ÁREA CIENTÍFICA DE ENDOCRINOLOGIA
Trabalho realizado sob a orientação de:
PROFESSORA DOUTORA MARIA LEONOR VIEGAS GOMES
NOVEMBRO/2018
MESTRADO INTEGRADO EM MEDICINA – TRABALHO FINAL
Cushing's Syndrome: the effects on the central nervous system
CAROLINA MIGUEL FERREIRA GONÇALVES
1PROFESSORA DOUTORA MARIA LEONOR VIEGAS GOMES
1,21Faculdade de Medicina da Universidade de Coimbra [email protected]
2Serviço de Endocrinologia, Diabetes e Metabolismo do Centro Hospitalar e Universitário de Coimbra [email protected]
NOVEMBRO/2018
Index
List of Abbreviations ... 4
Abstract ... 5
Keywords ... 5
Resumo ... 6
Palavras-chave ... 6
Introduction ... 7
Methods ... 7
Results ... 8
Cushing’s Syndrome ... 8
Hypothalamic-pituitary-adrenal axis and the circadian rhythm of glucocorticoids ... 8
Brain damage pathogenesis ... 9
Neuropsychiatric symptoms, cognitive dysfunction and quality of life ...10
1. Neuropsychiatric symptoms ...10
2. Cognitive dysfunction ...12
3. Exogenous Cushing’s Syndrome ...13
4. Quality of life ...14
Brain structure, function and cerebral metabolites ...14
1. Amygdala ...15
2. Anterior pituitary gland ...15
3. Cerebellum ...16
4. Frontal cortex ...16
5. Hippocampus ...17
6. White matter involvement ...18
7. Other areas ...19
8. Functional magnetic resonance imaging ...19
9. Reversibility of brain damage ...20
Serum markers of affective changes ...22
Pseudo-Cushing’s Syndrome or functional hypercortisolism ...22
Neurodegenerative disorders ...23
Tables...25
Discussion and Conclusion ...33
Acknowledgments ...34
References ...35
Annex ...40
List of Abbreviations
ACTH: Adrenocorticotrophic Hormone BDNF: Brain-Derived Neurotrophic Factor CD: Cushing’s Disease
CS: Cushing’s Syndrome
DKI: Diffusional Kurtosis Imaging DTI: Diffusion Tensor Imaging GAD: Generalized Anxiety Disorder
HPA axis: Hypothalamic-Pituitary-Adrenal axis QoL: Quality of Life
SSRI: Selective Serotonin Reuptake Inhibitors
11-β-HSD1: 11-β-Hydroxysteroid Dehydrogenase Type 1
Abstract
Introduction: Cushing’s Syndrome is an endocrine disorder with cardiovascular, metabolic, thrombotic and bone manifestations, as well as cognitive dysfunction and neuropsychiatric symptoms. Cortisol excess is the cause of the above-mentioned alterations and the full extent of brain damage induced by cortisol overexposure is yet to be established. Therefore, studies in Cushing’s Syndrome patients are extremely important to further conclusions in this matter. The aim of this review is to describe the effects of cortisol excess on the central nervous system, particularly in Cushing’s Syndrome, and to summarize the results of original articles published in the last ten years.
Methods: In order to write this review, it was performed a literature search during June 2018 in Pubmed and Embase. It was used MeSH terms and equivalent Emtree terminology, with filters of “English”, “Humans”, “Ten years” and excluding "Case Reports".
Results: Several neuropsychiatric symptoms and disorders, along with cognitive symptoms have been described in both active and remitted disease, despite their improvement after biochemical cure in some cases. Furthermore, these patients have decreased quality of life, which should be an important concern when diagnosis is made and while managing this disease. In fact, these symptoms are largely attributed to structural and functional brain alterations, whose reversibility is still controversial. Thus, earlier diagnosis is desired, as well as prolonged follow-up. Some symptoms and brain alterations are similar to stress-related psychiatric disorders and neurodegenerative disorders, however the mechanisms involved are probably not equal.
Conclusion: Cushing’s Syndrome is widely recognized as a good human model to evaluate excessive cortisol effects on the brain. However, past and current studies have similar limitations and different objectives, with numerous questions raised without further researches to give continuity to them. Awareness of these matters should be raised, not only around clinicians, but also around future researchers.
Keywords: Cushing Syndrome, Mental disorders, Brain, Pituitary ACTH hypersecretion/pathology, Pituitary ACTH hypersecretion/psychology.
Resumo
Introdução: A Síndrome de Cushing é uma doença endócrina com manifestações cardiovasculares, metabólicas, trombóticas e ósseas, assim como disfunção cognitiva e sintomas neuropsiquiátricos. É causada por excesso de cortisol e a dimensão das lesões cerebrais provocadas não é completamente conhecida. Neste sentido, estudos em doentes com Síndrome de Cushing são extremamente importantes para futuras conclusões neste tema. O objetivo deste trabalho de revisão foi descrever os efeitos da exposição ao excesso de cortisol no Sistema Nervoso Central, particularmente na Síndrome de Cushing, e sumarizar os resultados das investigações neste tópico, publicadas nos últimos dez anos.
Métodos: Foi realizada uma revisão da literatura existente nos motores de busca Pubmed e Embase em julho de 2018. Foi usada terminologia MeSH e Emtree, com filtros “Inglês”,
“Humanos”, “Dez anos” e excluindo “Casos Clínicos”.
Resultados: Foram descritas diversas alterações, doenças e sintomas neuropsiquiátricos, assim como sintomas cognitivos durante a fase ativa da doença e após remissão apesar de, em alguns casos, ter ocorrido uma melhoria após a constatação da referida remissão bioquímica. Não obstante, estes doentes evidenciaram uma qualidade de vida diminuída, parâmetro que é importante considerar aquando do diagnóstico da doença, assim como no seu posterior seguimento. Estes sintomas são geralmente atribuídos às alterações estruturais e funcionais que ocorrem no cérebro destes doentes, cuja reversibilidade é controversa. Neste sentido, o diagnóstico precoce e o seguimento prolongado do doente são desejáveis. Alguns sintomas e alterações cerebrais são semelhantes aos observados nas doenças psiquiátricas relacionadas com o stress ou em doenças neuro-cognitivas, no entanto, os mecanismos envolvidos nas mesmas são, provavelmente, distintos.
Conclusão: A Síndrome de Cushing é reconhecida como um bom modelo humano para avaliar os efeitos da exposição cerebral ao excesso de cortisol. Contudo, os estudos disponíveis partilham várias limitações e têm diferentes objetivos, pelo que as questões ou problemas indicados não têm, frequentemente, seguimento em estudos posteriores. Assim, torna-se importante consciencializar médicos e investigadores relativamente a estes temas para que investigações futuras possam vir a esclarecê-los.
Palavras-chave: Síndrome de Cushing, Doenças mentais, Cérebro, Hipersecreção hipofisária ACTH/patologia, Hipersecreção hipofisária ACTH/psicologia.
Introduction
Cushing’s Syndrome is characterized by a group of symptoms (1) caused by chronic elevated glucocorticoids levels exposure, (2-5) namely cardiovascular, metabolic, thrombotic and bone disorders, (2,5) as well as neuropsychiatric disorders (2,3) and cognitive impairment. (2,3,5)
Psychiatric and cognitive symptoms also known as steroid dementia Syndrome, occur in 57- 79% of Cushing’s Syndrome patients, (3) and contrary to other reversible Cushing’s Syndrome features, an incomplete recovery may be observed after biochemical cure. (2-4) Former studies documented several alterations in brain structure, function and metabolites in Cushing’s Syndrome patients. (6) In fact, these patients have increased morbidities and mortality and a worse health-related quality of life, (4, 7) including after disease remission. (2, 4,5,7)
The mechanisms resulting in brain damage during excessive cortisol are not fully understood (3,7,8) and Cushing’s Syndrome is considered a good human model to study these alterations (2,8) and their possible reversibility. (9) Nevertheless, studies in this field have been very limited. (10) However with the recent advances in imaging technics (8,11) new information is available. (8)
The aim of this review is to describe the effects of cortisol excess on the central nervous system, particularly in Cushing’s Syndrome, and to summarize the results of original articles published in the last ten years.
Methods
During June 2018, we performed a literature search in PubMed using the following MeSH terms: "Pituitary ACTH Hypersecretion/pathology”, "Pituitary ACTH Hypersecretion/psychology", "Cushing Syndrome", "Mental disorders" and "Brain" and in Embase using the equivalent Emtree terminology, narrowing the results with filters of English, studies in Humans and publications in the last ten years and excluding "Case Reports" publication types. A total of 180 articles were screened and 64 excluded because they did not match the main objective of this article or had repetitive information. After full text accessing of the remaining articles, 57 were eligible for inclusion in this review. Other similar articles considered relevant were also included.
Results
Cushing’s Syndrome
Cushing’s Syndrome (CS) can have an exogenous/iatrogenic cause or a less common endogenous cause. (3,12) Endogenous CS is divided in adrenocorticotrophic hormone (ACTH)-dependent forms, mostly due to a pituitary adenoma (Cushing’s disease (CD)) (1-4, 7) or less frequent independent forms (adrenocortical tumors and adrenal hyperplasia). (2,3, 7) In pseudo-Cushing’s Syndrome, hypothalamic-pituitary-adrenal (HPA) axis dysfunction is not the cause of the functional hypercortisolemia and this condition, also leading to CS symptoms, may be observed in psychosomatic disorders such as depression, anxiety disorders or alcoholism. (1)
Hypothalamic-pituitary-adrenal axis and the circadian rhythm of glucocorticoids
The HPA axis consists on a cyclic endocrine activity, (13) important in stress response. (8, 12) The circadian rhythm involves the hypothalamic suprachiasmatic nucleus and other hypothalamic nuclei, as well as the pineal gland, pituitary gland and adrenal gland. The neurotransmission depends on various photic and nonphotic environmental factors (13), the most important input being the light-dark cycle. It begins in the hypothalamic suprachiasmatic nucleus, also called the central pacemaker, mainly reaching the hypothalamus. At the same time other outputs reach other areas, namely the basal forebrain and midline thalamus, which control higher functions such as attention, memory, emotion and psychomotor performance. (14) Once activated, the hypothalamic paraventricular nucleus releases corticotropin-releasing hormone, controlling the production and post translational changes of pro-opiomelanocortin, the precursor of ACTH, and stimulating its release by the anterior pituitary gland. Arginine vasopressin also leads to ACTH release. (12,14) The end products and effectors of HPA axis are plasma glucocorticoids – cortisol in humans, (13) produced by the adrenal cortex (2, 12) after ACTH stimulation. Cortisol has a negative feedback on the hypothalamus and pituitary gland, preventing ACTH hypersecretion. (12)
In normal conditions, cortisol secretion peaks after morning awakening and decreases during the rest of day, with minimal values at midnight. (12,13) This circadian rhythm is controlled by variations in the amplitude and/or frequency of ACTH secretion and possibly by the expression of clock genes in the components of the above-mentioned HPA axis. (13) However, in CD, increased mean pulsatile ACTH amplitude, abnormal cortisol secretion rhythm, no decrease in cortisol levels in the evening and resistance to cortisol inhibitory feedback in corticotroph adenomas were described. (13) Conversely, other CD patients still
have a cortisol diurnal rhythm despite high cortisol levels. (13,14) In fact, CS is characterized by the loss of the circadian rhythm of cortisol. (1,13,14)
Recently, a study suggested that the glucocorticoid rhythm has an impact on behavior, cognition and brain health. (15)
Brain damage pathogenesis
Glucocorticoid receptors are present through the whole brain, while mineralocorticoids receptors are mainly in the limbic system and prefrontal cortex. (16) Thus, there is a high density of glucocorticoid and mineralocorticoid receptors in the hippocampus and its surrounding areas. (6) Some of the limbic structures, such as the hippocampus, the amygdala and the anterior cingulate cortex have a role in the regulation of HPA axis and effects of cortisol excess in these structures, both structural and functional, have been reported. (17) It is still unknown whether the brain effects of chronic hypercortisolemia are due to glucocorticoid or mineralocorticoid receptors.(16) However, some authors refer that brain damage due to cortisol excess is mostly related to gene transcription mediated by glucocorticoid receptors (6) and that they are preferentially activated in chronic exposure.
This stimulation has been related to memory impairments. (18)
The lack of 11-β-hydroxysteroid dehydrogenase type 2 in brain areas related to emotional and cognition processing favors the hyper activation of glucocorticoid and mineralocorticoid receptors, consequently damaging the brain. (3) The mechanisms of this damage are not known, (3,7,8) but multiple theories try to explain it. A direct toxic effect is proposed due to accumulation of glutamate causing dendritic and hippocampal atrophy and due to activation of N-methyl-D-aspartate receptors leading to neural apoptosis. On the other hand, glucocorticoids may decrease neurogenesis, leading to hippocampal volume loss, and decrease neurotrophic factors synthesis, which compromises learning process and memory.
Reduced glucose uptake (3,7) and water contents may also have a role in pathogenesis. (3) Studies described inhibited neurogenesis after glucocorticoid receptor activation and inconsistent results regarding mineralocorticoid receptors, either increasing or decreasing neurogenesis. (18)
Genomic and non-genomic mechanisms are involved in the effects of glucocorticoids in the brain after binding to glucocorticoid and mineralocorticoid receptors, and the time and duration of stress are important for the development of these effects. (19) In fact, stress response leading to behavioral changes, consists on fast changes due to catecholamines’
sympathetic nervous system activation and to cortisol’s nongenomic action, as well as on slower changes involving mineralocorticoid and glucocorticoid receptor stimulation.
Therefore, cortisol has an important role in this response. (20) Additionally, glucocorticoids also have a role in the immune system, cognition and memory. (18)
Regarding the etiology of cognitive impairment, a study in long-term remitted CS patients suggested that glucocorticoid sensitivity and prereceptor regulation might influence long-term CS consequences. They mentioned specific polymorphisms in 11-β-hydroxysteroid dehydrogenase type 1 (11-β-HSD1) and glucocorticoid receptor genes related to increased HPA axis activity, depression risk and impaired cognitive function in the first, and increased fatigue and impaired cognitive function in the second. (21)
Neuropsychiatric symptoms, cognitive dysfunction and quality of life (see Table 1) Endogenous and exogenous CS may have similar neuropsychiatric and neurocognitive symptoms (3,20,22) which are non-specific symptoms. (23)
Psychiatric disorders and cognitive impairment in CS are generally recognized to be caused by brain structural and functional alterations, (2,3,10, 24) induced by chronic hypercortisolism and HPA axis dysregulation. Inadequate coping with this chronic disease, (2,24) personality traits and compromised decision making might also effect the development of neuropsychiatric symptoms. (24) It is suggested that pathologic mechanisms of this CD symptoms differ from psychiatric disorders, even though hypercortisolism may also be present. (6,9)
Furthermore, mood disorders and cognitive dysfunction do not appear to be interrelated, (22) which is in accordance to a study that found no effects of fatigue or affective disorder in cognitive tests. (25)
1. Neuropsychiatric symptoms
An elevated frequency of mood disorders is described in CS (26) and major depression is the most commonly found. (5,7, 20, 26) In fact, mood disorders have been included in the clinical index for CS severity. (20, 26) Genetic predisposition, (2,5, 26) personality and in CD, but not in CS, stressful life events, might be involved in the etiology. (26) Psychiatric symptoms appear to be more influenced by the disease severity and higher cortisol levels than by CS etiology. (2,5)
In active disease, major depressive disorder is observed in approximately 50-80% of patients (2-5) and is present in up to 25% at the onset of CS. (1,2) In fact, psychiatric symptoms may occur months or years before other CS symptoms. (1) Concerning depression related symptoms, several studies described that up to 17% of patients had suicidal thoughts, 5.7%
suicide attempts, 43% hopelessness, 63% referred crying (2) and 74% depressed mood. (7)
Depression appears to be related to older age, women, severe disease, higher baseline urinary cortisol, (1,2,5,7,8,20,26) no detectable pituitary adenoma, (2,5,7,8,20,26) adverse life events (2,5) and is a predictor of failed pituitary surgery and disease relapse. (2) Since depression and anxiety are usually present at the same time in non-endocrine depression, it is not known if anxiety is dependent on the occurrence of depression. (5) Other psychiatric conditions and symptoms are commonly witnessed in several studies: generalized anxiety disorder (GAD) (79%), panic disorder (3-37%), (2,5) mania or hypomania (3-30%), (2) psychotic disorder (8%) more common in adrenal carcinoma, (2,5) irritability (up to 86%), (2, 7) reduced libido (50-69%), (2) middle (69%), late (57%) or early (29%) insomnia (2,7) and emotional lability (17%). (2) Lower sleep quality but preserved sleep quantity (27) and increased (34%) or decreased (20%) appetite were observed as well. (7,22)
In remitted patients, an improvement of the above-mentioned disorders and symptoms might occur, however its complete reversibility is controversial (2,7,8) and new symptoms may appear after cure. (2,5,7) Accordingly, a study found 13.7% of patients with a new psychiatric diagnose after normal cortisol levels. (2) Atypical depression was found to be the most common disorder after hypercortisolism correction (20) and one year after remission. (24) Few studies analyzed personality disorders in these patients, (2) but it was described maladaptive personality traits (8), elevated anxiety traits (28) with higher neuroticism scores and harm avoidance (2,28) and reduced externalizing traits with less novelty seeking and extraversion. Furthermore, while persistent hypercortisolism and presence of hypopituitarism were associated with these personality traits, previous radiotherapy and active disease duration were not. (28) Contrarily, other studies did not find maladaptive personality traits.
(20) In turn, social phobia, apathy, decrease libido, insomnia, hypersomnia, loss of emotional stability have been reported. (2) Several studies focused on the degree and the time of improvement in multiple above-mentioned symptoms which are not identical: depressed mood improvement in 72% of the cases related to the decrease of cortisol levels, and a full recovery of depression in 70%, middle insomnia in 62% and increase in libido in 28%, (22) while psychopathology decreased from 67% to 54%, 36% and 24% at 3,6 and 12 months, respectively. (20,22) Regarding the time of this irritability and sleep improvement, it usually occurred before the depressed mood. (22) Similar frequency and intensity in psychopathological symptoms was reported in male and female remitted CD patients and while in men the time to diagnosis was a strong predictor of this impairment, in women comorbidities that require coping were associated. (29)
Although screening tools can be used by general clinicians, since these features might be hard to diagnose, (2) referral to a specialist is advised. (2,5) On the other hand, these symptoms may help in diagnosis, as at least a triad including irritability, middle insomnia and decreased libido was initially present in spontaneous CS patients. Furthermore, several
features differ from primary major depressive disorder: prominent irritability, adrenergic stimulation symptoms such as shacking and increased sweating, labile affect, episodic depressed mood, worse depressive symptoms in the morning, and ability to experience pleasure. (22)
Regarding treatment, a multidisciplinary approach is required. (2,5) As symptoms in patients with active CS might not respond to antidepressant treatment until normal cortisol levels are reached, (2,5,30) the initial treatment aims to treat hypercortisolemia. (2,5,22) Regarding the use of antidepressants and benzodiazepines, controlled studies in CS patients are scarce.
(5) Drug treatment with selective serotonin reuptake inhibitors (SSRI) and corticosteroid synthesis inhibitors might be used during active disease. (2) For psychosis, a feature difficult to treat, clozapine, mifepristone (alone or with etomidate) (1,2,5) and aripiprazole with mirtazapine (5) have been considered effective in some cases. Mifepristone might be used for a rapid cortisol level control, (2) however it is controversial as a long-term strategy due to several associated adverse effects. (2,5) In remitted patients, treatment might be similar to patients without CS, including psychoeducation, physical activities, group therapy and cognitive-behavioral therapies and, if necessary, SSRI for depression and benzodiazepines for anxiety. Finally, the exact relation between adrenal insufficiency and psychiatric symptoms is unknown, nevertheless it should be treated with glucocorticoid replacement therapy. (2,5)
Education of patients and their families and support groups might be useful (2,5) and return to usual daily activities and work, new hobbies, support from others, treatment compliance and self-care improvement may help improving quality of life (QoL). (5) All CS patients including the ones after disease remission, should be continually monitored using available screening tools if necessary. (1-3,5,7,22,24,31)
2. Cognitive dysfunction
Neurocognitive symptoms have been described in about two thirds of CS patients. (7,8) Several findings have been described in studies with active and remitted CS patients: verbal (8,11,32,33) and visual memory, (8,11,33-35) executive dysfunction such as impairments in working memory, (8,35) attention, (8,33,35) verbal fluency (8) or in decision-making process (8,36) and other cognitive functions such as impairments in visuoconstructive skills, (8,35) language, (8) motor functions (8,34) or in information processing speed. (8,25,33) Moreover, a study suggested that chronic cortisol exposure has ageing-like effects on cognition. (35) There is no consensus throughout these studies and further larger and longitudinal studies are needed. (8)
In active disease, neurocognitive alterations such as memory and concentration impairment were observed in 83% and 66% of CS patients, respectively. Verbal and non-verbal control and visual and spatial capabilities might be affected. (3,7)
As in neuropsychiatric symptoms, remitted patients may exhibit persistent or intensified symptoms or a residual cognitive disorder. (3,7) Several studies suggest persistent or partially irreversible alterations, (11,25,33,37) particularly in attention, memory and executive functions. (37) A study concluded that more demanding cognitive tests are needed to assess neurocognitive dysfunction in CS patients and described mental fatigue and executive function impairment as features in remitted CS patients. Both were not related to etiology, radiotherapy or glucocorticoid replacement therapy, (38) which is in accordance with other study that found similar cognitive results for CD and adrenal adenoma. (25) Concerning improvement, a study described it in approximately 80% and 70% of patients regarding concentration and memory, respectively. It reported also that it differs in the several cognitive tasks and that older age is related to fewer improvements. (22) Currently the etiology of these persistent symptoms is unknown. (39)
CS active and remitted patients should be continually monitored. (7)
3. Exogenous Cushing’s Syndrome
Exogenous glucocorticoids are used in several medical conditions. Differences in blood-brain barrier penetration as well as in the receptors affinities of glucocorticoids hinders studies results and further conclusions. In contrast to chronic cortisol excess exposure, in this type of CS the brain is exposed to a rapid increase in cortisol concentration. Symptoms are not identical throughout patients and the same patient can have different manifestations in different administrations. (22)
While short-term administration of moderate and high doses of exogenous glucocorticoids, hypomanic and manic symptoms have been more commonly described (26%), also depression (10%), hyperarousal, mild euphoria, anxiety and declarative verbal-memory affection are revealed. In long-term administration, although sleep alterations and increased appetite are the most common symptoms, depressive symptoms, depressive mood disorder (50%), manic (5%) and panic disorders (5%) and concentration impairment have also been described. Reversibility of these symptoms after drug discontinuation has been reported.
Regarding short-term administration, dose and female gender might be risk factors. (22) Regarding treatment, dose adjustment and atypical antipsychotics (olanzapine) are options.
(22) In cases of acute or chronic exogenous CS, lamotrigine and memantine may be partially effective in cognitive dysfunction (3) while lithium (3,22) and phenytoin may be used as
prevention drugs. (3) Proper clarification of these side-effects to the patient and family is advised. (22)
4. Quality of life
Specific QoL questionnaires for CS patients, including a symptomatic, psychological and social assessment, have been proposed and studied. QoL comprises daily functional capacity, perceptions of well-being and life and the impairments due to disease symptoms.
(26) A significant number of patients describe a noteworthy impact of CS on their life. (5) Studies reported worse QoL in active CS (2) and CD (40) and impaired QoL in long-term remitted CS patients despite etiology, hormonal deficiencies and treatment. (41)
In patients with HPA axis dysfunction, QoL was impaired and physical dimensions were the most affected. Regarding CS, this impairment might persist after biochemical cure and it was worse when associated with hypercortisolism and CD. (31) Furthermore, it was worse in some dimensions of QoL questionnaires in women, in shorter remission in the dimensions
“depression” and “concentration” and in the presence of hypopituitarism and hormonal deficiencies. (41) Apart from CS with cortisol deficiency where a deterioration of mental health was observed, a stable QoL over time appeared in the other cases. (31)
Regarding CD patients, a study after surgery found lower QoL in physical functioning, health evaluation, body area satisfaction (42) and alterations in bodily restrictions and cognition dimensions. (43).
This impairment appears to be multifactorial (2,41) and further research is necessary to establish its precise causes. (41) Remission status, time until diagnosis, radiotherapy, hypopituitarism, body mass index, gender and age were identified as predictors of an impaired QoL. Moreover, maladaptive coping strategies, which is a modifiable factor, also had a strong influence. (40) Less effective coping strategies have been described in patients with pituitary adenomas. (29,40) In fact, impaired QoL was associated with late diagnosis of CS, (24) although the main predictor of impaired QoL was found to be depressive symptoms.
(3,24) In contrast, pituitary radiation, time after surgery and age were not related to QoL results in other studies. (29)
Brain structure, function and cerebral metabolites (see Table 2, Table 3)
Structural brain changes, (30) both in structural grey and white matter, functional and metabolites abnormalities (10) have been reported (see Fig. 1). Similar brain abnormalities have been described in endogenous and exogenous CS. (10) Their reversibility after biochemical cure is controversial, (8,30) and some authors mention that long-term severe
the other hand, correction of hypercortisolism corrects some of these alterations while symptoms also improve. However, other alterations in long-term remitted patients are not fully reversible, neither are the neuropsychiatric and cognitive symptoms. (10)
Figure 1. Brain areas affected by CS. Adapted from https://ebsco.smartimagebase.com/the- brain-sagittal-section/view-item?ItemID=74826
1. Amygdala
The amygdala is a subcortical structure (8) that despite playing an important role in emotion response, still lacks attention from research studies. (30) The amygdala is connected to the hippocampus and when medium glucocorticoid levels act on the amygdala they help memory consolidation, while very high or low levels have a deleterious effect. On the other hand, a negative effect regarding memory retrieval was described. (18)
It was observed that glucocorticoid excess in CS may lead to smaller amygdala volumes, particularly smaller right amygdala volumes. Furthermore, negative correlations between left amygdala volumes and depression/anxiety levels were described. Besides hyperactivation of HPA axis in patients with chronic hypercortisolism, other mechanisms are probably implicated in the reduction of amygdala volume, since an absence of correlation between hormone levels and amygdala volume was observed, while in healthy population a correlation was established. Mood disorders and chronic hypercortisolism before CS diagnosis may influence amygdala volume and may justify these results. (30)
2. Anterior pituitary gland
Crooke’s changes due to accumulation of cytokeratin filaments in the cytoplasm are transformed corticotroph cells of the anterior pituitary gland described in CS patients. A study established their occurrence in 75-80% of CS patients, depending on the severity of
hypercortisolism and on individual variability. It also concluded that despite these changes are a strong indication of CS even when no pituitary adenoma is found, their absence does not exclude the diagnosis. (44)
3. Cerebellum
The cerebellum is a subcortical structure (8) related to motor control, balance and coordination, but also to emotional control and cognition, including executive functions, visual, verbal working, procedural and declarative memory, visuospatial skills, information processing speed, emotional processing and language. (8,34)
A study in active CS patients found smaller cerebellar cortex than in controls, however other factors rather than cortisol excess exposure may influence this atrophy, once higher triglycerides and older age at diagnosis were related to smaller volumes. (8,10,34) Moreover a positive correlation between right cerebellar cortex volume and QoL and between left cerebellar volume and visual memory was described. (8,10,34)
4. Frontal cortex
The frontal cortex is a cortical structure (8) that regulates the HPA axis during acute stress and participates in emotional responses to stress and executive functions as in decision- making process. (8,36) Particularly, the ventromedial prefrontal cortex has connections to the amygdala and has a role in fear learning and extinction, thus being related to anxiety and mood disorders. (45)
In fact, excess cortisol exposure related to stress has been associated with more risk-taking behavior. Accordingly, a negative association between decision-making and salivary cortisol levels in healthy subjects after stress induction or administration of exogenous cortisol was described. (8,36)
A study in remitted and medically treated CS patients described decision-making process impairments and learning problems associated with decreased cortical thickness, particularly in frontal areas. Moreover, it showed an interaction between the hippocampus and frontal cortex because lower performances in verbal memory, which is hippocampus related, were associated to impaired decision-making process. (8,36) This study also found no correlation between impaired decision-making and cortical thickness, (10,36) probably because other structures are involved in this process. (36) There is also no association between performance in decision-making tests or cortical thickness and hypercortisolism duration.
(10,36)
Regarding brain metabolites, a study observed abnormalities in ventromedial prefrontal cortex of CS patients with lower glutamate, an excitatory neurotransmitter, and lower N-
acetyl-aspartate concentrations, related to neuronal integrity. (46) The observed hypoactivation of this area (45,46) might be related to the lower levels of glutamate. This study included both active and remitted CS patients and established a negative correlation between total N-acetyl-aspartate or creatinine concentrations and duration of hypercortisolism and anxiety, suggesting long-term excessive cortisol as the cause of this abnormalities, as well as between creatinine levels and depression symptoms. Thus, besides cortisol, these psychiatric symptoms may also have a role in the metabolite abnormalities. In healthy subjects, but not in CS patients, a relation between age and brain metabolites was observed, suggesting a premature ageing of the brain caused by cortisol excess. (46) Similarly, an early study found alterations in the cholinergic system because of the decreased creatinine and phosphocreatine ratios, related to metabolism, and choline- containing compounds, related to the membrane, in frontal and thalamic areas. (10)
5. Hippocampus
The hippocampus is a subcortical structure specially studied in CS. (8) This limbic structure has an anatomical and functional segmentation: the anterior or hippocampus head connected to the amygdala and prefrontal regions, which is involved in HPA axis regulation, affective and stress responses and possibly in explicit memory; and the posterior or hippocampus body and tail connected to sensory cortex regions and parietal cortex, which is involved in memory and spatial learning. (47) Hippocampus and parahippocampal gyrus are part of the medial temporal lobe, a region involved in the formation and consolidation of declarative memory. (6)
In fact, in active disease, hippocampal volumes were related to verbal learning and recall (10) and a negative correlation between hippocampal volumes and plasma cortisol levels was described. (10,22) A positive correlation between externalizing traits in experience seeking and hippocampus volume, principally in anterior region of right hippocampal grey matter, has been reported, and CD patients revealed reduced externalizing traits, thus suggesting potential hippocampal damage. (28)
Regarding this important subcortical area, (8) some studies reported no decrease in grey matter volumes (48) or in hippocampus volume; (10,11,49) while in other studies atrophy was described. (8,10,22,48) It is suggested that glucocorticoids firstly cause cortical grey matter atrophy and that hippocampal atrophy occurs after longer exposure in patients with severe memory impairment, specially older, (8,11) and that reduced hippocampus may be caused by alterations in grey and white matter. (48) This emphasizes the importance of an early diagnosis and treatment, (8) although it is not confirmed that these changes would be prevented. (11)
Recently, microstructural changes in the parahippocampal gyrus and in other areas of the left medial temporal lobe were described. The alterations in grey matter of the left hippocampus/parahippocampal gyrus had a positive correlation with CD severity. Indeed, the increased diffuse parameter values in grey matter observed in the left medial temporal lobe may be explained by the decreased grey matter volume. (6)
Finally, a study in cured CS patients using proton magnetic resonance spectroscopy found abnormal metabolites with low N-acetyl-aspartate and high glutamate + glutamine levels in hippocampus, suggesting respectively neuronal damage and glial proliferation, which is a repair mechanism. (8,10,49) These functional brain alterations are believed to be prior to structural abnormalities and might be early biochemical markers. (8,49) Moreover, this study suggests that these abnormalities are not associated with duration of cortisol excess exposure. (10,49)
6. White matter involvement
White matter lesions have been associated with cognitive dysfunction, particularly in executive functions, information processing speed, memory, attention and psychomotor speed and with risk of dementia, stroke or death. (50)
Some studies using diffusion tensor imaging (DTI) have found widespread white matter alterations persisting after CS remission or cure, (10,51,52) and therefore not dependent on current cortisol levels. (51) They described a relation between depressive symptoms and its severity and the loss of white matter integrity (8,52,53) that had a pattern consistent with demyelination (51,53) particularly in frontal lobe, which is associated with affective disorders.
(53) Although a positive correlation between white matter integrity and information processing speed score was established, this study did not observe any difference in processing speed in CS when compared to normal subjects. (53) A recent study using diffusional kurtosis imaging (DKI), with better sensitivity in identifying microstructural changes than DTI, found alterations in white matter and grey matter of left medial temporal lobe of CD patients. This is a more reliable proof of loss of integrity and demyelination in white matter.
(6)
Increased cardiovascular risk and long-term hypertension in CS patients were proposed to play a role in white matter lesions development, highlighting the importance of comorbidity control. A study found more severe white matter lesions, a negative correlation between ten- year cardiovascular risk/vascular age and brain volume/cognitive function and a positive correlation between white matter lesions and cardiovascular risk/hypertension. In this study, these findings were only observed in remitted CS patients. Further larger and longitudinal studies in active patients are proposed. (50) Conversely, a study found contradictive results
with white matter lesions being independent of cardiovascular risk factors, hypothesizing excess cortisol exposure as the principal cause. (51)
7. Other areas
Regarding other brain regions less information is available. (8)
The anterior cingulate cortex is an important region for cognition and emotion. (17) Connections between its anterior regions and the amygdala and hippocampus are a neural network involved in stress response. (17)
Cerebral atrophy, (2,10,17,54) reduced total and cortical grey matter, (8,10,11) increased third ventricle and bicaudate diameter (8,10) and smaller grey matter volume in the anterior cingulate cortex were described in CS. (8,10,17) While in active CD bicaudate diameter was associated with urinary free cortisol, in adrenal CS, urinary free cortisol correlated with degree of cerebral atrophy. Cerebral atrophy was influenced by disease duration. (10)
8. Functional magnetic resonance imaging
Several areas are hypothesized to have impaired functional connectivity in CS. The limbic network has a role in emotional regulation and processing and in memory and its components the hypothalamus, hippocampus, amygdala, insula and nucleus accumbens, in the stress response and HPA axis activation. (55) The cingulate cortex is also important to the limbic system. (9) On the other hand, the default mode network has a role in episodic memory, prospective memory, semantic knowledge, and self-referential processing and includes the precuneus, medial prefrontal cortex, posterior cingulate cortex and areas of parietal cortex. (55)
In fact, an association between affective processing difficulties and increased or decreased activation of several frontal and medial temporal areas important to emotion perception, processing or regulation was described. (56) An early study in active CS patients during emotional faces identification, with worse performance in this task, (45,56) showed decreased activation of left anterior superior temporal gyrus, (10,56) which is significant to emotion processing. (56) Increased activation of other areas was also found: in left dorsal anterior cingulate which was associated with disease severity, in thalamus nuclei and in the left middle frontal gyrus suggesting a compensation mechanism in order to a better performance, (56) and in frontal, medial and subcortical areas. (10,45,56) These last findings are similar in acute stress and psychiatric diseases studies. (56) Conversely, a study in long- term remitted CD patients demonstrated hypoactivation of ventromedial prefrontal cortex during emotion processing of facial expression, as well as decreased functional coupling between ventromedial prefrontal cortex and posterior cingulate cortex. (45) This suggests a
change from hyperactivation to hypoactivation in ventromedial prefrontal cortex after hypercortisolism correction (45) and alterations in emotion processing regions. (10)
Furthermore, widespread decreased functional brain response to episodic and working memory tests, particularly in prefrontal cortex and in left dorsolateral prefrontal cortex, important in executive functions and working memory, and in hippocampus in episodic memory encoding, was observed in women with CS in remission. There was no associations between functional brain responses in CS and age, duration of hypercortisolism or remission, (16) in contrast with other studies that found relations between cognitive performance and age, (11,16) hypopituitarism, radiotherapy, duration of remission, (16,33) and hydrocortisone dependency. (33) The cognitive tasks used in this study are not sensitive tests for cognition and this may explain why no differences on episodic and working memory between CS patients in remission and healthy subjects were found. (16) In contrast other studies found worse verbal and visual memory tests performance (11,16,33) and impaired executive function in CS patients (16,33).
Regarding resting-state studies in CD patients, one observed widespread alterations in spontaneous brain activity and that its increase in several regions in the default-mode network, such as the posterior cingulate cortex/precuneus, was related to hypercortisolism.
Similar findings in spontaneous brain activity were reported in stress-related disorders. (9) Accordingly, an older study found an increased resting-state functional connectivity involving the limbic network and default mode network in long-term remitted CD patients, which may suggest respectively, psychiatric symptoms/adaptive behavior and a worse use of the default mode network. (55)
9. Reversibility of brain damage
Longer disease and older age were related to fewer possibilities in recovery. (8) Several studies evaluated the potential reversibility of brain alterations after correction of cortisol excess. (10) On the other hand, studies in long-term remitted patients described decreased QoL, increased psychopathology, maladaptive personality traits and subtle cognitive dysfunction supporting the irreversibility on brain function and structure. (17)
Smaller right amygdala volumes were observed in active CS but not in patients in remission, suggesting a possible volumetric increase after biochemical cure. However future follow up studies are needed in order to confirm this hypothesis. (30) Accordingly, a study in long-term remitted CS patients found no alterations in the amygdala. (17)
Cerebellar damage may also be partially reversible. (8) Studies in remitted patients did not show smaller cerebellar cortex than in controls (8,10,34) and one study found an increased
cerebellar left posterior lobe (8,10,17) probably caused by hypertrophy, but also atrophy of other parts, following the damage induced by chronic hypercortisolism. (8)
In fact, a study from 2017 has found a relation between structural reversibility and remission times. This study showed structural repair in the cerebellum and the medial frontal gyrus of patients in short-term remission of CD, with no differences in grey matter volumes to normal subjects, and a positive correlation between this grey matter restoration and remission time.
While age was also related to grey matter volume in the medial frontal gyrus, and might influence the recovery process, this was not the case in the cerebellum, suggesting an incomplete recovery or a different speed recovery.(48)
An early study analyzing brain metabolites found an increase in frontal and thalamic choline levels until six months after cortisol excess correction, suggesting a recovery from the alterations in the described cholinergic system. (10)
An incomplete reversibility of memory and hippocampus volume was suggested. (11) Studies found no significant alterations in grey matter of hippocampus in long-term remitted CD patients (17) and a significant increase in hippocampal volumes in CD patients after surgery was described. (8,10) A previous study found improvements in learning related to the volume increase after cortisol excess correction. (10) In fact, the head of the hippocampus may be more sensitive to the effects of cortisol excess, as indicated by an increase in both right and left hippocampus head volumes in contrast with body and tail results after surgery described in CD patients. (10,47) This difference in sensitivity may be explained by higher excitatory cells density and higher susceptibility to ischemia of hippocampus head. (47) On the other hand, abnormal metabolites were described in hippocampus of cured CS patients suggesting irreversible damage after biochemical cure, (49) as mentioned above. Finally, the results of a recent DKI study lead the authors to suggest that alterations in medial temporal lobe might be partially reversible. (6)
Regarding white matter alterations, persistent consequences of cortisol excess were suggested. (8) Reduced widespread white matter integrity was described in remitted CS patients, (8,51,52) as mentioned above. Furthermore, in long-term remission there were no correlations between white matter integrity and disease or remission duration and clinical severity. (10,52)
Incomplete recovery of grey matter is also suggested, as indicated by similar cortical frontal thickness and impaired decision-making between cured and active CS patients. (8,36) On the other hand, no volumetric differences between CS patients in long-term remission and controls were found in one study, (16) while other reported smaller grey matter in the anterior cingulate cortex. (16,17) This could be justified by some limitations in the early studies. (16) Indeed, other early studies found increased brain volume after CS treatment (25) and after
CD treatment, (54) nevertheless smaller than the control group. (25,54) Similarly, a greater grey matter volume in bilateral caudate of the short remitted patients is mentioned. This might be multifactorial and may indicate a compensation strategy after cure. (48) An increase in right caudate has been related to improvements in mood and related ideation. (10) Finally, reversibility of the increased third ventricle, bicaudate diameter (8,10) and brain atrophy was described. (10)
Similarly, in short-term remitted CD patients a partial restoration of altered spontaneous brain activity was described, suggesting a potential reversibility of functional abnormalities even before structural and metabolic abnormalities. (9)
Serum markers of affective changes (see Table 4)
The nerve growth factor, also designated brain-derived neurotrophic factor (BDNF), is highly active in the hippocampus and prefrontal cortex. As low levels of serum BDNF were associated with anxiety, depression, stress and affective alterations in remitted CS patients, this study suggests BDNF as a potential serum marker of subtle affective changes in these cases. In fact, low levels of BDNF are equally present in stress-induce disorders. Similarly, elevated salivary cortisone concentrations were related to impaired affective status. (24)
Pseudo-Cushing’s Syndrome or functional hypercortisolism (see Table 4)
Similar neuropsychiatric and neurocognitive symptoms, as well as some structural or functional brain alterations, have been described in stress-related psychiatric disorders, suggesting a probable common mechanism. (55)
GAD is a very common anxiety disorder and late-life studies suggest that anxiety-related chronic hypercortisolemia may have a different effect on grey and white matter integrity, with a superior impact on grey matter. Grey matter changes are present in emotion regulation areas, with lower cortical thickness in the inferior frontal gyrus, rostral anterior cingulate cortex and orbitofrontal cortex, while white matter integrity changes are limited but may also play a role in the late-life emotion regulation. This difference is justified by other studies that suggest stress and glucocorticoids decrease neurogenesis and increase oligodendrogenesis.
(57)
Other conditions associated with hypercortisolism are depression, post-traumatic stress disorder and alcoholism. (8) In fact, several authors agree that cortisol is the most probable factor involved in depression-related cognitive impairment because this impairment was related to excessive cortisol levels. (58) In major depressive disorders, multiple studies focused on several brain areas and connectivity alterations, such as prefrontal cortex,
amygdala and hippocampus, with smaller prefrontal cortex and hippocampus volumes and inconsistent amygdala volume results. (59) However, according to a meta-analysis, a smaller amygdala volume in major depressive disorder was described, particularly in unmedicated patients, while other studies in treatment-resistant depression and elderly depressed patients had results similar to CS in which only the right amygdala was smaller. (30) In fact, studies have described smaller hippocampal volumes in affective disorders, similarly to CS. (2,5) In chronic depression, abnormal glutamate, N-acetyl aspartate and choline levels in ventromedial prefrontal cortex have been described. (46) Conversely, cognitive dysfunction in depression seems to be more related with white matter abnormalities due to cerebrovascular disease and less to cortisol. (18) Regarding post-traumatic stress disorder, focal abnormalities have been described, (47) despite the low cortisol levels found in some studies, instead of high. (18) Cerebellar atrophy was also found in depressive patients and post-traumatic disorder. (8) Reduced white matter integrity in stress-related psychiatric disorders has been described. (52)
Moreover, studies involving stress-related psychopathology have described decreased anterior cingulate cortex and hippocampus volume and the reversibility of the latter. (55) It is suggested that in alcoholism, cortisol excess might lead to psychiatric disorders and be associated with depression severity. (58) Furthermore, in chronic alcoholism decreased frontal grey matter volume was related to decision making impairments. (8,36)
Regarding eating disorders, cortisol is believed to contribute to psychiatric and cognitive symptoms. An association between the absence of suppression in dexamethasone suppression test and the presence or severity of associated anxiety and depression was described. Also, a negative correlation between urinary free cortisol levels and grey matter and a correlation between its increase after treatment and the decrease in morning plasma cortisol levels were described. (58)
Finally, there is evidence supporting the role of cortisol in cognitive impairment in diabetes mellitus type 2. (58) Studies described hippocampal damage (18,58) and an association between higher morning plasma cortisol and cognitive impairment. (58) Conversely, the role of hyperglycemia, instead of cortisol, is suggested in this damage. (18)
Neurodegenerative disorders (see Table 4)
Several studies suggested glucocorticoids and chronic stress as risk factors for Alzheimer’s disease. (18) Chronic elevation of cortisol and/or alteration of its diurnal rhythm has been described in normal elderly (22), Alzheimer’s disease (22,39) and mild dementia. (39). Thus, CS and dementia patients may have identical features such as cognitive dysfunction and hypercortisolemia. (39) DTI studies in Alzheimer’s patients showed increased diffuse
parameter values in grey matter of hippocampus and, similarly to CD patients, decreased hippocampus grey matter volumes, that are believe to be the cause of this altered values. (6) Conversely, a study found that cerebrospinal fluid biomarkers in CS patients were identical to healthy subjects, suggesting neurodegenerative disorders have a different mechanism responsible for cognitive dysfunction. (39) Furthermore, a different pattern from Alzheimer patients in retention was described in CD patients: performance one-half hour after learning was equal to controls. (22)
Tables Table 1. Symptoms and QoL (original articles in the last ten years) Year ObjectiveResultsLimitations 2017 (31)
● Assessment of the influence of HPA axis dysregulation and cortisol levels on QoL (in CS patients)
● Lower QoL scores than healthy population ● Worse scores in CS of pituitary origin ● Negative impact of hypercortisolism on QoL
● Patients recruited from a reference center ● Small groups ● Generalist questionnaires of QoL 2016 (37)
● Assessment of long-term effects on cognition 3 years after surgery (in remitted CS patients)
● Worse performance on attention, executive function and non-verbal memory tests● Reduced sample 2016 (40)
● Assessment of QoL, psychosocial dysfunction, coping strategies and its interactions (in CD patients after surgery)
● High psychological impairment ● Maladaptive coping styles as predictors of psychosocial impairment ● Association between coping strategy and self-rated impairment of QoL, embitterment and depression
● Probable selection bias ● Data given by the patients ● Limited reproducibility 2016 (43)
● Assessment of QoL and comparison between active and remitted disease (in CD patients)
● Impaired QoL in both active and remitted patients ● More bodily restrictions and cognitive impairment ● Worse scores in active patients● Not mentioned 2015 (27) ● Evaluation of sleep quality and duration (in active CS patients) ● Sleep quality alterations ● Preserved sleep quantity● Reduced sample ● No use of polysomnography 2015 (38) ● Assessment of mental fatigue, executive function and attention, and test sensitivity (in remitted CS patients)
● Common mental fatigue ● More sensitivity to cognitive deficits in the most demanding part of the test
● Sample heterogeneity
