Cortisol, cytokines, and hippocampal volume interactions in the elderly.

Separate bodies of literature report that elevated pro-inflammatory cytokines and cortisol negatively affect hippocampal structure and cognitive functioning, particularly in older adults. Although interactions between cytokines and cortisol occur through a variety of known mechanisms, few studies consider how their interactions affect brain structure. In this preliminary study, we assess the impact of interactions between circulating levels of IL-1Beta, IL-6, IL-8, IL-10, IL-12, TNF-alpha, and waking cortisol on hippocampal volume. Twenty-eight community-dwelling older adults underwent blood draws for quantification of circulating cytokines and saliva collections to quantify the cortisol awakening response. Hippocampal volume measurements were made using structural magnetic resonance imaging. Elevated levels of waking cortisol in conjunction with higher concentrations of IL-6 and TNF-alpha were associated with smaller hippocampal volumes. In addition, independent of cortisol, higher levels of IL-1beta and TNF-alpha were also associated with smaller hippocampal volumes. These data provide preliminary evidence that higher cortisol, in conjunction with higher IL-6 and TNF-alpha, are associated with smaller hippocampal volume in older adults. We suggest that the dynamic balance between the hypothalamic-pituitary adrenal axis and inflammation processes may explain hippocampal volume reductions in older adults better than either set of measures do in isolation.

Differences in verbal memory performance in postmenopausal women receiving hormone therapy: 17ß-estradiol versus conjugated equine estrogens.

OBJECTIVE: Much controversy exists and many questions remain unanswered about the effects of hormone therapy (HT) on cognition in postmenopausal women. There is growing evidence suggesting that HT compounds containing conjugated equine estrogen (CEE) have negative effects on cognition whereas 17ß-estradiol (17ß-E) either has positive or neutral effects. The present study sought to further examine this issue in a sample of postmenopausal women with risk factors for Alzheimer's disease (AD). DESIGN: Cross-sectional neuropsychological evaluation. SETTING: Academic research clinic. PARTICIPANTS: 68 healthy postmenopausal women (aged 49-68) receiving either 17ß-E or CEE for at least one year with increased risk for AD. MEASUREMENTS: Neuropsychological test battery of the cognitive domains of attention/working memory/processing speed, verbal memory, visual memory, and executive functioning. RESULTS: Multivariate analyses of variance (MANOVA) showed significantly better verbal memory performance in women receiving 17ß-E compared to women receiving CEE regardless of age, IQ, years of education, risk factors for AD (including APOE-ε4 carriership), duration of endogenous and exogenous estrogen exposure, concurrent progesterone use, or natural versus surgical menopause status. CONCLUSIONS: Verbal memory performance was better in postmenopausal women receiving 17ß-E compared to CEE in a sample population of women with risk factors for AD. Genetic risk for AD as well as other confounds did not affect this finding. The results suggest a differential effect of HT type on verbal memory, with 17ß-E being a preferential compound. Further evaluation of HT types, regimens and duration of use on cognitive performance in postmenopausal women in a controlled longitudinal design is warranted.

Differences in regional brain metabolism associated with specific formulations of hormone therapy in postmenopausal women at risk for AD.

Differential cerebral metabolic effects of various hormone therapy formulations, and their associations with cognitive status, remain to be established. The principal aim of the current study was to assess relationships between regional cerebral metabolism and estrogen-based hormone therapies. Postmenopausal women (n=53) at elevated risk for Alzheimer's disease (AD) were on estrogen-containing hormone therapy for at least one year prior to enrollment in a prospective, randomized clinical trial. Subjects underwent an FDG-PET scan, along with neuropsychological, medical, and demographic assessments at time of enrollment, to be repeated one year following randomization to hormone therapy continuation versus discontinuation, and results from analyses of the baseline assessments are reported here. Across all subjects, years of endogenous estrogen exposure correlated most closely with metabolism in right superior frontal gyrus (p<0.0005). Women taking 17ß-estradiol (E) performed three standard deviations higher in verbal memory than women taking conjugated equine estrogen (CEE), and their verbal memory performance positively correlated with metabolism in Wernicke's (p=0.003) and auditory association (p=0.002) areas. Women taking progesterone-plus-estrogen had lower metabolism than women taking unopposed estrogen within the mesial and inferior lateral temporal regions (p<0.0005) and the inferior frontal cortex, contralateral to Broca's area (p<0.0005). In conclusion, particular areas of relatively preserved metabolism were seen in women with more years of endogenous estrogen exposure, as well as in women taking estradiol-based formulations or estrogen therapies unopposed by progesterone, together suggesting regionally specific neuroprotective estrogenic effects.

Insulin resistance and hippocampal volume in women at risk for Alzheimer's disease.

Insulin resistance (IR) is the main pathological condition underlying vascular disorders, such as diabetes and cardiovascular disease, which are well established risk factors for cognitive decline and Alzheimer disease (AD). Hippocampal atrophy has been associated with cognitive decline, but little is known about the influence of IR on hippocampus integrity in non-diabetic, cognitively intact individuals. Herein, 50 women ages 50-65, current users of hormone therapy, underwent magnetic resonance imaging, cognitive testing, and homeostatic assessment of insulin resistance (HOMA-IR), as part of a longitudinal study examining brain structure and function in postmenopausal women at risk for AD. Results demonstrated a significant negative relationship between HOMA-IR and right and total hippocampal volume, overall cognitive performance, and selective tests of verbal and non-verbal memory. The main effect of HOMA-IR on brain structure and cognition was not altered by the presence of APOE-ε4 allele or by reproductive history, such as duration of endogenous and exogenous estrogen exposure. These results suggest that IR in middle-aged individuals at risk for AD may be biomarker for dementia risk.

Rosiglitazone add-on in treatment of depressed patients with insulin resistance: a pilot study.

A number of cross-sectional studies have suggested an association between insulin resistance (IR) and affective disorders. However, limited data exist on potential changes in IR in a prospective treatment of depression. The present pilot study tested the hypothesis that improvement of IR with the addition of an insulin-sensitizing agent would improve mood in nondiabetic patients with unipolar or bipolar depression, who had surrogate blood markers suggestive of IR. Surrogate IR-criteria blood markers were fasting plasma glucose >100 mg/dl or triglyceride (TG) to high density lipoprotein (HDL) ratio >3.0. Open-label rosiglitazone, titrated to a dose of 8 mg/day, was administered for 12 weeks to 12 patients with depressive disorder receiving treatment as usual (TAU). Eight patients who completed the 12-week study exhibited significant declines in both depression severity by the Hamilton Depression Rating Scale and the Clinical Global Impression scale, with moderate effect sizes noted. Modest improvement in Matsuda Index scores was also noted at 12 weeks, yet declines in depression severity scores were not associated with improvements in the endocrine markers (Matsuda Index, TG/HDL ratio, and body mass index). These results suggest the potential novel use for an insulin-sensitizing agent in the treatment of depressive disorders. Larger placebo-controlled studies are warranted.