This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bourdeau, I. Articles by Lacroix, A. Search for Related Content PubMed PubMed Citation Articles by Bourdeau, I. Articles by Lacroix, A.

Loss of Brain Volume in Endogenous Cushing’s Syndrome and Its Reversibility after Correction of Hypercortisolism

Department of Medicine and Department of Diagnostic Radiology, Division of Endocrinology, Centre Hospitalier de l’Université de Montréal, Montréal, Canada H2W 1T8

Address all correspondence and requests for reprints to: Céline Bard, M.D., Department of Diagnostic Radiology, Hôtel-Dieu du CHUM, 3840 St-Urbain Street, Montréal, Québec, Canada H2W 1T8. E-mail: . celine.bard.chum{at}ssss.gouv.qc.ca

Abstract

Chronic exposure to excess glucocorticoids results in cognitive and psychological impairment. A few studies have indicated that cerebral atrophy can be found in patients with Cushing’s syndrome (CS), but its evolution after cure has not been studied extensively. We report the presence of apparent cerebral atrophy in CS and its reversibility after the correction of hypercortisolism. Thirty-eight patients with CS, including 21 with Cushing’s disease and 17 with adrenal CS were studied. The control groups consisted of 18 patients with other non-ACTH-secreting sellar tumors and 20 normal controls. Twenty-two patients with CS were reevaluated after cure. Subjective loss of brain volume was present in 86% of patients with Cushing’s disease and 100% of patients with adrenal CS. The values for third ventricle diameter, bicaudate diameter, and subjective evaluation were significantly increased in CS groups in comparison with the control group (P 0.001). Imaging reevaluated at 39.7 ± 34.1 months after achieving eucortisolism showed an improvement of the third ventricle diameter (P = 0.001), bicaudate diameter (P < 0.0005), and subjective evaluation (P = 0.05). We conclude that brain volume loss is highly prevalent in CS and is at least partially reversible following correction of hypercortisolism.

Cushing’s syndrome (CS) results from the chronic exposure to supraphysiological levels of glucocorticoids and other steroids, which often produce neuropsychological and emotional modifications in affected patients (1, 2, 3). Psychiatric disease is present in up to 66% of patients suffering from CS and is expressed primarily by major atypical depression in 50–54% of patients (4, 5). However, the data on structural alterations of human brain in endogenous CS are limited and not emphasized in endocrinology or radiology literature as being part of detectable manifestations of this syndrome (6, 7). An older study using pneumoencephalography described the presence of diffuse cerebral atrophy in patients with Cushing’s disease (CD) (8). More recently, using magnetic resonance imaging (MRI), Starkman et al. (9) found decreased hippocampal formation volume in 27% of 12 patients with CS, in whom the values were below the 95% confidence interval of a literature reference normal population; however, the other areas of the brain were not described. Recently, Simmons et al. (10), using a subjective score in assessing computerized tomography (CT)/MRI scans, also noted significant cerebral atrophy in 63 patients with CD, compared with a control group. The morphological changes observed in the brain imaging of CS patients have been frequently referred as representing cerebral atrophy, but we prefer to use the term loss of brain volume in view of the lack of demonstration of true pathological cell atrophy or loss.

The potential reversibility of this premature loss in brain volume in CS after correction of hypercortisolism was evaluated in only two reports, to date. Heinz et al. (11) described a 9-yr-old boy with CD and apparent severe cerebral atrophy who recuperated almost completely after cure. Starkman et al. (12) reported a mean 3.2% ± 2.5% (SD) increase of hippocampal formation volume following treatment of 22 patients with CD.

In this report, we studied a population of 38 patients with endogenous CS, either with CD or adrenal CS (ACS), to assess the presence and distribution of loss of brain volume, using both objective (third ventricle diameter and bicaudate diameter) and subjective measures on CT and/or MRI examinations. The possible relationship between urinary free cortisol and tumor size with premature signs of decreased brain volume was also examined. In addition, we evaluated the evolution of brain volume after the correction of hypercortisolism in 22 patients.

Materials and Methods

Patients

In the first part of the study, clinical and radiological records of patients who underwent CT and/or MRI of the pituitary gland during the etiological investigation of CS were reviewed. Data were collected retrospectively among clinical and radiological records from 1984 to 1996 and prospectively between 1997 and 1999. All patients and control groups were younger than 65 yr of age, free of other chronic diseases, previous cerebral trauma, or neurological diseases. Four groups were included: patients with proven CS secondary to CD (21 patients) or primary adrenal causes (ACS, 17 patients) along with control groups composed of patients with other (non-ACTH-secreting) sellar tumors (OST, 18 patients) and normal controls with no sellar tumors (NST, 20 patients). The control groups were paired for age with the CD group. The selection criteria were as follows: biochemically and surgically proven ACTH-secreting pituitary corticotroph adenoma for CD and primary cortisol secreting adenoma or bilateral macronodular hyperplasia for ACS; pituitary adenoma of other etiology (OST) included nine prolactinomas, seven nonfunctioning adenomas, one GH-secreting tumor, and one mixed GH- and PRL-secreting tumor. The NST group was part of a group referred since 1983 for a possible increased sella turcica or an asymmetric sellar floor on skull x-ray, which were shown to be normal on CT investigation. Number, sex, and mean age for each group are listed in Table 1.

Urinary-free cortisol levels measured in two to four baseline 24-h collections were retrieved from patients’ charts. Urinary cortisol measurements were performed either by a commercial RIA kit (Quanticoat Kallestad Diagnostics, Chaska, MN) before 1997 and since then by an immunofluorometric assay (Immuno I system, Bayer Corp., Tarrytown, NY).

Imaging techniques

All patients and control subjects were examined with conventional coronal CT and/or coronal MRI examinations performed before pituitary/adrenal surgery or the beginning of medical therapy. CT and MRI studies were done in the three hospital sites of Center Hospitalier de l’Université de Montréal. For the purpose of consistency and validity of the data, only coronal CT and MRI images perpendicular to the pituitary gland were assessed. On MRI, measurements were done on routine coronal spin-echo T₁ images on a 1.5 and 1.0 TESLA MRI unit. Imaging included sagittal and coronal T₁ spin-echo sequence (350–600/18–25/2–4, 3-mm-thick section/16–20 cm FOV, 192 matrix) without and with gadolinium. Only the more recent examinations included T₂ spin-echo sequences.

Measures

Three parameters were used to evaluate indices of apparent atrophy. They included the third ventricle diameter measured at the level of the foramen of Monroe (14, 15) and the bicaudate diameter measured in the largest distance between the midportion of the head of the caudate nuclei (16). Two blinded independent radiologists performed subjective estimation of the degree of apparent cerebral atrophy using a scale graded from 0–3: 0 (no atrophy), 1 (mild atrophy), 2 (moderate atrophy), and 3 (severe atrophy). Comments on the distribution of atrophy were also recorded. Pituitary or adrenal tumor sizes were measured in their largest diameter when they were radiologically visible.

Statistical analysis

A group-matched design was used for age, with mean age difference within 2 yr between the OST and NST groups with the CD group. The ACS group was collected later and was not matched for age with other groups; they were on average 8 yr older than the other groups (Table 1). There was no correlation between age and sex with the various measures of brain volume loss. There was therefore no need to adjust the correlations for age and sex. CT and MRI were considered equivalent for accuracy in evaluating cerebral volume loss. Comparison among the four groups was performed using one-way ANOVA. When differences were identified, the Tukey B procedure was performed as a multiple-range test. This approach allows comparing all pairs of means (three pairs when three means are involved) and keeping the overall level at 0.05, thus avoiding inflation of type one error (7). The relationship among tumor sizes, 24-h urinary-free cortisol levels in CD and ACS, and the degree of brain volume loss was studied using the Pearson product moment correlation in CD and the Spearman product moment correlation in the ACS. The Spearman’s method is not parametric and better adapted to the size of the adrenal tumors. Initial and last available radiological evaluations of brain atrophy were compared using ANOVA for repeated measures.

Results

Assessment of the loss of brain volume

The evaluation of brain volume loss in the various groups of patients at the initial basal period is presented in Table 1. Bicaudate diameter could not be determined in eight patients and third ventricle diameter in three patients because CT examinations contained magnified pictures that did not allow these determinations. There were no differences in the various measures of indices of cerebral volume between the OST and NST groups. Significant increases in third ventricle diameter, bicaudate diameter, and subjective evaluation were present both in the CD and ACS groups, compared with the NST group. There were no differences in those parameters between the CD and ACS groups. The data for the CD and ACS groups could thus be pooled in a combined CS group and compared with the NST control group. The mean third ventricle diameter value was 5.78 mm in the pooled CS groups, which is 1.9 times wider than in NST (P = 0.001). The average bicaudate diameter was 1.3 times larger in CS, compared with the NST (P = 0.001). The strongest association was seen with the subjective assessment of cerebral atrophy in which the pooled CS obtained a mean ranking close to 2 (moderate atrophy), and the mean was near 0 (no atrophy) in the NST control group (Table 2; P < 0.001).

No correlation was found between age and any measures of brain volume loss in this relatively young population. On the basis of subjective evaluation, apparent cerebral atrophy was present in 86% of patients with CD (14% mild, 43% moderate, 29% severe) and 100% of ACS (35% mild, 35% moderate, 30% severe), compared with 10% in controls (NST) (P < 0.005). Subjective evaluation of loss of brain volume in the groups with CD or ACS revealed a diffuse cortical and subcortical apparent atrophy on the basis of sulcal and ventricle enlargement (Fig. 1).

View larger version (199K): [in this window] [in a new window]   Figure 1. Coronal T1-weighted MRI. A, A 33-yr-old normal control woman without any sellar tumor. B, A 42-yr-old man with a surgically proven ACTH-secreting pituitary macroadenoma shows brain volume loss characterized by increased subarachnoid space and ventricle enlargement. C, A 33-yr-old woman with CS from a surgically proven adrenal adenoma also presents similar evidence of apparent brain volume. D, Control MRI 12 months after correction of hypercortisolism in patient shown in C. Regression of brain volume loss is illustrated by the reduction of ventricles and sulci dilatation.

There was a significant improvement in the estimations of third ventricle, bicaudate diameter, and subjective evaluation in the group of 22 patients reevaluated after the correction of hypercortisolism (Table 2 and Fig. 1). The majority of patients showed regression of the three measurements.

The effect of duration of correction of hypercortisolism on this improvement was studied. In examining sequential estimations in individual patients in which repeated measures were performed, there appeared to be a progressive improvement that has not reached a plateau yet in our patient with the longest sequential follow-up period (Fig 2). The subgroup of 11 patients with a follow-up from 7–24 months (mean 15.5 ± 4.8 months) was compared with the second group of 11 patients with a follow-up of 25–123 months (mean 63.9 ± 33.5 months); there were no differences in the improvement of the two subgroup values for the three parameters of brain volume assessment.

View larger version (15K): [in this window] [in a new window]   Figure 2. Sequential determinations of objective indices of brain volume loss during 45 months of follow-up after correction of hypercortisolism in a woman with CD. Both parameters improve gradually and have not reached a plateau yet.

This study examined the effects of chronic excess of endogenous glucocorticoids in 38 patients with either pituitary or adrenal etiologies of CS on the loss of brain volume. Using modern neuroradiological diagnostic methods and both objective and standardized subjective measures of apparent cerebral atrophy, our data show that loss of brain volume is present in a very large proportion of patients either with pituitary corticotroph adenomas or primary adrenal etiologies. The subjective assessment showed a diffuse pattern of apparent cerebral atrophy in accordance with older pneumoencephalographic data (8).

The objective measures, the bicaudate diameter and third ventricle diameter, were both found to be significantly larger in CS patients, compared with the normal control group (NST); no such findings were present in the patients with other sellar tumors (except for grade 1 subjective atrophy in one case of acromegaly), excluding that a loss in brain volume is related to the mere presence of a pituitary lesion. In this study, these objective measures are used as an indirect sign of volume loss (hydrocephalus ex vacuo) in correlation with the increased subarachnoid space. They could also be related to an increased in cerebral spinal fluid volume in the ventricles.

This study revealed that a similar degree of brain structure modifications was present in the 17 primary adrenal CS patients as in the 21 CD patient group; only two other ACS patients had been studied previously (9). In a study of the neuropsychiatric manifestations of patients with CS, a relationship was found between the neuropsychiatric disability rating and ACTH levels (1), suggesting that ACTH levels may play a role in cognitive function. Because we found no difference in loss of brain volume between patients with ACTH-dependent (CD) and ACTH-suppressed (ACS) patients, our results suggested that ACTH levels are not an independent factor for cerebral structural alterations in endogenous CS.

The absence of consistent correlations between the 24-h urinary-free cortisol values and the indices of brain volume loss is not surprising, taking into account the lack of precise data on the duration of the hypercortisolism, as well as the variability of cortisol production in CS patients on a day-to-day basis (6). Difficulty to evaluate the onset of the disease prevented us from determining the effect of duration of exposure to excess cortisol production.

The mainly retrospective nature of this study posed some methodological restrictions. The coronal studies were centered on the sella turcica but were not optimally standardized. They did not all include the landmarks necessary to perform all the objective measurements. It did not allow us to use planimetry (17, 18) or histogram curve analysis (19, 20) methods. We have therefore included a set of subjective assessments of the overall aspect of visible central nervous system structures. The ACS group was collected later and was not age matched with NST. However, because there was no correlation between the age and different measurements of brain volume loss among the groups, this does not modify our conclusion.

Although limited in number, reported autopsy data revealed cerebral atrophy in CS (8, 21, 22, 23). Pharmacological doses of glucocorticoids were also found to cause apparent cerebral atrophy in 10% of a young population on CT scans (24). In children treated for congenital adrenal hyperplasia with slightly supraphysiological doses of glucocorticoids, increased prevalence of temporal lobe atrophy was found on MRI (25). Other studies demonstrated a possible link between the increased activity of the pituitary-adrenal axis and cerebral atrophy in the context of alcoholism (26), depression (27, 28, 29), and stress (30, 31).

Data on the evolution of the apparent cerebral atrophy following correction of hypercortisolism have been very limited, to date (11, 12). In our study of 22 CS patients reevaluated after correction of hypercortisolism, a mean improvement of 28% of the third ventricle diameter and 17.8% of the bicaudate diameter was observed. The longer follow-up period and the differences in measures and areas of brain volume in this study, compared with that of Starkman et al. (12), might explain the more important improvement noted here. Despite a significant improvement following correction of hypercortisolism, it must be stressed that the values did not return to the normal control group values (Table 2); longer follow-up will be necessary to determine whether complete correction will be possible. The partial reversibility of anatomical modifications of brain volume is in agreement with the recovery of the brain choline level (marker of degradation products of cell membrane) in the frontal and thalamic areas in CS following correction of hypercortisolism (32).

The pathogenesis of loss in brain volume induced by chronic glucocorticoid excess is probably multifactorial (2, 33). Glucocorticoids can occupy both MRs and GRs. MRs are usually protected from glucocorticoid exposure by the catabolic effects of 11ß-HSD2, which converts cortisol into the inactive cortisone molecule; however, 11ß-HSD2 is not expressed in hippocampus or other limbic structures allowing MR activation by glucocorticoids (2). High-affinity MRs, mainly localized in hippocampal regions, are heavily occupied by basal levels of adrenal steroids during the diurnal cycle; elevation of glucocorticoid concentrations in stress and CS increases the occupation of the lower-affinity GRs, which are more largely distributed in several regions of the brain (2). The occupation of MRs in hippocampus cells in culture by physiological concentrations of cortisol is essential to maintain neuronal cell survival and function; the occupation of GRs by supraphysiological doses of glucocorticoids initially leads to decreased cell excitability and a reversible phase of atrophy of apical dendrites of CA3 pyramidal neurons in culture (33, 34). If the exposure to excess glucocorticoids persists, neuronal cell death can occur.

Glucocorticoids have been shown to increase the synaptic accumulation of glutamate, possibly through an effect on its removal by glial cells; the enhanced stimulation of N-methyl-D-aspartate receptors will increase intracellular cytosolic Ca²⁺ in postsynaptic neurons, which activates several processes leading to increased susceptibility to injury (cell endangerment) and cell death (2, 33, 34). Whereas chronic absence of glucocorticoids leads to an apoptotic-like hippo-campal cell death (2), the cell endangerment following excess glucocorticoids does not involve an apoptotic mechanism (35). The mechanisms implicated are not fully understood yet but may also involve effects of glucocorticoids on several growth factors and receptors including brain-derived neurotropic factor, nerve growth factor, basal fibroblast growth factor, and TGFs (2). A reduced glucose metabolism is observed on positron emission tomography scan of patients receiving high-dose glucocorticoids (36); this may be secondary to the inhibitory action of glucocorticoids on glucose transporter synthesis and translocation in neurons and glial cells (33, 37). It must be mentioned that the studies of the effects of glucocorticoids have been conducted essentially in hippocampal cells in culture and it is unknown whether the same mechanisms apply to neurons in other brain regions. However, the partial reversibility of cerebral atrophy after correction of hypercortisolism would certainly indicate that the decrease in brain volume is not only secondary to neuronal cell death. Dexamethasone is very potent in treating cerebral edema (38), and the loss of brain volume in CS could be secondary, in part, to a loss in water; this decrease in water content of brain tissue has been assessed in vivo in animal models (39).

We conclude that loss of brain volume is not limited to hippocampal volume formation and is very prevalent in patients with CS from pituitary or adrenal etiologies. The loss of brain volume is at least partially reversible after the correction of hypercortisolism. Signs of cerebral atrophy should be evaluated in patients suffering of CS. Further studies will be necessary to determine whether complete reversal of brain volume loss is possible and whether these observations correlate with neuropsychological improvement (1, 40)

Acknowledgments

We thank Marc Dumont, M.Ps., for statistical analysis; Louis Bélair, M.D., for contribution to this work; and Victoria Baranga for secretarial assistance.

Footnotes

This work was supported by a grant from the Association des Radiologistes du Québec, Fonds de la Recherche en Santé du Québec (FRSQ 980702). This work was presented in part at the 81st Annual Meeting of The Endocrine Society, San Diego, California, 1999.

Abbreviations: ACS, Adrenal Cushing’s syndrome; CD, Cushing’s disease; CS, Cushing’s syndrome; CT, computerized tomography; MRI, magnetic resonance imaging; NST, no sellar tumors; OST, other (non-ACTH-secreting) sellar tumors.

Received June 14, 2001.

Accepted January 22, 2002.

References

1. Starkman MN, Schteingart DE 1981 Neuropsychiatric manifestations of patients with Cushing’s syndrome. Relationship to cortisol and adrenocorticotropic hormone levels. Arch Intern Med 141:215–219[Abstract/Free Full Text]
2. De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M 1998 Brain corticosteroid receptor balance in health and disease. Endocr Rev 19:269–301[Abstract/Free Full Text]
3. Forget H, Lacroix A, Somma M, Cohen H 2000 Cognitive decline in patients with Cushing’s syndrome. J Int Neuropsychol Soc 6:20–29[CrossRef][Medline]
4. Sonino N, Fava GA, Raffi AR, Boscaro M, Fallo F 1998 Clinical correlates of major depression in Cushing’s disease. Psychopathology 31:302–306[CrossRef][Medline]
5. Dorn LD, Burgess ES, Dubbert B, Simpson SE, Friedmann T, Kling M, Gold PW, Chrousos GP 1995 Psychopathology in patients with endogenous Cushing’s syndrome: ‘atypical’ or melancholic features. Clin Endocrinol (Oxf) 43:433–442[Medline]
6. Nieman LK 2001 Cushing’s syndrome. In: De Groot LJ, Jameson JLE, eds. Endocrinology. Philadelphia: WB Saunders Co.; 1691–171
7. Osborn AG 1994 Diagnostic neuroradiology. St. Louis: Mosby Year Book Inc.; 651
8. Momose KJ, Kjellberg RN, Kliman B 1971 High incidence of cortical atrophy of the cerebral and cerebellar hemispheres in Cushing’s disease. Radiology 99:341–348[Medline]
9. Starkman MN, Gebarski SS, Berent S, Schteingart DE 1992 Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing’s syndrome. Biol Psychiatry 32:756–765[CrossRef][Medline]
10. Simmons NE, Do HM, Lipper MH, Laws Jr ER 2000 Cerebral atrophy in Cushing’s disease. Surg Neurol 53:72–76[CrossRef][Medline]
11. Heinz ER, Martinez J, Haenggeli A 1977 Reversibility of cerebral atrophy in anorexia nervosa and Cushing’s syndrome. J Comput Assist Tomogr 1:415–418[Medline]
12. Starkman MN, Giordani B, Gebarski SS, Berent S, Schork MA, Schteingart DE 1999 Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing’s disease. Biol Psychiatry 46:1595–1602[CrossRef][Medline]
13. Lacroix A, Hamet P, Boutin JM 1999 Leuprolide acetate therapy in luteinizing hormone-dependent Cushing’s syndrome. N Engl J Med 341:1577–1581[Free Full Text]
14. Hawrylyshyn PA, Tasker RR, Organ LW 1976 Third ventricular width and the thalamocapsular border. Appl Neurophysiol 39:34–42[Medline]
15. Dyke CG, Davidoff LM 1940 The pneumo-encephalographic appearance of hemangioblastoma of the cerebellum. Am J Roentgenol Radiat Ther 44:1–8
16. Barr AN, Heinze WJ, Dobben GD, Valvassori GE, Sugar O 1978 Bicaudate index in computerized tomography of Huntington disease and cerebral atrophy. Neurology 28:1196–1200[Abstract/Free Full Text]
17. Winer BJ 1971 Statistical principles in experimental designs. New York: McGraw Hill
18. Synek V, Reuben JR 1976 The ventricular-brain ratio using planimetric measurement of EMI scans. Br J Radiol 49:233–237[Abstract/Free Full Text]
19. Schwartz M, Creasy H, Grady CL, DeLeo J, Frederickson HA, Cutler NR, Rapoport SI 1985 Computed tomographic analysis of brain morphometrics in 30 healthy men. Ann Neurol 17:147–157
20. Huber VG 1982 Measurements of the intracranial CSF spaces by computer tomography. Fortschr Röngenstr 137:42–47
21. Trethowan WH, Cobb S 1952 Neuropsychiatric aspects of Cushing’s syndrome. Arch Neurol Psychiatry 67:283–309[Abstract/Free Full Text]
22. Cope O, Raker JW 1955 Cushing’s disease. The surgical experience in the care of 46 cases. N Engl J Med 253:119–129
23. Soffer LJ, Iannaccone A, Gabrilove JL 1961 Cushing’s syndrome. A study of fifty patients. Am J Med 30:129–146[CrossRef]
24. Bentson J, Reza M, Winter J, Wilson G 1978 Steroids and apparent cerebral atrophy on computed tomography scans. J Comput Assist Tomogr 2:16–23[Medline]
25. Nass R, Heier L, Moshang T, Oberfield S, George A, New MI, Speiser PW 1997 Magnetic resonance imaging in the congenital adrenal hyperplasia population: increased frequency of white-matter abnormalities and temporal lobe atrophy. J Child Neurol 12:181–186[Abstract/Free Full Text]
26. Marchesi C, De Risio C, Campanini G, Piazza P, Grassi M, Chiodera P, Vescovi PP 1994 Cerebral atrophy and plasma cortisol levels in alcoholics after short or a long period of abstinence. Prog Neuropsychopharmacol Biol Psychiatry 18:519–535[CrossRef][Medline]
27. Rothschild AJ, Benes F, Hebben N, Woods B, Luciana M, Bakanas E, Samson JA 1989 Relationships between brain CT scan findings and cortisol in psychotic and nonpsychotic depressed patients. Biol Psychiatry 26:565–575[CrossRef][Medline]
28. Sheline YL, Wang PW, Mokhtar HG, Csernansky JG, Vannier MW 1996 Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA 98:3908–3913
29. Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS 2000 Hippocampal volume reduction in major depression. Am J Psychiatry 157:115–118[Abstract/Free Full Text]
30. Lupien SJ, de Leon M, de Santi S, Convit A, Tarshish C, Nair NP, Thakur M, McEwen BS, Hauger RL, Meaney MJ 1998 Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat Neurosci 1:69–73[CrossRef][Medline]
31. Bremner JD, Randall P, Scott TM, Bronen RA, Sebyl JP, Southwick SM 1995 MRI-based measurement of hippocampal volume in patients with combat-related post-traumatic stress disorder. Am J Psychiatry 151:973–981
32. Khiat A, Bard C, Lacroix A, Boulanger Y 2000 Recovery of the brain choline level in treated Cushing’s patients as monitored by proton magnetic resonance spectroscopy. Brain Res 862:301–307[CrossRef][Medline]
33. McEwen BS, Sapolsky RM 1995 Stress and cognitive function. Curr Opin Neurobiol 5:205–216[CrossRef][Medline]
34. Sapolsky RM 1994 The physiological relevance of glucocorticoid endangerment of the hippocampus. Ann N Y Acad Sci 746:294–304[Medline]
35. Masters JN, Finch CE, Sapolsky RM 1989 Glucocorticoid endangerment of hippocampal neurons does not involve deoxyribonucleic acid cleavage. Endocrinology 124:3083–3088[Abstract/Free Full Text]
36. Fulham MJ, Brunetti A, Aloj L, Raman R, Dwyer AJ, Di Chiro G 1995 Decreased cerebral glucose metabolism in patients with brain tumors: an effect of corticosteroids. J Neurosurg 83:657–664[Medline]
37. Horner HC, Packan DR, Sapolsky RM 1990 Glucocorticoids inhibit glucose transport in cultured hippocampal neurons and glia. Neuroendocrinology 52:57–64[Medline]
38. Criscuolo GR 1993 The genesis of peritumoral vasogenic brain edema and tumor cysts: a hypothetical role for tumor-derived vascular permeability factor. Yale J Biol Med 66:277–314[Medline]
39. Tjuvajev J, Uehara H, Desai R, Beattie B, Matei C, Zhou Y, Kreek MJ, Koutcher J, Blasberg R 1996 Corticotropin-releasing factor decreases vasogenic brain edema. Cancer Res 56:1352–1360[Abstract/Free Full Text]
40. Dorn LD, Burgess ES, Friedman TC, Dubbert B, Gold PW, Chrousos GP 1997 The longitudinal course of psychopathology in Cushing’s syndrome after correction of hypercortisolism. J Clin Endocrinol Metab 82:912–919[Abstract/Free Full Text]

This article has been cited by other articles:

				H. T. Chui, B. K. Christensen, R. B. Zipursky, B. A. Richards, M. K. Hanratty, N. J. Kabani, D. J. Mikulis, and D. K. Katzman Cognitive Function and Brain Structure in Females With a History of Adolescent-Onset Anorexia Nervosa Pediatrics, August 1, 2008; 122(2): e426 - e437. [Abstract] [Full Text] [PDF]

				S M Webb, X Badia, M J Barahona, A Colao, C J Strasburger, A Tabarin, M O van Aken, R Pivonello, G Stalla, S W J Lamberts, et al. Evaluation of health-related quality of life in patients with Cushing's syndrome with a new questionnaire Eur. J. Endocrinol., May 1, 2008; 158(5): 623 - 630. [Abstract] [Full Text] [PDF]

				L. K. Nieman, B. M. K. Biller, J. W. Findling, J. Newell-Price, M. O. Savage, P. M. Stewart, and V. M. Montori The Diagnosis of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1526 - 1540. [Abstract] [Full Text] [PDF]

				L F Chan, H L Storr, P N Plowman, L A Perry, G M Besser, A B Grossman, and M O Savage Long-term anterior pituitary function in patients with paediatric Cushing's disease treated with pituitary radiotherapy Eur. J. Endocrinol., April 1, 2007; 156(4): 477 - 482. [Abstract] [Full Text] [PDF]

				J. R. Lindsay, T. Nansel, S. Baid, J. Gumowski, and L. K. Nieman Long-Term Impaired Quality of Life in Cushing's Syndrome despite Initial Improvement after Surgical Remission J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 447 - 453. [Abstract] [Full Text] [PDF]

				I. Zervolea, H. Pratsinis, S. Tsagarakis, N. Karavitaki, D. Stathakos, N. Thalassinos, and D. Kletsas The impact of chronic in vivo glucocorticoid excess on the functional characteristics of human skin fibroblasts obtained from patients with endogenous Cushing's syndrome Eur. J. Endocrinol., June 1, 2005; 152(6): 895 - 902. [Abstract] [Full Text] [PDF]

				M. O. van Aken, A. M. Pereira, N. R. Biermasz, S. W. van Thiel, H. C. Hoftijzer, J. W. A. Smit, F. Roelfsema, S. W. J. Lamberts, and J. A. Romijn Quality of Life in Patients after Long-Term Biochemical Cure of Cushing's Disease J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3279 - 3286. [Abstract] [Full Text] [PDF]

				S. M. Gold, I. Dziobek, K. Rogers, A. Bayoumy, P. F. McHugh, and A. Convit Hypertension and Hypothalamo-Pituitary-Adrenal Axis Hyperactivity Affect Frontal Lobe Integrity J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3262 - 3267. [Abstract] [Full Text] [PDF]

				D. P. Merke, J. N. Giedd, M. F. Keil, S. L. Mehlinger, E. A. Wiggs, S. Holzer, E. Rawson, A. C. Vaituzis, C. A. Stratakis, and G. P. Chrousos Children Experience Cognitive Decline Despite Reversal of Brain Atrophy One Year After Resolution of Cushing Syndrome J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2531 - 2536. [Abstract] [Full Text] [PDF]

				G. Arnaldi, A. Angeli, A. B. Atkinson, X. Bertagna, F. Cavagnini, G. P. Chrousos, G. A. Fava, J. W. Findling, R. C. Gaillard, A. B. Grossman, et al. Diagnosis and Complications of Cushing's Syndrome: A Consensus Statement J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5593 - 5602. [Abstract] [Full Text] [PDF]

				B. S. McEwen Cortisol, Cushing's Syndrome, and a Shrinking Brain--New Evidence for Reversibility J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 1947 - 1948. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bourdeau, I. Articles by Lacroix, A. Search for Related Content PubMed PubMed Citation Articles by Bourdeau, I. Articles by Lacroix, A.