Last updated on February 2018

Quality of Life Fatigue and Cognitive Affective and Emotional Dysfunction in Patients With Cushing's Syndrome


Brief description of study

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.

Detailed Study Description

  1. 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.

2. 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:

     -  Structural MRI. To evaluate total brain volume and volume of structures important
      for cognitive function such as hippocampus and frontal cortex.

     -  Diffusion Tensor Imaging (DTI). To evaluate structural connectivity and integrity
      of white matter

     -  Resting state and task related functional MRI (fMRI). To evaluate brain functional
      connectivity during rest and during testing of cognitive and emotional functioning.
      Primary regions of interests are the hippocampus, the frontal cortex and other key
      regions of the limbic circuitry.

     -  Fludeoxyglucose Positron emission tomography (FDG-PET). To study glucose
      utilization in the above mentioned brain regions.

     -  CSF analysis. To understand the significance of inflammatory and neurodegenerative
      biomarkers in CSF and blood in patients with CS.

     -  Genetic and epigenetic analysis. To evaluate the influence of polymorphisms in the
      GC receptor gene, and genes involved in metabolism and transport of GCs, on
      cognitive and emotional functioning in patients with CS.

3. Design

This is a prospective, case-controlled study, conducted at three centres:

  • The Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden.
  • The Department of Endocrinology/Medicine, Hospital Sant Pau, Barcelona, Spain.
  • The Department of Medicine, Division of Endocrinology, and Leiden Institute for Brain and Cognition/Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.

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.

4. 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.

5. 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.

     1. The fatigue impact scale (FIS) will be used to evaluate fatigue.

     2. The EuroQol and CushingQoL will be used to evaluate quality of life.

     3. The Beck Depression Inventory and Beck Anxiety Inventory will be used to evaluate
      depression and anxiety

     4. The apathy scale will be used to evaluate apathy.

     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.

6. 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.

7. 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.

8. Financial disclosure

An unrestricted grant has been provided by HRA Pharma.

Clinical Study Identifier: NCT03211624

Contact Investigators or Research Sites near you

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Oskar Ragnarsson, MD, PhD

Dept of Medicine, Division of Endocrinology, and Center for Endocrine Tumors, Leiden University Medical Center
Leiden, Netherlands
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Susan Webb, MD, PhD

Dept of Endocrinology, Hospital Sant Pau
Barcelona, Spain
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Oskar Ragnarsson, MD, PhD

Sahlgrenska University Hospital
Gothenburg, Sweden
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