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Stomby, A., Salami, A., Dahlqvist, P., Evang, J. A., Ryberg, M., Bollerslev, J., . . . Ragnarsson, O. (2019). Elevated resting-state connectivity in the medial temporal lobe and the prefrontal cortex among patients with Cushing's syndrome in remission. European Journal of Endocrinology, 180(5), 329-338
Open this publication in new window or tab >>Elevated resting-state connectivity in the medial temporal lobe and the prefrontal cortex among patients with Cushing's syndrome in remission
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2019 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 180, no 5, p. 329-338Article in journal (Refereed) Published
Abstract [en]

Objective: Cushing's syndrome is associated with long-term cognitive deficits and affective symptoms such as depression and anxiety. The alterations in brain function under lying these deficits after Cushing's syndrome are unclear and therefore we aimed to explore alterations in resting-state functional connectivity in patients with Cushing's syndrome in remission. Design: Cross-sectional case-control study. Methods: Nineteen women with Cushing's syndrome in remission for a median time of 7 years (IQR: 6-10) and a mean age of 45 years were included at three university clinics. These patients and 38 age-matched female controls underwent brain imaging at a single center. The main outcome measure was functional connectivity at rest, measured with functional magnetic resonance imaging. Results: The medial temporal lobe (MTL) and prefrontal cortex networks, exhibited elevated functional connectivity among patients compared to controls. The degree of elevated functional connectivity in the MTL was negatively associated with time in remission. Conclusions: Resting-state functional connectivity within glucocorticoid receptor-rich regions, particularly the MTL and medial prefrontal cortex, was increased in patients. These differences in connectivity may provide a neural basis for the cognitive deficits and affective symptoms commonly experienced by patients with Cushing's syndrome in remission.

Place, publisher, year, edition, pages
Bioscientifica, 2019
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-159205 (URN)10.1530/EJE-19-0028 (DOI)000466509100003 ()30939453 (PubMedID)
Available from: 2019-05-21 Created: 2019-05-21 Last updated: 2019-05-21Bibliographically approved
Ragnarsson, O., Olsson, D. S., Papakokkinou, E., Chantzichristos, D., Dahlqvist, P., Segerstedt, E., . . . Johannsson, G. (2019). Overall and Disease-Specific Mortality in Patients With Cushing Disease: A Swedish Nationwide Study. Journal of Clinical Endocrinology and Metabolism, 104(6), 2375-2384
Open this publication in new window or tab >>Overall and Disease-Specific Mortality in Patients With Cushing Disease: A Swedish Nationwide Study
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2019 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 104, no 6, p. 2375-2384Article in journal (Refereed) Published
Abstract [en]

Context: Whether patients with Cushing disease (CD) in remission have increased mortality is still debatable.

Objective: To study overall and disease-specific mortality and predictive factors in an unselected nationwide cohort of patients with CD.

Design, Patients, and Methods: A retrospective study of patients diagnosed with CD, identified in the Swedish National Patient Registry between 1987 and 2013. Medical records were systematically reviewed to verify the diagnosis. Standardized mortality ratios (SMRs) with 95% CIs were calculated and Cox regression models were used to identify predictors of mortality.

Results: Of 502 identified patients with CD (n = 387 women; 77%), 419 (83%) were confirmed to be in remission. Mean age at diagnosis was 43 (SD, 16) years and median follow-up was 13 (interquartile range, 6 to 23) years. The observed number of deaths was 133 vs 54 expected, resulting in an overall SMR of 2.5 (95% CI, 2.1 to 2.9). The commonest cause of death was cardiovascular diseases (SMR, 3.3; 95% CI, 2.6 to 4.3). Excess mortality was also found associated with infections and suicide. For patients in remission, the SMR was 1.9 (95% CI, 1.5 to 2.3); bilateral adrenalectomy and glucocorticoid replacement therapy were independently associated with increased mortality, whereas GH replacement was associated with improved outcome.

Conclusion: Findings from this large nationwide study indicate that patients with CD have excess mortality. The findings illustrate the importance of achieving remission and continued active surveillance, along with adequate hormone replacement and evaluation of cardiovascular risk and mental health.

Place, publisher, year, edition, pages
Oxford University Press, 2019
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-161459 (URN)10.1210/jc.2018-02524 (DOI)000471028400058 ()30715394 (PubMedID)
Available from: 2019-07-09 Created: 2019-07-09 Last updated: 2019-07-09Bibliographically approved
Ragnarsson, O., Olsson, D. S., Chantzichristos, D., Papakokkinou, E., Dahlqvist, P., Segerstedt, E., . . . Johannsson, G. (2019). The incidence of Cushing's disease: a nationwide Swedish study. Pituitary, 22(2), 179-186
Open this publication in new window or tab >>The incidence of Cushing's disease: a nationwide Swedish study
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2019 (English)In: Pituitary, ISSN 1386-341X, E-ISSN 1573-7403, Vol. 22, no 2, p. 179-186Article in journal (Refereed) Published
Abstract [en]

Background: Studies on the incidence of Cushing’s disease (CD) are few and usually limited by a small number of patients. The aim of this study was to assess the annual incidence in a nationwide cohort of patients with presumed CD in Sweden.

Methods: Patients registered with a diagnostic code for Cushing’s syndrome (CS) or CD, between 1987 and 2013 were identified in the Swedish National Patient Registry. The CD diagnosis was validated by reviewing clinical, biochemical, imaging, and histopathological data.

Results: Of 1317 patients identified, 534 (41%) had confirmed CD. One-hundred-and-fifty-six (12%) patients had other forms of CS, 41 (3%) had probable but unconfirmed CD, and 334 (25%) had diagnoses unrelated to CS. The mean (95% confidence interval) annual incidence between 1987 and 2013 of confirmed CD was 1.6 (1.4–1.8) cases per million. 1987–1995, 1996–2004, and 2005–2013, the mean annual incidence was 1.5 (1.1–1.8), 1.4 (1.0–1.7) and 2.0 (1.7–2.3) cases per million, respectively. During the last time period the incidence was higher than during the first and second time periods (P < 0.05).

Conclusion: The incidence of CD in Sweden (1.6 cases per million) is in agreement with most previous reports. A higher incidence between 2005 and 2013 compared to 1987–2004 was noticed. Whether this reflects a truly increased incidence of the disease, or simply an increased awareness, earlier recognition, and earlier diagnosis can, however, not be answered. This study also illustrates the importance of validation of the diagnosis of CD in epidemiological research.

Place, publisher, year, edition, pages
Springer, 2019
Keywords
Cushing's syndrome, Epidemiology, Incidence, Validation
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-157741 (URN)10.1007/s11102-019-00951-1 (DOI)000461291200010 ()30799512 (PubMedID)2-s2.0-85062015323 (Scopus ID)
Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2019-04-09Bibliographically approved
Saevik, Å. B., Åkerman, A.-K., Grønning, K., Nermoen, I., Valland, S. F., Finnes, T. E., . . . Husebye, E. S. (2018). Clues for early detection of autoimmune Addison's disease - myths and realities. Journal of Internal Medicine, 283(2), 190-199
Open this publication in new window or tab >>Clues for early detection of autoimmune Addison's disease - myths and realities
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2018 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 283, no 2, p. 190-199Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Early detection of autoimmune Addison's disease (AAD) is important as delay in diagnosis may result in a life-threatening adrenal crisis and death. The classical clinical picture of untreated AAD is well-described, but methodical investigations are scarce.

OBJECTIVE: Perform a retrospective audit of patient records with the aim of identifying biochemical markers for early diagnosis of AAD.

MATERIAL AND METHODS: A multicentre retrospective study including 272 patients diagnosed with AAD at hospitals in Norway and Sweden during 1978-2016. Scrutiny of medical records provided patient data and laboratory values.

RESULTS: Low sodium occurred in 207 of 247 (84%), but only one-third had elevated potassium. Other common nonendocrine tests were largely normal. TSH was elevated in 79 of 153 patients, and hypoglycaemia was found in 10%. Thirty-three per cent were diagnosed subsequent to adrenal crisis, in whom electrolyte disturbances were significantly more pronounced (P < 0.001). Serum cortisol was consistently decreased (median 62 nmol L(-1) [1-668]) and significantly lower in individuals with adrenal crisis (38 nmol L(-1) [2-442]) than in those without (81 nmol L(-1) [1-668], P < 0.001).

CONCLUSION: The most consistent biochemical finding of untreated AAD was low sodium independent of the degree of glucocorticoid deficiency. Half of the patients had elevated TSH levels. Only a minority presented with marked hyperkalaemia or other nonhormonal abnormalities. Thus, unexplained low sodium and/or elevated TSH should prompt consideration of an undiagnosed AAD, and on clinical suspicion bring about assay of cortisol and ACTH. Presence of 21-hydroxylase autoantibodies confirms autoimmune aetiology. Anticipating additional abnormalities in routine blood tests may delay diagnosis.

Keywords
Addison, adrenal insufficiency, autoimmune disease, cortisol, electrolytes, endocrinology
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-141853 (URN)10.1111/joim.12699 (DOI)000425830100007 ()29098731 (PubMedID)
Available from: 2017-11-14 Created: 2017-11-14 Last updated: 2018-06-09Bibliographically approved
Eriksson, D., Bianchi, M., Landegren, N., Dalin, F., Skov, J., Hultin-Rosenberg, L., . . . Kämpe, O. (2018). Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison's disease in Sweden. Scientific Reports, 8, Article ID 8395.
Open this publication in new window or tab >>Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison's disease in Sweden
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 8395Article in journal (Refereed) Published
Abstract [en]

Autoimmune Addison's disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.

National Category
Endocrinology and Diabetes Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-149017 (URN)10.1038/s41598-018-26842-2 (DOI)000433538800022 ()29849176 (PubMedID)2-s2.0-85047930642 (Scopus ID)
Available from: 2018-06-15 Created: 2018-06-15 Last updated: 2019-05-16Bibliographically approved
Eriksson, D., Dalin, F., Eriksson, G. N., Landegren, N., Bianchi, M., Hallgren, A., . . . Kampe, O. (2018). Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS1. Journal of Clinical Endocrinology and Metabolism, 103(1), 179-186
Open this publication in new window or tab >>Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS1
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2018 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 1, p. 179-186Article in journal (Refereed) Published
Abstract [en]

Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features autoimmune Addison disease as a major component. Although APS1 accounts for only a small fraction of all patients with Addison disease, early identification of these individuals is vital to prevent the potentially lethal complications of APS1.

Objective: To determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease.

Design: We systematically screened 677 patients with Addison disease enrolled in the Swedish Addison Registry for autoantibodies against interleukin-22 and interferon-α4. Autoantibody-positive patients were investigated for clinical manifestations of APS1, additional APS1-specific autoantibodies, and DNA sequence and copy number variations of AIRE.

Results: In total, 17 patients (2.5%) displayed autoantibodies against interleukin-22 and/or interferon-α4, of which nine were known APS1 cases. Four patients previously undiagnosed with APS1 fulfilled clinical, genetic, and serological criteria. Hence, we identified four patients with undiagnosed APS1 with this screening procedure.

Conclusion: We propose that patients with Addison disease should be routinely screened for cytokine autoantibodies. Clinical or serological support for APS1 should warrant DNA sequencing and copy number analysis of AIRE to enable early diagnosis and prevention of lethal complications.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-145619 (URN)10.1210/jc.2017-01957 (DOI)000424934300021 ()29069385 (PubMedID)
Available from: 2018-04-04 Created: 2018-04-04 Last updated: 2019-05-16Bibliographically approved
Vouzouneraki, K., Franklin, K. A., Forsgren, M., Wärn, M., Persson, J. T., Wik, H., . . . Dahlqvist, P. (2018). Temporal relationship of sleep apnea and acromegaly: a nationwide study. Endocrine (Basingstoke), 62(2), 456-463
Open this publication in new window or tab >>Temporal relationship of sleep apnea and acromegaly: a nationwide study
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2018 (English)In: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 62, no 2, p. 456-463Article in journal (Refereed) Published
Abstract [en]

Purpose:

Patients with acromegaly have an increased risk of sleep apnea, but reported prevalence rates vary largely. Here we aimed to evaluate the sleep apnea prevalence in a large national cohort of patients with acromegaly, to examine possible risk factors, and to assess the proportion of patients diagnosed with sleep apnea prior to acromegaly diagnosis.

Methods: Cross-sectional multicenter study of 259 Swedish patients with acromegaly. At patients' follow-up visits at the endocrine outpatient clinics of all seven university hospitals in Sweden, questionnaires were completed to assess previous sleep apnea diagnosis and treatment, cardiovascular diseases, smoking habits, anthropometric data, and S-IGF-1 levels. Daytime sleepiness was evaluated using the Epworth Sleepiness Scale. Patients suspected to have undiagnosed sleep apnea were referred for sleep apnea investigations.

Results: Of the 259 participants, 75 (29%) were diagnosed with sleep apnea before the study start. In 43 (57%) of these patients, sleep apnea had been diagnosed before the diagnosis of acromegaly. After clinical assessment and sleep studies, sleep apnea was diagnosed in an additional 20 patients, yielding a total sleep apnea prevalence of 37%. Higher sleep apnea risk was associated with higher BMI, waist circumference, and index finger circumference. Sleep apnea was more frequent among patients with S-IGF-1 levels in the highest quartile.

Conclusion: Sleep apnea is common among patients with acromegaly, and is often diagnosed prior to their acromegaly diagnosis. These results support early screening for sleep apnea in patients with acromegaly and awareness for acromegaly in patients with sleep apnea.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Acromegaly, Sleep apnea, Comorbidities, Risk factors
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-153655 (URN)10.1007/s12020-018-1694-1 (DOI)000449306400022 ()30066288 (PubMedID)
Available from: 2018-11-27 Created: 2018-11-27 Last updated: 2019-05-16Bibliographically approved
Ueland, G. Å., Methlie, P., Øksnes, M., Thordarson, H. B., Sagen, J., Kellmann, R., . . . Husebye, E. S. (2018). The Short Cosyntropin Test Revisited: New Normal Reference Range Using LC-MS/MS. Journal of Clinical Endocrinology and Metabolism, 103(4), 1696-1703
Open this publication in new window or tab >>The Short Cosyntropin Test Revisited: New Normal Reference Range Using LC-MS/MS
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2018 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 4, p. 1696-1703Article in journal (Refereed) Published
Abstract [en]

Background: The cosyntropin test is used to diagnose adrenal insufficiency (AI) and nonclassical congenital adrenal hyperplasia (NCCAH). Current cutoffs for cortisol and 17-hydroxyprogesterone (17-OHP) are derived from nonstandardized immunoassays. Liquid chromatography tandem mass spectrometry (LC-MS/MS) offers direct measurement of steroids, prompting the need to re-establish normal ranges. Objective: The goal of this study was to define cutoff values for cortisol and 17-OHP in serum by LC-MS/MS 30 and 60 minutes after intravenous administration of 250 µg tetracosactide acetate to healthy volunteers and to compare the results with LC-MS/MS with routine immunoassays. Methods: Cosyntropin testing was performed in healthy subjects (n = 138) and in patients referred for evaluation of adrenocortical function (n = 94). Steroids were assayed by LC-MS/MS and compared with two immunoassays used in routine diagnostics (Immulite and Roche platforms). The cutoff level for cortisol was defined as the 2.5% percentile in healthy subjects not using oral estrogens (n = 121) and for 17-OHP as the 97.5% percentile. Results: Cortisol cutoff levels for LC-MS/MS were 412 and 485 nmol/L at 30 and 60 minutes, respectively. Applying the new cutoffs, 13 of 60 (22%) subjects who had AI according to conventional criteria now had a normal test result. For 17-OHP, the cutoff levels were 8.9 and 9.0 nmol/L at 30 and 60 minutes, respectively. Conclusions: LC-MS/MS provides cutoff levels for cortisol and 17-OHP after cosyntropin stimulation that are lower than those based on immunoassays, possibly because cross-reactivity between steroid intermediates and cortisol is eliminated. This reduces the number of false-positive tests for AI and false-negative tests for NCCAH.

Place, publisher, year, edition, pages
Oxford University Press, 2018
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-147341 (URN)10.1210/jc.2017-02602 (DOI)000429442000054 ()29452421 (PubMedID)
Available from: 2018-05-14 Created: 2018-05-14 Last updated: 2019-05-16Bibliographically approved
Dalin, F., Nordling Eriksson, G., Dahlqvist, P., Hallgren, Å., Wahlberg, J., Ekwall, O., . . . Bensing, S. (2017). Clinical and immunological characteristics of Autoimmune Addison's disease: a nationwide Swedish multicenter study. Journal of Clinical Endocrinology and Metabolism, 102(2), 379-389
Open this publication in new window or tab >>Clinical and immunological characteristics of Autoimmune Addison's disease: a nationwide Swedish multicenter study
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2017 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 2, p. 379-389Article in journal (Refereed) Published
Abstract [en]

CONTEXT: Studies on clinical and immunological features of Autoimmune Addison's disease (AAD) are needed to understand the disease burden and increased mortality.

OBJECTIVE: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles and cardiovascular risk factors.

DESIGN, SETTING AND PARTICIPANTS: Cross sectional, population-based study. 660 AAD patients were included utilizing the Swedish Addison Registry (SAR) 2008-2014. When analyzing cardiovascular risk factors, 3,594 individuals from the population-based survey in Northern Sweden, MONICA (MONItoring of Trends and Determinants of CArdiovascular Disease), served as controls.

MAIN OUTCOME MEASURE: Prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined.

RESULTS: Sixty percent of the SAR cohort consisted of females. Mean age at diagnosis was significantly higher for females than for males (36.8 vs. 31.1 years). The proportion of 21-hydroxylase autoantibody positive patients was 83% and 62% of patients had one or more associated autoimmune diseases, more frequently coexisting in females (p<0.0001). AAD patients had lower BMI (p<0.0001) and prevalence of hypertension (p=0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of patients; with the mean dose 28.1±8.5 mg/day. The mean hydrocortisone equivalent dose normalized to body surface was 14.8±4.4 mg/m(2)/day. Higher hydrocortisone equivalent dose was associated with higher incidence of hypertension (p=0.046).

CONCLUSIONS: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients do not have increased prevalence of overweight, hypertension, T2DM or hyperlipidemia. However, high glucocorticoid replacement doses may be a risk factor for hypertension.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-128097 (URN)10.1210/jc.2016-2522 (DOI)000397240900009 ()27870550 (PubMedID)
Available from: 2016-11-23 Created: 2016-11-23 Last updated: 2019-05-20Bibliographically approved
Ragnarsson, O., Stomby, A., Dahlqvist, P., Evang, J. A., Ryberg, M., Olsson, T., . . . Johannsson, G. (2017). Decreased prefrontal functional brain response during memory testing in women with Cushing's syndrome in remission. Psychoneuroendocrinology, 82, 117-125
Open this publication in new window or tab >>Decreased prefrontal functional brain response during memory testing in women with Cushing's syndrome in remission
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2017 (English)In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 82, p. 117-125Article in journal (Refereed) Published
Abstract [en]

Neurocognitive dysfunction is an important feature of Cushing's syndrome (CS). Our hypothesis was that patients with CS in remission have decreased functional brain responses in the prefrontal cortex and hippocampus during memory testing. In this cross-sectional study we included 19 women previously treated for CS and 19 commis matched for age, gender, and education. The median remission time was 7 (IQR 6-10) years. Brain activity was studied with functional magnetic resonance imaging during episodic- and working memory tasks. The primary regions of interest were the prefrontal cortex and the hippocampus. A voxel-wise comparison of functional brain responses in patients and controls was performed. During episodic-memory encoding, patients displayed lower functional brain responses in the left and right prefrontal gyrus (p < 0.001) and in the right inferior occipital gyrus (p < 0.001) compared with controls. There was a trend towards lower functional brain responses in the left posterior hippocampus in patients (p = 0.05). During episodic-memory retrieval, the patients displayed lower functional brain responses in several brain areas with the most predominant difference in the right prefrontal cortex (p < 0.001). During the working memory task, patients had lower response in the prefrontal cortices bilaterally (p < 0.005). Patients, but not controls, had lower functional brain response during a more complex working memory task compared with a simpler one. In conclusion, women with CS in long-term remission have reduced functional brain responses during episodic and working memory testing. This observation extends previous findings showing long-term adverse effects of severe hypercortisolaemia on brain function.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Cushing's syndrome, Cognitive function, Hippocampus, Prefrontal cortex, Functional magnetic resonance imaging
National Category
Neurology Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-137931 (URN)10.1016/j.psyneuen.2017.05.010 (DOI)000405254700015 ()28544904 (PubMedID)
Available from: 2017-08-04 Created: 2017-08-04 Last updated: 2018-06-09Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-6471-9503

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