Increasing testosterone levels and effects on cognitive functions in elderly men and women: a review.

Low testosterone (T) levels may predispose to Alzheimer disease (AD), but it is unclear whether this is a co-morbid effect due to cachexia, subclinical hyperthyroidism or other co-morbidity. The biological plausibility for potential protective effects of T on brain functions is substantial. In addition, higher levels of gonadotropins found in older cases with AD suggest that low levels of T are not due to brain degeneration and that the hypothalamic-pituitary-gonadal (HPG) axis is still intact. Men genetically at risk for AD were also already found to have lower levels of T. However, despite having lower levels of T, women do not show accelerated cognitive decline with age when compared to men. In addition, castration has not necessarily shown a decline in cognitive functions; some studies even found improvement of memory recall. Age may be an important factor when assessing optimal levels of T and several studies suggest that free or bioavailable T may be a better marker than total T levels when investigating associations of androgen activity with cognitive function. Small-scale T intervention trials in elderly men with and without dementia suggest that some cognitive deficits may be reversed, at least in part, by short term T supplementation. Age and prior hypogonadism may play an important role in therapy success and these factors should be investigated in more detail in future large scale randomized controlled studies. For elderly women, T treatment does not seem to have additional benefits over estrogen treatment for postmenopausal complaints and cognitive decline and may increase cardiovascular disease.

Free testosterone and risk for Alzheimer disease in older men.

OBJECTIVE: To investigate the relationships between age-associated decreases in endogenous serum total testosterone (T) and a free T index (FTI) in men and the subsequent development of Alzheimer disease (AD). METHOD: The authors used a prospective, longitudinal design with follow-up in men since 1958. Participants were from the Baltimore Longitudinal Study of Aging, a community-dwelling volunteer sample with baseline ages of 32 to 87 years. All subjects were free of AD at baseline T assessment. Five hundred seventy-four men assessed at multiple time points were followed for a mean of 19.1 years (range, 4 to 37 years). Diagnoses of AD were based on biennial physical, neurologic, and neuropsychological evaluations. RESULTS: Diagnosis of AD was associated inversely with FTI by itself and after adjustments for age, education, smoking status, body mass index, diabetes, any cancer diagnoses, and hormone supplements. In separate analyses, total T and sex hormone binding globulin were not significant predictors after adjustment with covariates. Increases in the FTI were associated with decreased risk of AD (hazard ratio = 0.74; 95% CI = 0.57 to 0.96), a 26% decrease for each 10-nmol/nmol FTI increase. CONCLUSIONS: Calculated free testosterone concentrations were lower in men who developed Alzheimer disease, and this difference occurred before diagnosis. Future research may determine whether higher endogenous free testosterone levels offer protection against a diagnosis of Alzheimer disease in older men.

Age differences in spatial memory in a virtual environment navigation task.

The use of virtual environment (VE) technology to assess spatial navigation in humans has become increasingly common and provides an opportunity to quantify age-related deficits in human spatial navigation and promote a comparative approach to the neuroscience of cognitive aging. The purpose of the present study was to assess age differences in navigational behavior in a VE and to examine the relationship between this navigational measure and other more traditional measures of cognitive aging. Following pre-training, participants were confronted with a VE spatial learning task and completed a battery of cognitive tests. The VE consisted of a richly textured series of interconnected hallways, some leading to dead ends and others leading to a designated goal location in the environment. Compared to younger participants, older volunteers took longer to solve each trial, traversed a longer distance, and made significantly more spatial memory errors. After 5 learning trials, 86% of young and 24% of elderly volunteers were able to locate the goal without error. Performance on the VE navigation task was positively correlated with measures of mental rotation and verbal and visual memory.

Callosal atrophy correlates with temporal lobe volume and mental status in Alzheimer's disease.

BACKGROUND: Recent studies have reported significant atrophy of the corpus callosum (CC) in Alzheimer's Disease (AD). However, it is currently unknown whether CC atrophy is associated with specific cortical volume changes in AD. Moreover, possible atrophy in extra-callosal commissures has not been examined to date. The purpose of the present study was to quantify atrophy in two cerebral commissures [the CC and the anterior commissure (AC)], to correlate this measure with cognitive status, and to relate commissural size to independent measures of temporal lobe volume in AD patients. METHODS: A sample of AD patients and of age- and education-matched normal control subjects (NCs) underwent MRI and a cognitive test battery including the Dementia Rating Scale and Mini Mental State examination. Mid-sagittal regional areas within CC and AC were measured along with superior, middle and inferior temporal lobes volumes. RESULTS: Alzheimer's Disease patients had significantly smaller callosa than did NCs. The callosal regions most affected in AD included the midbody, isthmus and genu. The isthmus and midbody areas of the CC were positively correlated with cognitive performance and with superior temporal lobe volume in AD patients. The mid-sagittal area of the AC and the superior temporal volumes did not differ between AD patients and NCs. CONCLUSIONS: The study demonstrated that the regional morphology of the CC correlates with current cognitive status and temporal lobe atrophy in AD. As well, the lack of difference for the AC suggests that commissural atrophy in AD is regionally specific.

The relationship between longitudinal declines in dehydroepiandrosterone sulfate concentrations and cognitive performance in older men.

BACKGROUND: The observation that dehydroepiandrosterone (DHEA) concentrations decrease markedly with age has led to the hypothesis that declining DHEA concentrations may contribute to age-related changes in cognition. In the United States, DHEA is widely available as an over-the-counter supplement that individuals are using in an effort to ameliorate age-related cognitive and physical changes. OBJECTIVE: To investigate the relationship between age-associated decreases in endogenous DHEA sulfate (DHEA-S) concentrations and declines in neuropsychological performance in a prospective, longitudinal study. METHODS: The subjects were 883 men from a community-dwelling volunteer sample in the Baltimore Longitudinal Study of Aging. The men were aged 22 to 91 years at the initial visit, and they were followed up for as long as 31 years (mean, 11. 55 years), with biennial reassessments of multiple cognitive domains and contemporaneous measurement of serum DHEA-S concentrations. Outcome measures were the results of cognitive tests of verbal and visual memory, 2 tests of mental status, phonemic and semantic word fluency tests, and measures of visuomotor scanning and attention. Serum DHEA-S concentrations were determined by standard radioimmunoassay. RESULTS: Neither the rates of decline in mean DHEA-S concentrations nor the mean DHEA-S concentrations within individuals were related to cognitive status or cognitive decline. A comparison between the highest and lowest DHEA-S quartiles revealed no cognitive differences, despite the fact that these groups differed in endogenous DHEA-S concentration by more than a factor of 4 for a mean duration of 12 years. CONCLUSION: Our longitudinal results augment those of previous prospective studies by suggesting that the decline in endogenous DHEA-S concentration is independent of cognitive status and cognitive decline in healthy aging men.

Longitudinal change in hippocampal volume as a function of apolipoprotein E genotype.

The epsilon4 allele of the apolipoprotein E (APOE) gene confers an increased risk for the development of AD. The authors compared longitudinal rates of change in hippocampal volume as a function of APOE genotype in nondemented elderly individuals. Rate of volumetric loss was significantly greater among epsilon4+ compared with epsilon4- individuals. These results indicate that individuals positive for the APOE epsilon4 allele may show a greater rate of hippocampal atrophy than their epsilon4- counterparts, even in the absence of a diagnosis of AD.

Salivary testosterone concentrations in left-handers: an association with cerebral language lateralization?

The level of testosterone exposure in early brain development may influence the direction or degree of cerebral language lateralization. Possible links between individual differences in testosterone levels and patterns of speech representation were investigated in 180 healthy young adults (97 left handed, 83 right handed) using the Fused Dichotic Words Test (T. Halwes, 1991). Among left-handed participants, significantly higher testosterone concentrations were observed in individuals with a left-ear advantage on dichotic listening than in individuals with a right-ear advantage. Among right-handed participants, the pattern of group differences in testosterone tended to be reversed, resulting in a statistically significant interaction. Results extend prior findings by S. D. Moffat and E. Hampson (1996a) and raise the possibility that higher testosterone is associated with patterns of brain organization in which speech and praxic functions are lateralized to the same hemisphere.

Morphology of the planum temporale and corpus callosum in left handers with evidence of left and right hemisphere speech representation.

In the present study we investigated planum temporale asymmetry and corpus callosum morphology in a sample of young adult left-handed males, using MRI. Two subgroups of left-handed males were identified on the basis of their differing speech lateralization patterns, which were inferred from results of the Fused Dichotic Words Test. These individuals then underwent MRI in order to obtain area measurements of the left and right planum temporale and the midsagittal corpus callosum. Comparisons between these left-handed males and an archival sample of age-matched right-handed males were also performed. Results demonstrated a strong leftward asymmetry in the planum temporale among subjects with left-hemisphere speech representation, regardless of handedness, but no consistent planum temporale asymmetry among subjects with right hemisphere speech representation. The results suggest that reversed speech lateralization is not necessarily accompanied by a concomitant reversal of planum temporale asymmetry. Examination of callosal areas revealed that left-handed subjects with left hemisphere speech functions had a larger corpus callosum than either left-handed subjects with right hemisphere speech functions or right-handed subjects. Increased interhemispheric communication may be required when the neural systems underlying speech and handedness are represented in opposite hemispheres.

Testosterone is correlated with regional morphology of the human corpus callosum.

Theoretical speculation in humans (S.F. Witelson, Psychoneuroendocrinology 16 (1991) 131-153) and empirical findings in animals (R.H. Fitch, P.E. Cowell, L.M. Schrott, V.H. Denenberg, Int. J. Dev. Neurosci. 9 (1991) 35-38) suggest that testosterone (T) may play a significant role in the development of the corpus callosum (CC). However, there are currently no empirical studies directly relating T concentrations to callosal morphology in humans. The purpose of the present study was to investigate the relationship between free T concentrations as determined by radioimmunoassay, and the mid-sagittal area of the corpus callosum, as determined by magnetic resonance imaging (MRI). Subjects were 68 young adult (20-35 years), neurologically normal, right-handed males. All subjects underwent MRI and provided two samples of saliva for radioimmunoassay of T and cortisol. Anatomical regions of interest included total brain volume, left and right hemisphere volume and regional areas of the CC. CC regions were defined using two different measurement techniques, each dividing the CC into six sub-sections. Anatomical measurements were performed blind with respect to the hormone levels of subjects. A significant positive correlation between T concentration and cross-sectional area of the posterior body of the CC was found. This finding was consistent across the two measurement techniques and was not attributable to individual differences in total brain volume. All correlations between cortisol and CC sub-regions were non-significant. The results of this study are consistent with the notion that T, at an earlier stage in development, may play a significant role in modulating cortical/callosal architecture in humans.

A curvilinear relationship between testosterone and spatial cognition in humans: possible influence of hand preference.

The nature of the relationship, if any, between performance on visuo-spatial tests in humans and circulating testosterone (T) concentrations remains controversial. We investigated possible relationships between salivary T and cortisol (C) concentrations and performance on visuo-spatial and verbal cognitive tests in a sample of healthy young adults. Among right-handers, salivary T was found to be negatively correlated with spatial performance in males, but was positively correlated with a measure of spatial visualization in females. This pattern was not evident in left-handers. Across the entire observed range of T, the relationship between spatial cognition and T was best described by an inverted quadratic function in right-handers, but not in left-handers. A significant difference in spatial accuracy was seen among right-handers tested in early vs. late morning testing sessions, in accordance with the expected diurnal change in circulating T. No significant relationships between salivary C and visuo-spatial performance were found. These results are consistent with prior literature suggesting a curvilinear relationship between spatial performance and circulating T concentrations, with intermediate levels of T being associated with better spatial functioning, but raise the possibility that hand preference may be one factor that moderates the observed relationship.

Salivary testosterone levels in left- and right-handed adults.

It has been proposed that prenatal testosterone (T) may contribute to the development of hand preference and cerebral functional asymmetry in humans. To investigate any persisting association between T and asymmetry in adulthood, left-handed (LH) and right-handed (RH) men and women were administered a hand preference questionnaire and the Fused Dichotic Words Test. Testosterone was measured in samples of saliva. Results showed that LH subjects of both sexes had lower salivary T concentrations than their RH counterparts. Among LH males, subjects with a right-ear advantage in dichotic listening tended to have lower T concentrations than subjects with a left-ear advantage. These results are consistent with the notion that T may be involved in the development of hand preference and cerebral functional asymmetry.

Noradrenergic involvement in the consolidation of maternal experience in postpartum rats.

If postpartum rats are separated from pups following cesarean delivery, their maternal responsiveness declines such that in tests on day 10 they show maternal onset latencies that do not differ from those shown by virgin rats. If, however, dams are permitted a 1-h experience with pups within 36 h of cesarean delivery, rats exhibit a high level of responsiveness to foster pups on day 10 after c-section. The present research investigates the effect of the noradrenergic system in the long-term consolidation of a brief maternal experience in new mother rats. Groups of dams were cesarean delivered and were either given pups for a brief period 36 h after section (experienced) or received no experience (inexperienced). Immediately following the experience phase, dams were injected with different concentrations of the beta-adrenergic antagonist, propranolol (0, 0.5, 1.0, 5.0 mg/kg), or the adrenergic agonist, isoproterenol (0, 0.25 or 0.5 mg/kg). Ten days after cesarean delivery rats were given maternal induction tests. Rats receiving 60 min of experience and injected with propranolol exhibited significantly longer maternal onset latencies than did saline-injected rats, although their latencies were not as long as shown by the maternally inexperienced groups. In contrast, rats receiving 15 min of experience and injected with isoproterenol exhibited significantly shorter onset latencies than did saline-injected rats, whether or not they exhibited maternal behavior during the initial 15 min exposure period. These results suggest that the noradrenergic system is involved in the consolidation of a maternal experience.