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Testosterone and Cognition in Normal Aging and Alzheimers Disease: An Update
Abstract and Figures
There is evidence to suggest that testosterone loss constitutes a risk for cognitive decline and possibly dementia, and that elderly men might benefit from exogenous supplementation of testosterone. Studies in non-human animals repeatedly report neuroexcitatory and neuroprotective properties of testosterone and enhanced memory performance after acute or chronic treatment. Positive effects of testosterone supplementation in older men have been reported in several, but not all, studies and require replication in larger randomized clinical trials before recommendations for clinical practice can be made. The current review summarizes recent studies on the neurobiological connection between testosterone and cognitive function in humans and non-human animals. When appropriate, we use the hippocampus as a model structure given it's involvement in sexually dymorphic spatial ability and sensitivity to both androgens and aging. In addition, a number of potential explanations of the discrepancy between data obtained in humans and non-human animals are discussed.
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... It involves the prevention of NMDA excitotoxicity as well as the increase of NGF levels within the hippocampus and also its receptor present in the forebrain. In animal models of AD, it also decreases amyloid overexpression and inhibits tau proteins' hyperphosphorylation [174]. ...
... In males and females, progesterone has neuroprotective benefits that consist of the prevention of neuronal edema, death, and improved functional retrieval [175]. Other neuroprotective properties of progesterone include: slowing cytokine (IL-1, IL-6, TNF-α) driven responses, reducing excitotoxicity by inhibiting glutamate receptors, inhibiting glial cell initiation in the CNS, and reducing oxidative stress by upregulating antioxidant enzymes [174]. Progesterone also stimulates signaling enzymes related to neuroprotection mechanisms in the brain, like serine/threonine protein kinase, extracellular signal-regulated kinase (ERK), and mitogenactivated protein kinase (MAPK). ...
Neurological disorders (NDDs) are diseases that affect the central and peripheral nervous systems. Gradual malfunction and destruction of the neurons or the nerve cells characterize them. Every year, NDDs affect millions of people worldwide. Over the years, several neuromodulatory techniques have been introduced to improve the quality of life for those affected by NDDs. NDDs are chronic and incurable conditions, however, bioactive substances derived from medicinal plants have emerged as the greatest choice for their prevention and treatment. Literature evidences several benefits of plant metabolites as alternative medicines for the prevention and treatment of NDDs. Numerous investigations have shown plant metabolites to possess beneficial biological effects because of their qualities, which include but are not limited to anti-inflammatory, antioxidant, and neuroprotective actions. Practices of folk medicine and several studies have also guided many phytopharmacological interventions toward the treatment of NDDs. This review aims to highlight secondary metabolites (alkaloids, flavonoids, steroids, terpenoids) of plants with neuroprotective action that could potentially play an important role in the prevention and management of NDDs.
... administered directly into the hippocampus improved spatial navigation performance (Roof and Havens, 1992), whereas flutamide, an androgen receptor antagonist, decreased spatial learning (Naghdi et al., 2001). Moreover, testosterone supplementation may improve spatial memory in men (Cherrier et al., 2001;Driscoll and Resnick, 2007;Janowsky, 2006;Sherwin, 2003). At a structural level, androgens in the hippocampus produce changes in spine density and neurogenesis in a sexually differentiated way (Atwi et al., 2016). ...
... In this study, we focused on female reproductive aging and discuss estrogen due to its high variability with reproductive stages, because the cerebellum is dense with estrogen receptors. However, testosterone levels have been associated with cerebellar volume asymmetry (Savic 2014) and cognition (Driscoll and Resnick 2007;Moffat 2005). The Cam-CAN repository does not offer hormonal assay data and as such estimates of testosterone levels cannot be assessed. ...
The cerebellum has established associations with motor function and a well-recognized role in cognition. In advanced age, cognitive and motor impairments contribute to reduced quality of life and are more common. Regional cerebellar volume is associated with performance across these domains and sex hormones may influence this volume. Examining sex differences in regional cerebellar volume in conjunction with age, and in the context of reproductive stage stands to improve our understanding of cerebellar aging and pathology. Data from 508 healthy adults (ages 18–88; 47% female) from the Cambridge Centre for Ageing and Neuroscience database were used here. CERES was used to assess lobular volume in T1-weighted images. We examined sex differences in adjusted regional cerebellar volume while controlling for age. A subgroup of participants (n = 370, 50% female) was used to assess group differences in female reproductive stages as compared to age-matched males. Sex differences in adjusted volume were seen across most anterior and posterior cerebellar lobules. Most of these lobules had significant linear relationships with age in males and females. While there were no interactions between sex and reproductive stage groups, exploratory analyses in females alone revealed multiple regional differences by reproductive stage. We found sex differences in volume across much of the cerebellum, linear associations with age, and did not find an interaction for sex and reproductive stage on regional cerebellar volume. Longitudinal investigation into hormonal influences on cerebellar structure and function is warranted as hormonal changes with menopause may impact cerebellar volume over time.
... В отношении воздействия половых гормонов на когнитивную сферу остается множество противоречий. С одной стороны, предполагалось, что андрогены и эстрогены обладают протективными свойствами против БА, что подтверждалось в опытах на животных с введением им тестостерона [41]. С другой стороны, несколько систематических обзоров, оценивающих связь между ЗГТ препаратами эстрогенов и поддержанием когнитивного здоровья у женщин, продемонстировали отсутствие № 01'2022 RUSSIAN JOURNAL OF GERIATRIC MEDICINE Reviews убедительных доказательств целесообразности подобного вмешательства, несмотря на тенденцию к положительной динамике по отдельным когнитивным шкалам у пациенток с БА [42]. ...
Osteoporosis and various cognitive disorders occupy a special place among a number of specific pathological conditions associated with age. Epidemiologically these two conditions are closely related thus the presence of cognitive impairment increases the risk of osteoporosis; and, visa versa, dementia, in particular, caused by Alzheimer's disease, and is more often detected among patients with osteoporosis. Osteoporosis in patients with dementia is an extremely serious problem, since the development of osteoporotic fractures is fraught with a sharp deterioration in cognitive status and a significant increase in disability and mortality. The connection between changes in bone mineral density and cognitive status in older adults is not well understood. The review presents data from non-clinical and clinical studies that describe common genetic and metabolic factors underlying the pathogenesis of the pathological conditions under discussion, which should be taken into account when planning future dementia and osteoporosis clinical trials.
... Interestingly, such decrease has been correlated with the development of age-related neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) [11]. Although testosterone supplementation in male patients was shown to improve cognitive function in AD [12,13], and to relieve motor and nonmotor symptoms in PD [14,15], it remains unclear whether testosterone beneficially influences mitochondrial function in the aging brain. This possibility is indeed supported by animal studies that showed that orchiectomy-induced testosterone deficiency reduces mitochondrial function and increases oxidative damage in the substantia nigra (SN) and the hippocampus (HIPP) of adult male rats [16][17][18]. ...
Brain mitochondrial dysfunction and reduced testosterone levels are common features of aging in men. Although evidence suggests that the two phenomena are interrelated, it is unclear whether testosterone supplementation ameliorates mitochondrial dysfunction in the aging male brain. Here, we show that testosterone supplementation significantly alleviates exploratory behavioral deficits and oxidative damage in the substantia nigra and hippocampus of aging male rats. These effects were consistent with improved mitochondrial function, reflected by testosterone-induced increases in mitochondrial membrane potential (MMP), antioxidant enzyme (GSH-PX, catalase, and Mn-SOD) expression/activity, and mitochondrial respiratory complex activities in both brain regions. Furthermore, elevated PGC-1α, NRF-1, and TFAM expression (suggestive of enhanced mitochondrial biogenesis), increased citrate synthase activity, mtDNA copy number, and ND1, COX1, and ATP6 expression (indicative of increased mitochondrial content), as well as increased PINK1/Parkin and decreased P62 expression (suggesting mitophagy activation), were detected in the substantial nigra and hippocampus of aged male rats after testosterone supplementation. These findings suggest that testosterone supplementation may be a viable approach to ameliorating brain mitochondrial dysfunction and thus prevent or treat cognitive-behavioral deficits and neurodegenerative conditions associated with aging.
... testosterone level is 10.4 -34.7 nmol/L or 300 -1000 ng/dL or 3-10 ng/mL [2]. Testosterone and its derivatives are well known for their androgenic properties and anabolic effects [3]. ...
Obesity has been proposed to affect male fertility both directly and indirectly, by inducing hormonal profiles. Male factor infertility is associated with a higher incidence of obesity. The link between obesity and low testosterone levels is found in men at all ages, even in young men and teenagers. The relationship between obesity and testosterone level in men is complex and bidirectional. This article is aimed to share the information about the cause and effect of obesity on serum testosterone level.
... Outcomes from studies of these groups include findings of no correlations between hormone levels and episodic memory (Fonda, Bertrand, O'Donnell, Longcope, & McKinlay, 2005;Hogervorst, 2013;Ulubaev, Lee, Purandare, Pendleton, & Wu, 2009;Yaffe et al., 2007), one case of a positive association between episodic memory and oestradiol but not testosterone (Zimmerman et al., 2011) and reports of significant correlations between episodic memory and free or total testosterone levels (Barrett-Connor et al., 1999;Moffat et 2006). While consensus for this age group remains unclear, more consistent findings link poor episodic memory performance with age-related testosterone decline in older and cognitively impaired men (Driscoll & Resnick, 2007;Gouchie & Kimura, 1991;Hogervorst, 2013;Janowsky, 2006;Pike et al., 2006;Rosario et al., 2011). These results match data from a previous study in rats where a significant decrease in ELM distinguished 12-month compared with 3-month-old males and was shown to be accompanied by a parallel, near threefold decrease in serum testosterone levels (Rossetti et al., 2018). ...
Episodic memory involves the integration and recall of discrete events that include information about what happened, where it happened and when it occurred. Episodic memory function is critical to daily life and its dysfunction is both a first identifiable indicator and an enduring core feature of cognitive decline in aging and in neuropsychiatric disorders including Alzheimer's disease and schizophrenia. Available evidence from human studies suggests that biological sex and sex hormones modulate episodic memory function in health and disease. However, knowledge of how this occurs is constrained by the limited availability and under‐utilization of validated animal models in investigating hormone impacts on episodic‐like memory function. Here, adult female, adult male and gonadally manipulated adult male rats were tested on the What Where When episodic‐like memory task to determine whether rats model human sex differences in episodic memory and how the hormonal milieu impacts episodic‐like memory processes in this species. These studies revealed salient ways in which rats model human sex differences in episodic memory, including a male advantage in spatial episodic memory performance. They also identified domain‐specific roles for estrogens and androgens in modulating What, Where and When discriminations in male rats that were unlike those engaged in corresponding Novel Object Recognition and Novel Object Location tasks. These studies thus identify rats and the What Where When task as suitable for investigating the neuroendocrine bases of episodic‐like memory, and provide new information about the unique contributions that sex and sex hormones make to this complex mnemonic process.
... Various observational studies report the relationship between low levels of endogenous T and poorer performance on measures of memory, visuospatial function, executive function, and processing speed. 2,19 Longitudinal studies also report a slower rate of decline in certain cognitive processes such as verbal memory, in individuals with higher FT levels. 20 These findings suggest differential effects of T on individual cognitive domains. ...
Background:
An increasing body of literature suggests a positive, neuroprotective effect for testosterone on cognition in older men. However, randomized clinical trials (RCTs) examining the effects of testosterone supplementation (TS) on cognitive function have been inconclusive.
Objective:
To investigate the potential for TS to prevent cognitive decline in otherwise cognitively healthy older men, by examining the differential effects of TS on cognitively healthy older men in RCTs.
Methods:
Comprehensive search of electronic databases, conference proceedings, and grey literature from 1990 to 2018 was performed to identify RCTs examining the effects of TS on cognition before and after supplementation, in cognitively healthy individuals.
Results:
A final sample of 14 eligible RCTs met inclusion criteria. Using pooled random effects expressed as Hedge's g, comparison of placebo versus treatment groups pre- and postsupplementation showed improvements in the treatment group in executive function (g (11) = 0.14, 95% confidence interval [CI]: 0.03-0.26, z = 0.56, p = 0.011). However, it was noted that two studies in our sample did not report a significant increase in mean serum total testosterone (TT) levels in the treatment group after supplementation. Following exclusion of these studies, analysis indicated improvement in the treatment group for the overall cognitive composite (g (11) = 0.18, 95% CI: 0.02-0.33, z = 2.18), psychomotor speed (g (3) = 0.22, 95% CI: 0.01-0.43, z = 2.07) and executive function (g (9) = 0.15, 95% CI: 0.03-0.28, z = 2.35). No significant differences were noted for the global cognition, attention, verbal memory, visuospatial ability or visuospatial memory domains.
Conclusion:
Overall, our findings support the potential for TS as a preventative measure against cognitive decline, although the effect sizes were small. These findings warrant further observational studies and clinical trials of good methodological quality, to elucidate the effect of TS on cognition.
... It has been shown that androgen deficiency contributes to the development of AD in elderly men [3,4]. Serologic tests have shown that men with AD have reduced levels of total or bioavailable testosterone, a major endogenous androgen, while testosterone supplementation could improve their cognitive functions to various degrees, with a particularly notable improvement in spatial memory [5][6][7][8]. ...
The non-genomic actions of androgen-induced synaptic plasticity have been extensively studied. However, the underlying mechanisms remain controversial. We recently found that testosterone-fetal bovine serum albumin (T-BSA), a cell membrane-impermeable complex, led to a rapid increase in the postsynaptic density 95 (PSD95) protein level through a transcription-independent mechanism in mouse hippocampal HT22 cells. Using T-BSA conjugated FITC, we verified the presence of membrane androgen-binding sites. Here, we show that T-BSA-induced PSD95 expression is mediated by G-protein-coupled receptor (GPCR)-zinc transporter ZIP9 (SLC39A9), one of the androgen membrane binding sites, rather than the membrane-localized androgen receptor. Furthermore, we found that T-BSA induced an interaction between ZIP9 and Gnα11 that lead to the phosphorylation of Erk1/2 MAPK and eIF4E, which are critical in the mRNA translation process. The PSD95 and p-eIF4E expression decreased when knockdown of ZIP9 or Gnα11 expression or inhibition of Erk1/2 activation. Taken together, these findings suggest that ZIP9 mediates the non-genomic action of androgen on synaptic protein PSD95 synthesis through the Gnα11/Erk1/2/eIF4E pathway in HT22 cells. This novel mechanism provides a theoretical basis to understand the neuroprotective mechanism of androgen.
Background:
There has been in recent decades a growing interest in the relationship between osteoporosis and cognitive decline.
Objective:
The goal of this study was to analyze the impact of osteoporosis on the risk of dementia in patients followed for up to 20 years in general practices in Germany.
Methods:
This study included patients who received an initial diagnosis of osteoporosis and were followed by 1,215 general practitioners in Germany between January 1993 and December 2012 (index date). Controls were matched (1:1) to osteoporosis patients using propensity scores based on age, gender, index year, comorbidities, and co-therapies. Kaplan-Meier curves were performed to study the development of dementia separately in men and women with or without osteoporosis within 20 years of the index date. Cox proportional regression models were used to estimate the relationship between osteoporosis and dementia in men and women.
Results:
The present study included 29,983 cases and 29,983 controls. After 20 years of follow-up, 20.5% of women with osteoporosis and 16.4% of controls had been diagnosed with dementia (log-rank p-value <0.001). At the end of the follow-up period, dementia was found in 22.0% of men previously diagnosed with osteoporosis and 14.9% of men without this chronic condition (log-rank p-value <0.001). Osteoporosis was associated with a 1.2-fold increase in the risk of being diagnosed with dementia in women and a 1.3-fold increase in the risk of being diagnosed with dementia in men.
Conclusions:
There was a positive association between osteoporosis and dementia in patients followed in general practices in Germany.
Aging is often accompanied by learning and memory problems, many of which resemble deficits associated with hippocampal damage. Studies of aging in nonhuman animals have demonstrated hippo-campus-related memory decline, and point to a possible locus for impairments associated with normal and pathological aging in humans. Two well-characterized hippocampus-dependent tasks in nonhuman animal literature are the Morris water task (MWT) and the transverse patterning discrimination task (TPDT). We employed the virtual MWT and the TPDT to assess hippocampus-dependent cogni-tion in humans. Magnetic resonance imaging and proton magnetic resonance spectroscopy were employed to measure hippocampal volume and neurochemistry respectively. Age-related deficits were observed in performance on both hippocampus-dependent tasks. This pattern of impairment was accompanied by decreased hippo-campal NAA/Cre ratios and volume, both of which imply neuronal loss and/or decrease in neuronal density. Collectively, our results suggest that hippocampus undergoes structural and biochemical changes with normal aging and that these changes may represent an important component of age-related deterioration in hippocampus-dependent cognition.
The relationship between menopause and cognitive decline has been the subject of intense research since a number of studies have shown that hormone replacement therapy could reduce the risk of developing Alzheimer’s disease in women. In contrast, research into andropause has only recently begun. Furthermore, evidence now suggests that steroidogenesis is not restricted to the gonads and adrenals, and that the brain is capable of producing its own steroid hormones, including testosterone and estrogen. Sex hormones have been demonstrated to be of critical importance in the embryonic development of the central nervous system (CNS); however, we are only just beginning to understand the role that these hormones may play in the normal functioning and repair of the adult mammalian CNS. This review will summarize current research into the role of androgens and andropause on cognition and the possible mechanisms of action of androgens, with particular reference to Alzheimer’s disease.
Three experiments using human participants examined a major prediction derived from cognitive mapping theory of place learning: In the absence of proximal cues, place performance depends on relations among distal cues. Experiments 1 and 2 showed that, after learning to find an invisible target in computer-generated (C-G) space, removing the full set of distal stimuli disrupted place performance but removing subsets of distal stimuli did not. These results demonstrate that the full array of distal cues are critical to stimulus control of place performance in this C-G space whereas individual stimuli are not. Experiment 3 showed that, after learning to find an invisible target in the same C-G space, changes in topographical relations among the distal stimuli disrupted place performance. As predicted by cognitive mapping theory, the results suggest that participants use relations among distal cues to guide place performance in C-G space. In addition, the results support the assertion that place learning in C-G space is comparable to both rat and human place learning in mundane space.
This study assessed age differences in navigational behavior in a virtual Morris water maze (vMWM) and examined the ability of older adults to develop cognitive maps after vMWM experience. Compared with younger participants, older volunteers traversed a longer linear distance to locate the hidden platform. On the probe trial, younger volunteers spent a greater proportion of their total distance traveled in proximity to the platform and had more platform intersections. Analysis of map reproductions demonstrated that older participants used proximal objects to locate the goal but did not use room-geometry cues to aid navigation. These findings demonstrate age-related deficits on a laboratory measure of place learning and suggest that deficiencies in allocentric mapping may contribute to these deficits.
Aged animals are impaired in many maze learning tasks, suggesting that they may have a spatial learning deficit. Alternatively, declining sensory/perceptual faculties in aged animals may impede their ability to use complex arrangements of Stimuli that are necessary for spatial learning. To test this possibility, we conducted place learning in the Morris water maze in the presence of a very simple and salient configuration of Stimuli that consisted of a black plexiglass sheet, subtending an arc of 110° around the inside wall of the water maze. In Experiment 1, place learning in young rats was guided by this configuration of Stimuli. In Experiment 2, a prominent place-learning deficit in aged rats was observed when animals were trained with this configuration. Thus, the place-learning impairment in aged animals may not be confined to perceptual deficits that decrease an animal’s ability to use complex configurations of stimuli.
Androgens in the male are essential for the development and maintenance of specific reproductive tissues such as testis, prostate, epididymis, seminal vesicles and penis, as well as other characteristic male properties such as increased muscle strength, hair growth, etc. (Mooradian et al. 1987). In order to maintain the androgen concentration at appropriate levels, the production rates of androgens must be balanced against the metabolic clearance and excretion. The action of androgens in target cells depends on the amount of steroid which can penetrate into the cells, the extent of metabolic conversions within the cells, the interactions with the receptor proteins and finally, upon the action of the androgen receptors at the genomic level.