The etiology and extent of impaired quality of life, fatigue and cognitive, affective and emotional dysfunction in patients with Cushing*s syndrome ;- Prospective studies using structural and functional magnetic resonance imaging, positron emission tomography, genetic and cerebrospinal fluid analysis -

Endogenous Cushing*s syndrome (CS) is the collective name for several rare
disorders of chronic glucocorticoid (GC) excess. GCs critically control many
brain functions.
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. These negative effects of hypercortisolism seem to improve after successful
treatment, however the previous exposure appears to be related to persisting
changes in brain function. Brain activity has not yet been studied previously
with fMRI in adult patients with active CS.
Analysis of biomarkers in cerebrospinal fluid (CSF) and serum is increasingly
being used in explorative research on neurochemical and neurodegenerative
processes. It has been demonstrated that the pattern of neurodegenerative and
inflammatory biomarkers in CSF in patients with CS in remission does not differ
from healthy subjects. However, whether the same accounts for patients with
active CS has not been studied previously. Furthermore, methods for analyzing
biomarkers of brain damage in blood have been recently been developed and have
not been used previously in the context of hypercortisolism.
Several polymorphisms in the GC receptor gene have been suggested to reflect GC
sensitivity. Furthermore, genetic variants in the mineralocorticoid receptor,
11β-Hydroxysteroid dehydrogenase type 1 and ATP binding cassette B1 genes may
also be important for the action of GCs. Recent studies indicate that GC
sensitivity and pre-receptor regulation of GC action may play a role in the
long-term consequences of CS. The influence of polymorphisms in the GC receptor
gene, and genes involved in metabolism and transport of GCs, on cognitive and
emotional function in patients with active CS has not been studied previously.
A major limitation of most previous studies regarding neurocognitive
consequences of hypercortisolism is the small sample size. Furthermore,
longitudinal research data is sparse.

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.

This is a prospective, case-controlled study, conducted at three centres.
Patients and matched controls will be recruited at each centre.

Not applicable