Monica N. Starkman

Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing's syndrome

Patients with chronic hypercortisolemia due to Cushings syndrome (CS) exhibit cognitive dysfunction. Because glucocorticoid excess is associated with hippocampal damage in animals, and the hippocampus participates in learning and memory, we explored the relationships between hippocampal formation (HF) volume, memory dysfunction, and cortisol levels in 12 patients with CS. After magnetic resonance imaging, HF volume was determined using digital sum of track ball traces of dentate gyrus, hippocampus proper and subiculum, correcting for total intracranial volume. For 27% of the patients, HF volume fell outside the 95% confidence intervals for normal subject volume given in the literature. In addition, there were significant and specific correlations between HF volume and scores for verbal paired associate learning, verbal recall, and verbal recall corrected for full-scale IQ (r = 0.57 to 0.70, p < 0.05). HF volume was negatively correlated with plasma cortisol levels (r = -0.73, p < 0.05). These studies suggest an association between reduced HF volume, memory dysfunction, and elevated cortisol in patients with CS.

Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing’s disease

BACKGROUND Decreased hippocampal volume is observed in patients with Cushings syndrome and other conditions associated with elevated cortisol levels, stress, or both. Reversibility of hippocampal neuronal atrophy resulting from stress occurs in animals. Our study investigated the potential for reversibility of human hippocampal atrophy. METHODS The study included 22 patients with Cushings disease. Magnetic resonance brain imaging was performed prior to transsphenoidal microadenomectomy and again after treatment. RESULTS Following treatment, hippocampal formation volume (HFV) increased by up to 10%. The mean percent change (3.2 +/- 2.5) was significantly greater (p < .04) than that of the comparison structure, caudate head volume (1.5 +/- 3.4). Increase in HFV was significantly associated with magnitude of decrease in urinary free cortisol (r = -.61, p < .01). This relationship strengthened after adjustments for age, duration of disease, and months elapsed since surgery (r = -.70, p < .001). There was no significant correlation between caudate head volume change and magnitude of cortisol decrease. CONCLUSIONS Changes in human HFV associated with sustained hypercortisolemia are reversible, at least in part, once cortisol levels decrease. While many brain regions are likely affected by hypercortisolemia, the human hippocampus exhibits increased sensitivity to cortisol, affecting both volume loss and recovery.

Depressed Mood and Other Psychiatric Manifestations of Cushing's Syndrome: Relationship to Hormone Levels

&NA; Thirty‐five consecutive patients with Cushings syndrome were studied prospectively prior to treatment. A consistent constellation of psychiatric disturbances was found, including impairments in affect (depressed mood and crying), cognitive functions (decreased concentration and memory), and vegetative functions (decreased libido and insomnia). A statistically significant relationship was found between the overall psychiatric disability rating and cortisol and ACTH level. The relationship of depressed mood and hormone levels was examined. Low ACTH levels were significantly associated with milder rather than pronounced depressed mood. The implications of the similarities in psychiatric manifestations between Cushings syndrome and the primary affective disorders are discussed.

Elevated cortisol levels in Cushing's disease are associated with cognitive decrements

Objective The objective of this study was to use Cushing’s disease as a unique human model to elucidate the cognitive deficits resulting from exposure to chronic stress-level elevations of endogenous cortisol. Methods Forty-eight patients with a first episode of acute, untreated Cushing’s disease and 38 healthy control subjects were studied. Results Scores for four of five verbal IQ subtests were significantly lower in patients with Cushing’s disease; their scores were significantly lower for only one nonverbal performance IQ subtest (block design). Verbal, but not visual, learning and delayed recall at 30 minutes were significantly decreased among patients with Cushing’s disease. Although verbal delayed recall was significantly lower in these patients, the retention index (percentage), which compares the amount of initially learned material to that recalled after the delay, was not significantly decreased. There was no significant association between depression scores and cognitive performance. A higher degree of cortisol elevation was associated with poorer performance on several subtests of learning, delayed recall, and visual-spatial ability. Conclusions Chronically elevated levels of glucocorticoids have deleterious effects on particular domains of cognition. Verbal learning and other verbal functions seem more vulnerable than nonverbal functions. The results suggest that both the neocortex and hippocampus are affected.

Cushing's syndrome after treatment: changes in cortisol and ACTH levels, and amelioration of the depressive syndrome.

Twenty-three patients with pituitary adrenocorticotropic hormone (ACTH)-dependent Cushings syndrome were studied before and after treatment. The relationship between the amelioration of the depressive syndrome and changes in cortisol and ACTH levels was investigated. There was a significant difference in mean change in 24-hour urinary free cortisol (UFC) excretion for changes in the depressed mood score from first to last visit. There were also significant correlations between decreases in UFC and decreases in both the depressed mood score and the modified Hamilton depression score. These relationships were not found for ACTH. Furthermore, with cortisol decreased to normal levels, continued high ACTH levels did not prevent improvement in depressed mood. The possibility that cortisol may also play a role in the pathogenesis and/or maintenance of the mood disorder in psychiatric patients is discussed.

Improvement in learning associated with increase in hippocampal formation volume

BACKGROUND Patients with spontaneous Cushings syndrome are exposed to elevated levels of endogenous cortisol for months to years. We previously reported that hippocampal formation volume (HFV) increased in such patients after treatment lowered cortisol to normal concentrations. In the present study, we examined whether the structural increase was associated with improvement in cognition. METHODS Twenty-four patients with Cushings disease were studied before treatment and following treatment. Magnetic resonance imaging was used to measure HFV and caudate head volume. Neuropsychologic tests of verbal cognition, learning, and memory were also administered. RESULTS Patients showed variability in improvement on neuropsychologic test performance. After partialing out age, education, duration of illness, and time since surgical treatment, greater improvement in word list learning, as measured by the Selective Reminding Test was associated with greater increase in HFV (r =.59, p <.02). There were no significant associations between improvement in paragraph or paired-word learning or memory tasks and increase in HFV. Improvement in other verbal tasks not strongly dependent on the hippocampus were not significantly associated with increase in HFV. CONCLUSIONS After cortisol levels decline to normal concentrations, structural volumetric increase in HFV is accompanied by functional improvement in learning of unrelated words.

Neuropsychological deficits in Cushing's syndrome.

In contrast to well documented reports of medical symptoms in Cushings syndrome (an endocrine disorder with the hallmark of corticoid overproduction), vague and infrequent references to associated mental changes reflect the subjective nature of previous clinical studies of psychological symptoms. This report presents neuropsychological test findings of 35 Cushings syndrome patients before initiation of medical therapy, and documents the frequency, nature, and severity of deficits. Performances on the Michigan Neuropsychological Test Battery revealed equivocal or no signs of neuropsychological deficits in 13 patients. Ten other patients had few and mild deficits, eight had moderate and more frequent signs of impairment, and four had frequent and marked deficits in language and nonlanguage tests of higher (cognitive) and/or lower (sensory and/or motor) level cerebral functions. The findings thus indicate varying degrees of diffuse bilateral cerebral dysfunction in two thirds of this population. Impairment was more frequent and severe in non verbal visual-ideational and visual memory functions. This pattern of deficits is similar to that in patients with other types of diffuse bilateral neuropathological processes such as toxicity, anoxia, and infectious cerebral disorders.

Patterns of cognitive change over time and relationship to age following successful treatment of Cushing's disease

Chronically elevated levels of cortisol have been associated with changes in cognitive functioning and brain morphology. Using Cushings disease as a model to assess the effects of high levels of cortisol on cognitive functioning, 27 patients with Cushings disease were examined at baseline and three successive follow-up periods up to 18 months after successful surgical treatment. At all follow-up periods, patients were administered cognitive tests as well as measures of plasma and urinary free cortisol. Structural MRIs and a depression measure were taken at baseline and one-year follow-up. Results showed that there is a specific pattern of significant cognitive and morphological improvement following successful treatment. Verbal fluency and recall showed recovery, although brief attention did not. Age of participants was a significant factor as to when recovery of function occurred; younger patients regained and sustained their improvement in cognitive functioning more quickly than older participants. Improvement in verbal recall also was associated with a decrease in cortisol levels as well as an increase in hippocampal formation volume one year after treatment. Overall, these findings suggest that at least some of the deleterious effects of prolonged hypercortisolemia on cognitive functioning are potentially reversible, up to at least 18 months post treatment.

Immune regulation in cushing's syndrome: Relationship to hypothalamic-pituitary-adrenal axis hormones

Hormones of the hypothalamic-pituitary-adrenal (HPA) axis are connected closely with immune measures. To investigate whether Cushings syndrome (CS) is associated with immune dysregulation, we compared the percentage of specific lymphocyte subsets as well as natural cell activity (NKCA) in 48 patients with Cushings syndrome and 48 age- and sex-matched normal controls. Lymphocyte subset analysis included the percentage of lymphocytes expressing CD3 (total T), CD4 (T helper/inducer), CD8 (T suppressor/cytotoxic) and CD56 (NK cell) antigens. Baseline plasma concentrations of cortisol, ACTH and beta-endorphin as well as 24 h urinary-free cortisol (UFC) levels also were determined. Results indicated a decrease in the percentage of CD4+ cells (p < 0.05), an increase in percentage of CD8+ cells (p < 0.05), a decrease in CD4/CD8 ratios (p < 0.01), and a reduction in NKCA (p < 0.05) in patients with CS compared to matched controls. We also found significant negative correlations between NKCA on the one hand and 24 h UFC (p < 0.05) and plasma beta-endorphin (p < 0.05) on the other. These results indicate there is immune dysregulation in CS patients which can be explained in part by an increase in HPA-axis hormones.

Chromosome aberrations in XO/XY mosaic individuals and their fathers

Abstract Three individuals with XO/XY mosaicism, not previously described, constitute the basis of this report. Chromosome analysis was performed on leukocyte, skin, and gonad cell cultures. A Y chromosome with peculiar morphology was identified in the karyotypes of 2 of the patients as well as in their fathers. A cell line possessing a centric fragment rather than a Y chromosome was present in the gonad culture of one of these patients. The third patient and her father had a Y chromosome that appeared normal; both, however, were found to have cells with various karyotype abnormalities. The relationship of these chromosomal findings to the etiology of mosaicism is discussed. In addition, other cases of XO/XY mosaicism are reviewed in an attempt to correlate the gonadal karyotype and histology with phenotype.