Musculoskeletal injury or Sports-Related Concussion (SRC) in a season of rugby union does not affect performance on concussion battery testing in university-aged student-athletes.

BACKGROUND: Sub-concussive and concussive impacts sustained during contact sports such as rugby may affect neurocognitive performance, vestibular-ocular-motor function, symptom burden and academic ability. METHOD: Student-athletes (n = 146) participating in rugby union British Universities or domestic competitions were assessed on the Immediate Post-Concussion and Cognitive Test, Post-Concussion Symptom Scale, vestibular-oculo-motor screening tool and revised perceived academic impact tool. Individual change from pre-season (July-September 2021) to 2-weeks following last exposure to contact (April-July 2022) was analysed. RESULTS: Symptom burden significantly worsened (p=0.016) over the season. Significant improvements on verbal memory (p=0.016), visual memory (p=0.008) and motor processing speed (p=0.001) suggest a possible learning effect. Surprisingly, the number of days lost to concussion significantly and positively affected performance on verbal memory (p = 0.018) and reaction time (p = 0.027). Previous concussive events significantly predicted a worsening in symptom burden (p < 0.028), as did in-season concussive events, predicting improved verbal memory (p = 0.033) and symptom burden change (p = 0.047). Baseline performance significantly affected change on several neurocognitive tests, with low-scorers showing more improvement over the season. CONCLUSION: Participation in rugby union was not associated with deleterious effects on brain function. Previous concussive events and in-season factors, possibly related to learning effects, may explain improvement in cognitive function across the season.

[18F]Sodium Fluoride PET has the potential to identify active formation of calcinosis cutis in limited cutaneous systemic sclerosis.

OBJECTIVES: Calcinosis cutis affects 20-40% of patients with systemic sclerosis (SSc). When calcinosis cutis becomes clinically apparent, it is irreversible in most cases. Detection of active calcification formation might allow early disease-modifying interventions. We assessed the feasibility of visualizing active calcifications using [18F]Sodium Fluoride ([18F]NaF) PET/low-dose CT (LDCT) in SSc patients with calcinosis cutis. METHODS: In this cross-sectional, observational pilot study patients underwent a whole body [18F]NaF PET/LDCT. All patients met the 2013 ACR/EULAR SSc criteria and had clinically detectable calcinosis cutis. (Sub)cutaneous calcifications were described by three investigators. RESULTS: Nine female patients were included (median age 59.0 years [IQR 51.5-70.5]). [18F]NaF uptake was mostly visible in the fingers (n=7) and knees (n=5). [18F]NaF PET showed calcifications in the fingers of 3 patients where calcifications were undetected on LDCT and in the clinic. Ninety-seven percent of [18F]NaF positive lesions was visible on LDCT. Of all lesions visible on LDCT, 70% was also visible on [18F]NaF PET. CONCLUSION: Imaging of active calcifications in SSc is feasible using [18F]NaF PET/LDCT. Seventy percent of calcifications on LDCT were [18F]NaF PET positive. Although these findings require replication, [18F]NaF PET/LDCT may detect active calcification formation, being potentially suitable for early disease-modifying interventions.

The Role of Physical Frailty Independent Components on Increased Disabilities in Institutionalized Older Women.

The purpose of this study was to identify the independent components of physical frailty that most influence disability indicators in institutionalized older women. A cross-sectional study with 319 participants (81.96±7.89 years old) was performed. Disability was assessed through dynamic and static balance tests, activities of daily life and falls risk screen. Fried physical frailty protocol was used to access physical frailty. The frail subgroup displayed the weakest results for all disability indicators (p < 0.05). Regression analysis showed that in the two models tested, low physical activity levels and slowness were the physical frailty independent components that better associated with the disability indicators. More studies with larger samples will help to better understand the independent relationship of each physical frailty component with disability outcomes and assist to design a co-adjuvant treatment to reverse physical frailty.

Prospective validation of the EuroSCORE II risk model in a single Dutch cardiac surgery centre.

OBJECTIVE: The EuroSCORE I was one of the most frequently used pre-operative risk models in cardiac surgery. In 2011 it was replaced by its successor the EuroSCORE II. This study aims to validate the EuroSCORE II and to compare its performance with the EuroSCORE I in a Dutch hospital. METHODS: The EuroSCORE II was prospectively validated in 2,296 consecutive cardiac surgery patients between 1 April 2012 and 1 January 2014. Receiver operating characteristic curves on in-hospital mortality were plotted for EuroSCORE I and EuroSCORE II, and the area under the curve was calculated to assess discriminative power. Calibration was assessed by comparing observed versus expected mortality. Additionally, analyses were performed in which we stratified for type of surgery and for elective versus emergency surgery. RESULTS: The observed mortality was 2.4% (55 patients). The discriminative power of the EuroSCORE II surpassed that of the EuroSCORE I (area under the curve EuroSCORE II 0.871, 95% confidence interval (CI) 0.832-0.911; area under the curve additive EuroSCORE I 0.840, CI 0.798-0.882; area under the curve logistic EuroSCORE I 0.761, CI 0.695-0.828). Both the additive and the logistic EuroSCORE I overestimated mortality (predictive mortality additive EuroSCORE I median 5.0%, inter-quartile range 3.0-8.0%; logistic EuroSCORE I 10.7%, inter-quartile range 5.8-13.9), while the EuroSCORE II underestimated mortality (median 1.6%, inter-quartile range 1.0-3.5). In most stratified analyses the EuroSCORE II performed better. CONCLUSION: Our results show that the EuroSCORE II produces a valid risk prediction and outperforms the EuroSCORE I in elective cardiac surgery patients.

ESHRE Guideline: management of women with premature ovarian insufficiency.

STUDY QUESTION: What is the optimal management of women with premature ovarian insufficiency (POI) based on the best available evidence in the literature? SUMMARY ANSWER: The guideline development group (GDG) formulated 99 recommendations answering 31 key questions on the diagnosis and treatment of women with POI. WHAT IS KNOWN ALREADY: NA. STUDY DESIGN, SIZE, DURATION: This guideline was produced by a multidisciplinary group of experts in the field using the methodology of the Manual for ESHRE Guideline Development, including a thorough systematic search of the literature, quality assessment of the included papers up to September 2014 and consensus within the guideline group on all recommendations. The GDG included a patient representative to ensure input from women with POI. After finalization of the draft, the European Society for Human Reproduction and Embryology (ESHRE) members and professional organizations were asked to review the guideline. PARTICIPANTS/MATERIALS, SETTING, METHODS: NA. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides 17 recommendations on diagnosis and assessment of POI and 46 recommendations on the different sequelae of POI and their consequences for monitoring and treatment. Furthermore, 24 recommendations were formulated on hormone replacement therapy in women with POI, and two on alternative and complementary treatment. A chapter on puberty induction resulted in five recommendations. LIMITATIONS, REASONS FOR CAUTION: The main limitation of the guideline is that, due to the lack of data, many of the recommendations are based on expert opinion or indirect evidence from studies on post-menopausal women or women with Turner Syndrome. WIDER IMPLICATIONS OF THE FINDINGS: Despite the limitations, the guideline group is confident that this document will be able to guide health care professionals in providing the best practice for managing women with POI given current evidence. Furthermore, the guideline group has formulated research recommendations on the gaps in knowledge identified in the literature searches, in an attempt to stimulate research on the key issues in POI. STUDY FUNDING/COMPETING INTERESTS: The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the implementation of the guideline. The guideline group members did not receive payment. Dr Davies reports non-financial support from Novo Nordisk, outside the submitted work; the other authors had nothing to disclose. TRIAL REGISTRATION NUMBER: NA.

Tempereversed effects of ovariectomy on brain function in rats: Effects of age and type of soy product.

BACKGROUD: The aims of this study were to analyze the differences in nutrient content and isoflavones in tempe flour and tofu flour, and to analyze the effect of tempe and tofu flour on cognitive function of female rats after ovariectomy. METHOD: Seventy two (72) white female Sprague Dawley strain rats, aged 12 months were used for this study. Before the intervention 52 rats underwent ovariectomy (OVx) and they were grouped into 4 intervention groups: tempe flour (Tp), tofu flour (Tf), estradiol (E2), and casein as a control protein (Cs). The remaining 20 rats were classed as controls and had no ovariectomy (NO). Cognitive function was measured using a maze test. Oneway ANOVA with polynomial contrasts and post hoc LSD were used with a p-value<0.05 to indicate significance. RESULTS: The content of nutrients (vitamin B6, vitamin B12, folic acid) and isoflavones (genistein) were all higher in tempe flour higher than in tofu flour. After 8 weeks, the Tp group had showed significantly increased cognitive function (P<0.05), while the Tf group, the E2 group and the Cs group also all had increased performance, but not significantly so (P>0.05). There was no change in scores in the NO group. CONCLUSIONS: Intervention by tempe flour can increase cognitive function in female ovariectomized female rats. Further research should focus onother aspects of cognitive function and the content of amyloid plaques and neurotransmitter synthesis in the brain.

Phytoestrogen consumption and risk for cognitive decline and dementia: With consideration of thyroid status and other possible mediators.

It is predicted that around 20% of the worlds population will be age 60 or above by 2050. Prevalence of cognitive decline and dementia is high in older adults and modifiable dietary factors may be able to reduce risk for these conditions. Phytoestrogens are bioactive plant chemicals found in soy, which have a similarity in structure to natural estradiol (the most abundant circulating estrogen). This structural likeness enables phytoestrogens to interact with estrogen receptors in the brain, potentially affecting cognition. However, findings in this domain are largely inconsistent, with approximately 50% of studies showing positive effects of phytoestrogens on cognition and the other half resulting in null/negative findings. This paper provides an updated review of the relationship between consumption of phytoestrogens and risk for cognitive decline and/or dementia. In particular, possible mediators were identified to explain discrepant findings and for consideration in future research. A case can be made for a link between phytoestrogen consumption, thyroid status and cognition in older age, although current findings in this area are very limited. Evidence suggests that inter-individual variants that can affect phytoestrogen bioavailability (and thus cognitive outcome) include age and ability to breakdown ingested phytoestrogens into their bioactive metabolites. Factors of the study design that must be taken into account are type of soy product, dosage, frequency of dietary intake and type of cognitive test used. Guidelines regarding optimal phytoestrogen dosage and frequency of intake are yet to be determined.

Individually modifiable risk factors to ameliorate cognitive aging: a systematic review and meta-analysis.

A number of health and lifestyle factors are thought to contribute to cognitive decline associated with age but cannot be easily modified by the individual patient. We identified 12 individually modifiable interventions that can be implemented during midlife or later with the potential to ameliorate cognitive aging. For ten of these, we used PubMed databases for a systematic review of long-duration (at least 6 months), randomized, controlled trials in midlife and older adults without dementia or mild cognitive impairment with objective measures of neuropsychological performance. Using network meta-analysis, we performed a quantitative synthesis for global cognition (primary outcome) and episodic memory (secondary outcome). Of 1038 publications identified by our search strategy, 24 eligible trials were included in the network meta-analysis. Results suggested that the Mediterranean diet supplemented by olive oil and tai chi exercise may improve global cognition, and the Mediterranean diet plus olive oil and soy isoflavone supplements may improve memory. Effect sizes were no more than small (standardized mean differences 0.11-0.22). Cognitive training may have cognitive benefit as well. Most individually modifiable risk factors have not yet been adequately studied. We conclude that some interventions that can be self-initiated by healthy midlife and older adults may ameliorate cognitive aging.

Premature ovarian insufficiency and neurological function.

Premature ovarian insufficiency (POI) involves loss of ovarian function before age 40. POI has been associated with neurological dysfunction and an increased risk of dementia, perhaps due to depletion in estrogen levels. The present review discusses the effects of POI caused by genetic disorder, natural premature menopause, surgical menopause, breast cancer treatment and gonadotropin-releasing hormone (GnRH) agonist treatment. Overall, data suggest an increased risk of neurological disorder where POI is due to premature menopause or induced from surgery. This increased risk appears to be most apparent on domains of global cognitive and verbal memory tests. Where POI is caused by genetic disorder, observed cognitive deficiencies may be more likely to have a genetic basis rather than being due to the effects of sex steroids on the brain. Findings related to loss of cognitive function after chemotherapy or GnRH treatments are mixed. There are also discrepant data related to use of hormone therapy after POI (particularly after surgical menopause). After surgery, hormone treatment appears to be most beneficial if initiated close to the average natural age of menopause.

Effects of gonadal hormones on cognitive behaviour in elderly men and women.

Over the last four decades, animal and cell culture studies have shown that sex steroids can have protective effects on the ageing brain. Limited short-term positive effects (2-4 months) of oestrogen treatment were found in women without (as well as with) dementia. By contrast to these initial promising findings, several large treatment studies showed that longer-term oestrogen treatment, particularly when given in combination with progesterone, could exert negative effects on cognitive function in women aged over 65 years. Several observational studies of older women and men also suggest that longer exposure to higher endogenous oestrogen levels at an older age might confer risk for accelerated cognitive decline and dementia. However, health of participants may modify this association and, in women closer to the age at the onset of menopause, positive associations of oestrogens with cognition were also found. The 'healthy cell bias' theory suggests that oestrogens have protective effects in healthy neurones, although cells undergoing pathological change show acceleration in their demise when exposed to oestrogens. In older men, most studies reported higher bioavailable testosterone levels to be associated with better cognitive function. Other studies have reported optimal testosterone levels for better global cognitive function and a reduced risk of cognitive decline. Variation in health status over time and the use of (in)sensitive cognitive tests and hormone assays may explain why this was not always found. In older women, this association (of testosterone with cognition) is less clear. Small studies reported some benefits of testosterone treatment in combination with oestrogen on cognition, although these were of short duration. Several observational studies, on the other hand, found negative associations between high testosterone levels and worse cognitive function in older women. Age, health status, duration of treatment and sex may thus modify effects of longer-term elevated sex steroid levels on brain function.

Prevention of dementia with sex hormones: a focus on testosterone and cognition in women.

Many perimenopausal women and their medical service providers have turned away from estrogens to treat their complaints. This mini-review investigated whether women could be prescribed androgens to promote cognitive function and to prevent dementia. Using PubMed and Google Scholar we identified several treatment studies but the majority had included insufficient controls. Tentatively some studies suggested that adding a testosterone to estrogen treatment promoted complex information processing over that of estrogens alone, but methodology of studies limited firm conclusions. While a larger study showed no effects in naturally menopausal women over that of placebo, some studies including only oophorectomized women showed positive effects of testosterone but these had only been carried out up to two months. Safety profiles of long-term androgen treatment, mode and type of treatment require more research. Observational data suggest that in older women who were not selected for optimal health, endogenous testosterone has a negative association with verbal memory, usually one of the first functions to decline in dementia.

Testosterone levels and cognition in elderly men: a review.

Average testosterone levels and many cognitive functions show a decline with age. There is evidence to suggest that this association is not just age related. Results from cell culture and animal studies provide convincing evidence that testosterone could have protective effects on brain function. Alzheimer's disease (AD) is characterised by brain pathology affecting cognitive function and AD prevalence increases with age. Testosterone levels are lower in AD cases compared to controls, and some studies have suggested that low free testosterone (FT) may precede AD onset. Men with AD may show accelerated endocrinological ageing, characterised by an earlier lowering of thyroid stimulating hormone, an earlier increase in sex hormone binding globulin (SHBG), a subsequent earlier decrease in FT and an earlier increase in gonadotropin levels in response to this. Positive associations have been found between testosterone levels and global cognition, memory, executive functions and spatial performance in observational studies. However, non-significant associations were also reported. It may be that an optimal level of testosterone exists at which some cognitive functions are improved. This may be modified with an older age, with a shifting of the optimal testosterone curve to maintain cognition to the left and a lower optimal level thus needed to be beneficial for the brain. Genetic factors, such as APOE and CAG polymorphisms may further interact with testosterone levels in their effects on cognition. The roles of SHBG, gonadotropins, thyroid hormones and estrogens in maintaining cognitive function and preventing dementia in men are also not completely understood and should be investigated further. Hypogonadal men do not seem to benefit from testosterone supplementation but small scale, short term intervention studies in eugonadal men with and without cognitive impairments have shown promising results. Larger randomised, controlled trials are needed to further investigate testosterone treatment in protecting against cognitive decline and/or dementia.

Modification of estrogen's association with Alzheimer's disease risk by genetic polymorphisms.

Contrasting effects of estrogen treatment on cognitive function and Alzheimer's disease (AD) risk have been reported. It may be that genetic factors modify these relations. In the present study, 696 participants from the Oxford Project to Investigate Memory and Ageing were included (355 AD cases, 341 controls). Those individuals with other types of dementia and those using hormone treatment had been excluded. Analyses controlled for body mass index, age at blood sampling, and education. Analyses of variance revealed main effects, but not an interaction, for apolipoprotein E (APOE) and Catechol-O-methyl transferase (COMT) genotypes on estradiol (E2) levels in men (p=0.003 and p=0.10, respectively), but not in women (p=0.82 and p=0.49, respectively). Men carrying the APOE ε4 allele had lower E2 levels, while those carrying the COMT Val/Val alleles had higher E2 levels compared to Met/Val (p<0.05) allele carriers. Higher estrone (E1) levels and carrying the APOE ε4 allele (but not COMT alone, or in combination with the APOE genotype) were independent risk factors for AD. Similar to earlier studies, the heterozygous COMT genotype (Met/Val) showed a synergistic effect with the APOE ε4 allele being non-significantly associated with lower cognitive function. In conclusion, the present study suggests that elevated E1 levels significantly increase AD risk in both men and women. However, interactions between APOE ε4 and genetic polymorphisms related to sex steroid metabolism and AD risk need to be further investigated.

Brain and cognition. Is there any case for improving cognitive function in menopausal women using estrogen treatment?

In the 1990s, estrogens were thought to protect the aging brain. Large randomized controlled studies, however, showed that estrogens did not treat dementia symptoms and even increased risk for dementia in older women. These findings contrast with earlier positive findings, including a wealth of cell culture and animal data all suggesting that estrogens could be a prophylactic treatment for dementia. Observational data had also suggested a significantly decreased risk for dementia in women who had been treated with estrogens for menopausal symptoms in midlife. This review discusses the "Critical Window", Healthy Cell Bias' and "Limited Duration" hypotheses, and forms of bias (healthy user, recall and survivor bias) and potential mediators (e.g., body mass, genetics) to attempt to explain the differences seen between the studies. On the basis of limited data, we conclude that estrogens only have limited positive effects on some tests for a number of months regardless of age. These effects were seen in recently menopausal women, but also in women with dementia, who are at least 15 years past the average age of menopause. In addition, after a longer period of time, treatment may confer risk, especially in older women. From this it would follow that longer term treatment with estrogens to maintain cognitive function is not indicated for older women. Whether there still is a case to treat surgical menopausal women with estrogens for a longer or shorter period of time remains to be tested.

High tofu intake is associated with worse memory in elderly Indonesian men and women.

BACKGROUND/AIMS: Cell culture studies suggest that phytoestrogens, abundant in soy products such as tempe and tofu, could protect against cognitive decline. Paradoxically, the Honolulu Asia Aging Study reported an increased risk for cognitive impairment and other dementia markers with high tofu (soybean curd) intake. METHODS: A cross-sectional study was carried out in 2 rural sites (Borobudur and Sumedang) and 1 urban site (Jakarta) among mainly Javanese and Sundanese elderly (n = 719, 52-98 years of age). Memory was measured using a word learning test sensitive to dementia and soy consumption was assessed using Food Frequency Questionnaire items. RESULTS: High tofu consumption was associated with worse memory (beta = -0.18, p < 0.01, 95% CI = -0.34 to -0.06), while high tempe consumption (a fermented whole soybean product) was independently related to better memory (beta = 0.12, p < 0.05, 95% CI = 0.00-0.28), particularly in participants over 68 years of age. Fruit consumption also had an independent positive association. The analyses were controlled for age, sex, education, site and intake of other foods. CONCLUSION: The results for tofu consumption as a risk factor for low memory function may tie in with the Honolulu Asia Aging Study data. It is unclear whether these negative associations could be attributed to potential toxins or to its phytoestrogen levels. Estrogen (through which receptors phytoestrogens can exert effects) was found to increase dementia risk in women over 65 years of age. Tempe contains high levels of phytoestrogens, but (due to fermentation) also exhibits high folate levels which may exert protective effects. Future studies should validate these findings and investigate potential mechanisms.

Hormone replacement therapy for cognitive function in postmenopausal women.

BACKGROUND: As estrogens have been found in animal models to be associated with the maintenance and protection of brain structures, it is biologically plausible that maintaining high levels of estrogens in postmenopausal women by medication could be protective against cognitive decline. OBJECTIVES: To investigate the effect of ERT (estrogens only) or HRT (estrogens combined with a progestagen) in comparison with placebo in RCTs on cognitive function in postmenopausal women. SEARCH STRATEGY: The CDCIG Specialized Register was searched 7 March 2006. Additional searches were made of MEDLINE (1966-2006/02); EMBASE (1985-2006/02); PsycINFO (1967-2006/02) and CINAHL (1982-2006/01). SELECTION CRITERIA: All double-blind RCTs trials of the effect of ERT or HRT on cognitive function over a treatment period of at least two weeks in postmenopausal women. DATA COLLECTION AND ANALYSIS: Selection of studies, assessment of quality and extraction of data were undertaken independently by three reviewers with disagreements resolved by discussion. MAIN RESULTS: In total, 24 trials were included, but only 16 (10,114 women) had analysable data. Meta-analyses showed no effects of either ERT or HRT on prevention of cognitive impairment after five and four years of treatment, respectively (odds ratio 1.34, 95% CI 0.95 to 1.9; odds ratio 1.05, 95% CI 0.72 to 1.54 respectively) (trend favouring control in both instances). Analyses assessing the effects of treatment over time found that both ERT and HRT did not maintain or improve cognitive function and may even adversely affect this outcome (WMD = -0.45, 95% CI -0.99 to 0.09; WMD = -0.16, 95% CI -0.58 to 0.26, respectively at maximum follow up). Negative effects were found for ERT after one year and HRT after three and four years of therapy. Results from smaller trials assessing effects on individual cognitive domains mostly reported no evidence of benefit. AUTHORS' CONCLUSIONS: There is good evidence that both ERT and HRT do not prevent cognitive decline in older postmenopausal women when given as short term or longer term (up to five years) therapy. It is not known whether either specific types of ERT or HRT have specific effects in subgroups of women, although there was evidence that combined hormone therapy in similarly aged women was associated with a decrement in a number of verbal memory tests and a small improvement in a test of figural memory. There is insufficient evidence to determine whether subgroups of women using specific types of hormone therapy could benefit from treatment. It remains to be determined whether factors such as younger age (< 60 years of age), type of menopause (surgical or natural) and type of treatment (type of estrogen with or without a progestagen), mode of delivery (transdermal, oral or intramuscular) and dosage have positive effects at a clinically relevant level. In addition, whether the absence or presence of menopausal symptoms can modify treatment effects should be investigated in more detail. Large RCTs currently underway in the USA may be able to provide answers to these uncertainties by the year 2010. In the meantime, based on the available evidence, ERT or HRT cannot be recommended for overall cognitive improvement or maintenance in older postmenopausal women without cognitive impairment.

Cases with mild cognitive impairment and Alzheimer's disease fail to benefit from repeated exposure to episodic memory tests as compared with controls.

Memory tests may be predictive for cognitive decline. We investigated the sensitivity and change in performance over time of the Hopkins Verbal Learning Test (HVLT) and the Mini-Mental Status Examination (MMSE) for Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD) when compared to cognitively healthy controls. Participants included elderly controls (n = 54), MCI (n = 19) and AD cases (n = 28) from OPTIMA. The MMSE and the HVLT (version 1) were administered twice to all subjects with an interval of 2-3 years.MCI and AD cases had poorer performance than controls on the HVLT and MMSE at both testing episodes (p < 0.05). The HVLT profile over time showed a learning effect in the control group (P < 0.0001), a trend to decline in the AD group (p = 0.09) and no change in the MCI group (P = 0.8). A subgroup of MCI subjects had lower HVLT scores at follow-up. The MMSE profile showed no significant change over time for all three groups (P > 0.05). The HVLT had better sensitivity and specificity compared to the MMSE for detecting MCI and AD. The HVLT is not only valuable for cross-sectional designs but has also proved to be valuable in a longitudinal design. Cognitively healthy controls showed evidence of learning strategies on the HVLT after a 2-3 year interval, with improved scores at the second testing episode. By contrast, an MCI group showed no benefits of previous exposure to this test. Lack of use of learning strategies on the HVLT may be an important marker of the likelihood of cognitive decline to MCI or dementia.

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.

Low free testosterone is an independent risk factor for Alzheimer's disease.

The purpose of this study was to assess pituitary gonadotropins and free testosterone levels in a larger cohort of men with Alzheimer's disease (AD, n=112) and age-matched controls (n=98) from the Oxford Project to Investigate Memory and Ageing (OPTIMA). We measured gonadotropins (follicle stimulating hormone, FSH, and luteinizing hormone, LH), sex hormone binding globulin (SHBG, which determines the amount of free testosterone) and total testosterone (TT) using enzyme immunoassays. AD cases had significantly higher LH and FSH and lower free testosterone levels. LH, FSH and SHBG all increased with age, while free testosterone decreased. Low free testosterone was an independent predictor for AD. Its variance was overall explained by high SHBG, low TT, high LH, an older age and low body mass index (BMI). In controls, low thyroid stimulating hormone levels were also associated with low free testosterone. Elderly AD cases had raised levels of gonadotropins. This response may be an attempt to normalize low free testosterone levels. In non-demented participants, subclinical hyperthyroid disease (a risk factor for AD) which can result in higher SHBG levels, was associated with low free testosterone. Lowering SHBG and/or screening for subclinical thyroid disease may prevent cognitive decline and/or wasting in men at risk for AD.

Thyroid function, depressed mood, and cognitive performance in older individuals: the Maastricht Aging Study.

The hypothesis was tested that thyroid function, as indicated by serum thyroid-stimulating hormone (TSH) level, is associated with cognitive performance in a healthy aging population. In a random sample of 120 participants recruited from the Maastricht Aging Study (MAAS), aged between 49 and 71 years, we assessed TSH level, mood state (Symptom Check List, subscale depression), and three domains of cognitive function: verbal memory, general sensorimotor speed, and complex flexibility. After correction for age, sex, and educational level, a negative association between TSH and memory function was apparent: higher levels of TSH predicted lower levels of memory performance. Exclusion of individuals with TSH levels suspect for thyroid disorder (n=2) or who were on thyroid replacement (n=3) attenuated this association. Furthermore, additional control for mood status reduced the association below the significance level. No interaction between age and TSH on cognition was found, which indicated that the TSH-memory association was independent of age group level. We conclude that the association between TSH level and memory performance was small and dependent on mood status and the presence of (possible) thyroid disease in this relatively healthy population based sample. Prospective studies are needed to address the role of thyroid function in age-related cognitive decline.