Previous studies showed that patients with active Cushing’s disease have cognitive impairments, especially concerning memory functions. Cognition entails the process of thought and incorporates several concepts like memory, association, attention, perception, and problem solving. Those previous studies in patients with active (thus untreated) Cushing’s disease reported impairments in memory, visual- and spatial information, reasoning, verbal learning, and language performance (1-7). Brain structures important in cognitive functioning, like the hippocampus and cerebral cortex, are rich in glucocorticoid receptors and are therefore particularly vulnerable to cortisol excess as is present in Cushing’s disease (4).

Previous studies in a limited number of patients have evaluated specific brain structures in Cushing’s syndrome. Starkman et al. (8) reported that 27% of the patients with active Cushing’s syndrome had smaller hippocampal volumes than normal subjects. After treatment, all patients showed an increase in hippocampal volume and half of the patients also showed an increase in cognitive function test scores (8;9). In accordance, many other studies in humans and animal models have documented that prolonged, increased exposure to cortisol may have long-lasting adverse effects on behavioral, psychiatric and cognitive functions. This is due to functional and, over time, structural changes in specific brain areas including the hippocampus (8;10-14). In contrast, other studies found no improvements in cognitive functioning within the first year after treatment of Cushing’s disease (15;16). Some studies reported impaired cognitive functioning in patients with treated Cushing’s disease (3;15-17). However, these studies included only a small numbers of subjects, and patients were tested relatively shortly (i.e. within the first 12-18 months) after remission of Cushing’s disease. There were hardly any studies on the long-term effects of Cushing’s disease on cognitive functioning. We, therefore, aimed to investigate cognitive function in patients after long-term remission of Cushing’s disease.

To assess cognitive functioning in Cushing’s disease, four groups of subjects were studied:

1. 74 patients after long-term remission of Cushing’s disease (mean duration of remission 13 yrs)
2. 74 gender-, age-, and education-matched controls
3. 54 patients previously treated for a non-functioning pituitary macroadenoma (NFMA)
4. 54 gender-, age-, and education-matched controls

First, we compared patients after remission of Cushing’s disease with their matched controls, to establish whether there were indeed cognitive impairments. Secondly, we compared them to patients previously treated for NFMA. Patients with NFMA also suffer from a pituitary tumor, which is treated via transsphenoidal surgery (surgery through the nose) as in Cushing’s disease. The only difference between the two patient groups is the excessive overexposure to cortisol in Cushing’s disease. Therefore, this comparison enables to distinguish whether the impairments result from the tumor and its treatment, or from the cortisol overexposure.

First, we asked all patients whether they experienced limitations with respect to memory and/or executive functioning. Sixty-two percent of the patients reported memory problems, and 47% reported problems in executive functioning. Thereafter, several cognitive tests were used to measure global cognitive functioning, memory, and executive functioning. Executive functioning are the higher functions of the brain (e.g. attention, planning, mental flexibility, fluency, and information processing). The tests were very diverse and ranged from remembering a list of words to connecting dots as fast and accurate as possible.

The results of the study demonstrate that patients after long-term remission of Cushing’s disease performed worse on cognitive tests measuring memory, mental flexibility, attention, and fluency compared to matched controls. In addition, when patients after long-term remission of Cushing’s disease were compared with patients after treatment for NFMA, they performed worse on tests measuring memory, mental flexibility, and fluency. The results indicate that patients after long-term remission of Cushing’s disease indeed show subtle impaired cognitive functioning compared to matched controls. These results are not merely related to pituitary disease in general, since patients after long-term remission of Cushing’s disease also revealed impaired cognitive function compared to patients previously treated for NFMA.

Several clinical characteristics influenced cognitive function. The presence of hypopituitarism was associated with mildly impaired executive functioning. Persistent hydrocortisone dependency and additional radiotherapy were negatively associated with memory and executive functioning, which indicates that patients who were hydrocortisone dependent and patients who underwent additional irradiation of the pituitary showed more impaired cognitive functioning. The duration of remission of Cushing’s disease was positively related to memory and executive functioning, which means that patients with a longer duration of remission scored slightly better on cognitive tests, compared to patients with a shorter duration of remission.

From the present study, the notion emerges that active Cushing’s disease is associated with cognitive impairments and that treatment of Cushing’s disease in general results in some, but not complete recovery of cognitive impairment. These persistent impairments in cognitive function might be explained by irreversible effects of previous cortisol excess on the central nervous system, especially on structures important for cognitive performance.

Tiemensma J, Kokshoorn NE, Biermasz NR, Keijser BSA, Wassenaar MJE, Middelkoop HAM, Pereira AM, Romijn JA. 2010 Subtle Cognitive Impairments in Patients with Long-Term Cure of Cushing’s disease. J Clin Endocrinol Metab 95(4):2699-2714

Authors: J. Tiemensma, MSc., N.R. Biermasz, MD PhD, A.M. Pereira, MD PhD, J.A. Romijn, MD PhD (Summer, 2011)

Editor’s note: All authors are associated with the Department of Endocrinology and Metabolism of the Leiden University Medical Center, Leiden, The Netherlands. Jitske Tiemensma is a neuroscientist/psychologist and PhD-student with a special interest in the long-term psychological effects of pituitary diseases. Nienke Biermasz, Alberto Pereira, and Johannes Romijn are her supervisors and are all internist-endocrinologist.

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