N. P. V. Nair

The modulatory effects of corticosteroids on cognition: studies in young human populations

In the present article, we report on two studies performed in young human populations which tested the cognitive impact of glucocorticoids (GC) in situations of decreased or increased ratio of mineralocorticoid (MR) and glucocorticoid (GR) receptor occupation. In the first study, we used a hormone replacement protocol in which we pharmacologically decreased cortisol levels by administration of metyrapone and then restored baseline cortisol levels by a subsequent hydrocortisone replacement treatment. Memory function was tested after each pharmacological manipulation. We observed that metyrapone treatment significantly impaired delayed recall, while hydrocortisone replacement restored performance at placebo level. In the second study, we took advantage of the circadian variation of circulating levels in cortisol and tested the impact of a bolus injection of 35 mg of hydrocortisone in the late afternoon, at a time of very low cortisol concentrations. In a previous study with young normal controls, we injected a similar dose of hydrocortisone in the morning, at the time of the circadian peak, and reported detrimental effects of GC on cognitive function. Here, when we injected a similar dose of hydrocortisone in the afternoon, at the time of the circadian trough, we observed positive effects of GC on memory function. The results of these two studies provide evidence that GC are necessary for learning and memory in human populations.

Increased cortisol levels and impaired cognition in human aging: implication for depression and dementia in later life.

Perhaps the most prominent feature of human aging is the variability in decline of intellectual processes. Although many research avenues have been used to study the origin of such an increased variability with aging, new studies show that some biological factors may be associated with normal and pathological cognitive aging. One biological parameter that came under scrutiny in the past few years is the hypothalamic-pituitary-adrenal (HPA) axis, an endocrine closed-loop system controlling the secretion of stress hormones (glucocorticoids). In this review, we summarize data obtained in both animals and humans suggesting that cumulative exposure to high levels of glucocorticoids can be particularly detrimental for the aged hippocampus, a brain structure involved in learning and memory in both animals and humans. We then analyze the implication of these data for the study of dementia and depression in later life, two disorders characterized by increased glucocorticoid secretion in a significant proportion of patients. Finally, we suggest various factors that could explain the development of glucocorticoid hypersecretion in later life.

Circadian rhythms of melatonin and cortisol in aging

The relationship of age to the circadian rhythms of melatonin and cortisol was investigated in 44 men and 27 women (age range 19-89 years). Subjects were physically and psychiatrically normal. Four hourly serial blood samples were drawn from 8:00 AM until 8:00 AM the next day, with additional samples at 10:00 PM and 2:00 AM. The indoor illumination was restricted to 300 lux during day and 50 lux during the night. Plasma melatonin and cortisol were estimated by radioimmunoassay. Results show that the means of melatonin and cortisol values decreased significantly with age when the subjects were divided into three age groups, i.e., 19-25 years, 42-65 years, and 66-89 years. They also showed a significant negative correlation with age. The acrophases of the two hormonal rhythms, however, showed different relationships to age. The acrophase of melatonin rhythm showed a positive correlation with age (r = 0.38, p less than 0.001), and cortisol showed a negative correlation with age (r = -0.56, p greater than 0.001). It is suggested that this may indicate a weakened responsiveness of the circadian system in the elderly to the day-night cycle and an altered relationship between the pacemakers driving melatonin and cortisol circadian rhythms. This may thus represent a biomarker for the intrinsic process of the aging of the brain.

Nucleus basalis neuronal loss, neuritic plaques and choline acetyltransferase activity in advanced Alzheimer's disease

All our advanced, severe cases of Alzheimers disease have dramatic cholinergic cell losses in the nucleus basalis of Meynert even after correction for cell or nucleoli shrinkage. There is a good correlation between choline acetyltransferase activity and healthy cell number in the nucleus basalis of Meynert. Half of the Alzheimer disease cases have markedly reduced cortical choline acetyltransferase activity in spite of preserved nucleus basalis of Meynert choline acetyltransferase activity, suggesting a deficiency of cortical origin and/or of axonal transport in Alzheimer disease. The relationship between cell loss in the various sub-divisions of the nucleus basalis of Meynert and plaque counts in corresponding and non-corresponding projection areas of the cortex has also been examined. Globally, this relation appears more obvious when cell loss in a sub-division of the nucleus basalis of Meynert is compared to plaque counts in its cortical projection area. However, the relation is discontinuous with few or no data to document the intermediary stages of the process, probably reflecting the severity of our Alzheimer disease cases.

Reduced lumbar CSF somatostatin in levels in Alzheimer's disease

Abstract The lumbar CSF of control, demented (Alzheimers and Korsakoffs) and schizophrenic patients was examined for markers of cholinergic, monoaminergic and peptidergic systems. In all groups, no alteration in CSF acetylcholinesterase was observed, with the monoamine metabolites homovanillic acid, monohydroxyphenylglycol, and 5-hydroxy-indole acetic acid expressing only minor alterations. In contrast, somatostatin (SRIH) was dramatically (50%) reduced in the CSF of Alzheimers dementia (AD) and mixed dementia patients. These decreases in CSF SRIH correlate with previous reports of reductions in cortical SRIH in AD suggesting that such measurements may be useful markers of AD.

Longitudinal study of basal cortisol levels in healthy elderly subjects : evidence for subgroups

A group of 51 healthy elderly volunteer subjects participated in a 3- to 6-year longitudinal study of basal cortisol levels. Once per year basal cortisol levels were examined using hourly sampling over a 24-h period. Analyses of three cortisol measures (last measure obtained, mean cortisol levels across years, and the cortisol slope) revealed that the slope of the regression line measuring cortisol levels at each year was the most predictive measure of cortisol secretion over the years in this elderly population. Cortisol levels were shown to increase with years in one subgroup, to decrease in another, and to remain stable in a third. The age of the subjects was not related to either cortisol levels or to the pattern of change in cortisol secretion over years. Free and total cortisol levels were highly correlated and the groups did not differ with regard to plasma corticosteroid binding globulin. No group differences were observed for weight, height, body mass index, pulse, blood pressure and glucose. However, significant group differences were reported for plasma triglycerides levels as well as high density lipoproteins levels. Positive correlations were reported between the obsession/compulsion subscale of the SCL-90 questionnaire and the cortisol slope of subjects. Finally, previously reported group differences in neuropsychological performance are summarized. Thus, there exists considerable variation in hypothalamo-pituitary-adrenal function amongst aged humans. These results are consistent with recent animal studies showing the existence of subpopulations of aged rats which differ in hypothalamo-pituitary-adrenal activity and cognitive efficiency.

Plasma melatonin—An index of brain aging in humans?

We investigated the age-related changes in the circadian rhythm of plasma melatonin as a potential index of brain aging in man. The subjects were 5 young men aged 19-25 years, 11 older men aged 51-65 years, 6 elderly men aged 66-89 years, 7 young women aged 19-25 years, 5 premenopausal women aged 45-50 years, 8 postmenopausal women aged 51-65 years, and 5 elderly women aged 66-75 years. They were all physically and psychiatrically normal. Serial blood samples were drawn from 8:00 AM until 8:00 AM on the next day, with the indoor illumination set at 300 Lux from 7:00 AM until 4:00 PM and at 50 Lux thereafter. Plasma melatonin was estimated by radioimmunoassay. The results show that there is a significant negative correlation between age and 24-hr secretion of plasma melatonin (r = -0.952, p less than 0.0001), between age and peak levels of plasma melatonin (r = -0.937, p less than 0.00001), and between age and the lag in time from sunset to the onset of significant elevation of plasma melatonin over daytime values (r = 0.916, p less than 0.0001). It is concluded that study of the circadian rhythm of plasma melatonin may prove to be a useful index of the aging process.

Circadian rhythm of plasma melatonin in endogenous depression

The circadian rhythm of plasma melatonin was investigated in normal men 18-30 years (N = 5), normal men 50-70 years (N = 5) and in six patients with endogenous depression. The environmental photoperiod was 11 hours. The subjects and patients were indoors with lights on from 07:00 until 23:00 hours. Blood samples were obtained every 4 hours over a 24 hour period, with additional sampling at 22:00 and 02:00 hours. Plasma melatonin was estimated by radioimmunoassay compared to both groups of controls. In the depressed patients, the levels of melatonin were low throughout the 24 hour period. The depressives had a delayed onset of the dark phase of the rhythm. The patients also showed peak melatonin levels occurring earlier than in the controls. Circadian rhythm of melatonin and therefore of its pacemaker may be altered in endogenous depression.

Individual differences in hypothalamic-pituitary-adrenal activity in later life and hippocampal aging

Variation in magnitude of cognitive decline in later life is a central feature of human aging. The more severe forms of dementias, such as Alzheimers disease, clearly define one end of the spectrum. However, among those showing no obvious signs of clinical dementia there are considerable individual differences. Thus, although evidence for learning, memory, and language loss appears in some individuals as early as 50-55 years of age, many people continue to function alertly well into their 90s. These individuals exemplify what Rowe and Kahn (1987) have termed successful aging. The wide variability in CNS aging, often a nuisance factor in studies, are becoming a major focus for brain aging research (e.g., Gage et al., 1984;Gallager and Pelleymounter, 1988; Aitken and Meaney, 1990; Issa et al., 1990). Our studies over the past few years have added support to the idea that individual differences in hypothalamic-pituitary-adrenal (HPA) activity can account for part of the variation seen in neurological function among the elderly. In this article we discuss the evidence for the idea that adrenal glucocorticoids can compromise hippocampal function and, thus, produce cognitive impairments, as well as the potential mechanisms for these effects.

Neurotransmitter and receptor deficits in senile dementia of the Alzheimer type.

Multiple neurotransmitter systems are affected in senile dementia of the Alzheimers type (SDAT). Among them, acetylcholine has been most studied. It is now well accepted that the activity of the enzyme, choline acetyltransferase (ChAT) is much decreased in various brain regions including the frontal and temporal cortices, hippocampus and nucleus basalis of Meynert (nbm) in SDAT. Cortical M2-muscarinic and nicotinic cholinergic receptors are also decreased but only in a certain proportion (30-40%) of SDAT patients. For other systems, it appears that cortical serotonin (5-HT)-type 2 receptor binding sites are decreased in SDAT. This diminution in 5-HT2 receptors correlates well with the decreased levels of somatostatin-like immunoreactive materials found in the cortex of SDAT patients. Cortical somatostatin receptor binding sites are decreased in about one third of SDAT patients. Finally, neuropeptide Y and neuropeptide Y receptor binding sites are distributed in areas enriched in cholinergic cell bodies and nerve fiber terminals and it would be of interest to determine possible involvement of this peptide in SDAT. Thus, it appears that multi-drug clinical trials should be considered for the treatment of SDAT.