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This is a prospective, multi-center, case-control study where neurocognitive function will be evaluated in 36 patients with Cushing syndrome (CS) and 36 controls matched for age, gender and education.
Full description
Background
Endogenous Cushing's syndrome (CS) is the collective name for several rare disorders of chronic glucocorticoid (GC) excess. The most common causes are ACTH producing pituitary adenoma [Cushing's disease (CD)], cortisol producing adrenal adenoma (CPAA) and ectopic ACTH producing tumors.
Cognitive dysfunction, psychiatric disorders, fatigue, and impaired quality of life (QoL) are frequently observed in patients with active CS. Morphological changes in the central nervous system have also been reported in patients with CS, including decreased total brain volume and hippocampal formation volume compared with healthy subjects.
After successful treatment of CS, cognitive function improves according to some studies while others have found no change from pre-treatment levels. Increased brain volume has also been reported following treatment, although not to the levels of a normal control group.
Various aspects of the neurocognitive consequences of hypercortisolism have been studied in recent years. However, a major limitation of most previous studies is the small sample size. Longitudinal research data is sparse. A further limitation is that CS is a heterogeneous disease with several etiologies, varied clinical findings at presentation and varying outcome after treatment. Consequently, and since CS is a rare syndrome, the number of patients needed to be studied is too large for a single center. A collaborative multi-centre effort is therefore a desirable approach.
Aim
The overall aims of this project are 1) to improve our understanding of CS, in particular the spectra and time course of impaired well-being, fatigue and cognition, 2) to study the mechanisms behind the apparently long-term negative consequences on the CNS in these domains after biochemical remission has been achieved. For this purpose, the investigators will use the following tools:
Design
This is a prospective, case-controlled study, conducted at three centres:
Patients and matched controls will be recruited at each centre.
The patients will be studied prior to medical and surgical treatment (baseline visit 0) and 3, 6, 9, 12, 18 and 24 months after surgical treatment. The controls will be studied on two occasions, namely at baseline and after 12 months.
Subjects Thirty-six patients with newly diagnosed endogenous CS and 36 matched controls will participate in the study.
Since CS is a rare disorder the investigators estimate that it will take 3 years to include 36 patients.
Methods
5.1 Inclusion
The study investigators at each individual centre will identify patients with newly diagnosed CS. Inclusion will take place before any intervention, including medical treatment for hypercortisolism.
5.2 Questionnaires
Questionnaires will be completed by patients at the individual centres in the morning 9-12 am, prior to treatment and 6, 12 and 24 months after treatment. Controls will complete the questionnaires at baseline and after 12 months.
5.3 Cognitive function
The Rey Complex Figure will be used to test memory. Digit symbol-coding from the WAIS-IV NI will be used to assess information processing speed. Auditory attention and working memory will be measured by the digit span test. The verbal fluency test (FAS) will be used to measure the ability to generate as many words as possible beginning with a specific letter within 1 minute.
5.4 Structural MRI (Magnetic Resonance Imaging)
Patients will undergo cranial magnetic resonance imaging before treatment as well as 12 and 24 months after surgery. Control subjects will be scanned twice with an interval of approximately 12 months. In line with previous MRI studies in patient populations, total time for participants in the scanner will be one hour or less.
5.5 Diffusion Tensor Imaging (DTI)
The investigators will also acquire DTI data along 32 directions, enabling analyses of integrity as well as fibre tracking.
5.6 Functional MRI
Functional MRI will be used to study resting state functional connectivity as well as brain activity during cognitive and emotional function prior to treatment, and 12 and 24 months after treatment.
5.7 Positron emission tomography
Resting state glucose utilization in the brain will be studied by using fludeoxyglucose positron emission tomography (FDG-PET) prior to treatment and 12 months after treatment (only in patients from Gothenburg). Controls will be studied with FDG-PET only at baseline.
5.8 Neurodegenerative and inflammatory biomarkers in CSF and blood
Neurodegenerative and neuroinflammatory CSF markers, as well as peptides and hormones important for GC metabolism, will be analysed prior to treatment and 12 months after treatment (only in Gothenburg). Controls will be studied only at baseline.
5.9 Genetics
Polymorphism in the GC receptor gene, and other genes involved in metabolism and transport of GCs will be analysed in all subjects at inclusion in the study. All genetic analysis will be performed at Sahlgrenska University Hospital, Gothenburg, Sweden, in a single run at the end of the study.
Blood samples for DNA and RNA will be collected at baseline and 24 months after treatment for analysis of methylation and mRNA expression.
Ethical considerations
The study will be conducted according to the Declaration of Helsinki. Application for Ethical approval will be applied from the local ethical committees in Barcelona, Gothenburg and Leiden. Informed written consent will be obtained from all patients and controls. Incidental findings of clinical significance will be investigated further by the respective participating centers.
Statistical methods - Power calculations A power analysis based on previous results from studies on cognitive function as well as fMRI findings in patients with Cushing syndrome suggests that between 14 and 28 subjects need to be included in the study to detect a difference between patients with CS in remission and controls with a significance level of 5% and power of 80%. Because multiple comparisons will be applied, comparing brain activity between different groups on three performance tasks as well as a resting state condition, 36 participants per group will be included.
Financial disclosure
An unrestricted grant has been provided by HRA Pharma.
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Inclusion and exclusion criteria
Inclusion criteria:
Exclusion criteria
72 participants in 2 patient groups
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Central trial contact
Oskar Ragnarsson, MD, PhD
Data sourced from clinicaltrials.gov
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