Effects of Altering Levothyroxine (L-T4) Doses on Quality of Life, Mood, and Cognition in L-T4 Treated Subjects.

Background: The brain is a critical target organ for thyroid hormone, but it is unclear whether variations in thyroid function within and near the reference range affect quality of life, mood, or cognition. Methods: A total of 138 subjects with levothyroxine (L-T4)-treated hypothyroidism and normal thyrotropin (TSH) levels underwent measures of quality of life (36-Item Short Form Health Survey, Underactive Thyroid-Dependent Quality of Life Questionnaire), mood (Profile of Mood States, Affective Lability Scale), and cognition (executive function, memory). They were then randomly assigned to receive an unchanged, higher, or lower L-T4 dose in double-blind fashion, targeting one of three TSH ranges (0.34 to 2.50, 2.51 to 5.60, or 5.61 to 12.0 mU/L). Doses were adjusted every 6 weeks based on TSH levels. Baseline measures were reassessed at 6 months. Results: At the end of the study, by intention to treat, mean L-T4 doses were 1.50 ± 0.07, 1.32 ± 0.07, and 0.78 ± 0.08 µg/kg (P < 0.001), and mean TSH levels were 1.85 ± 0.25, 3.93 ± 0.38, and 9.49 ± 0.80 mU/L (P < 0.001), respectively, in the three arms. There were minor differences in a few outcomes between the three arms, which were no longer significant after correction for multiple comparisons. Subjects could not ascertain how their L-T4 doses had been adjusted (P = 0.55) but preferred L-T4 doses they perceived to be higher (P < 0.001). Conclusions: Altering L-T4 doses in hypothyroid subjects to vary TSH levels in and near the reference range does not affect quality of life, mood, or cognition. L-T4-treated subjects prefer perceived higher L-T4 doses despite a lack of objective benefit. Adjusting L-T4 doses in hypothyroid patients based on symptoms in these areas may not result in significant clinical improvement.

Effect of Thyroid Function Variations Within the Laboratory Reference Range on Health Status, Mood, and Cognition in Levothyroxine-Treated Subjects.

BACKGROUND: There has been recent debate within the thyroid field regarding whether current upper limits of the thyrotropin (TSH) reference range should be lowered. This debate can be better informed by investigation of whether variations in thyroid function within the reference range have clinical effects. One important target organ for thyroid hormone is the brain, but little is known about variations in neurocognitive measures within the reference range for thyroid function. METHODS: This was a cross-sectional study of 132 otherwise healthy hypothyroid subjects receiving chronic replacement therapy with levothyroxine (LT4) who had TSH levels across the full span of the laboratory reference range (0.34-5.6 mU/L). Subjects underwent detailed tests of health status, mood, and cognitive function, with an emphasis on memory and executive functions. RESULTS: Subjects with low-normal (≤2.5 mU/L) and high-normal (>2.5 mU/L) TSH levels did not differ on most tests of health status, mood, or cognitive function, and there were no correlations between TSH, free T4, or free T3 levels and most outcomes. There was, however, a suggestion that thyroid function affected performance on the Iowa Gambling Task, which mimics real life decision-making. Subjects with low-normal TSH levels made more advantageous decisions than those with high-normal TSH levels. CONCLUSIONS: Variations in thyroid function within the laboratory reference range do not appear to have clinically relevant effects on health status, mood, or memory in LT4 treated subjects. However, decision making, which encompasses many executive functions, may be affected. Unless further studies strengthen this finding, these data do not support narrowing the TSH reference range.

The effects of levothyroxine replacement or suppressive therapy on health status, mood, and cognition.

CONTEXT: TSH-suppressive doses of levothyroxine (L-T4) have adverse effects on bone and cardiac function, but it is unclear whether central nervous system function is also affected. OBJECTIVE: The aim of the study was to determine whether women receiving TSH-suppressive L-T4 doses have decrements in health status, mood, or cognitive function. DESIGN AND SETTING: A cross-sectional comparison was made among three groups of women in an academic medical center research clinic. PATIENTS: Twenty-four women receiving chronic TSH-suppressive L-T4 doses, 35 women receiving chronic replacement L-T4 doses, and 20 untreated control women participated in the study. INTERVENTIONS: Subjects underwent testing at a single outpatient visit. MAIN OUTCOME MEASURES: We measured health status (SF-36), mood (Profile of Mood States, Symptom Checklist 90-R, Affective Lability Scale), and cognitive function (declarative memory [Paragraph Recall], working memory [N-back, Subject Ordered Pointing], motor learning [Pursuit Rotor, Motor Sequence Learning Test], and executive function [Letter Cancellation Test, Trail Making Test, Iowa Gambling Test]). RESULTS: Women receiving TSH-suppressive or replacement L-T4 doses had decrements in health status and mood compared to healthy controls. These decrements were more pronounced in women receiving replacement, rather than suppressive, L-T4 doses. Memory and executive function were not affected in either treated group, compared to healthy controls. CONCLUSIONS: Women receiving TSH-suppressive doses of L-T4 do not have central nervous system dysfunction due to exogenous subclinical thyrotoxicosis, but TSH-suppressed and L-T4-replaced women have slight decrements in health status and mood that may be related to self-knowledge of the presence of a thyroid condition or other uncharacterized factors. These mood alterations do not impair cognitive function.

Recovery from anorexia nervosa includes neural compensation for negative body image.

OBJECTIVE: To examine whether frontal lobe mediated regulation of emotion permits women to recover from anorexia nervosa (AN). METHOD: Brain activity associated with the disruption of working memory by images of bodies was examined in women who had recovered from AN and in control women. RESULTS: Negatively rated images were more disruptive to working memory than neutral or positively rated images in both groups; however, amygdala and fusiform activation were greater in women who had recovered from AN than in controls when viewing images of bodies during the working memory task. There were no group differences in lateral prefrontal activity. However, there was more suppression of medial prefrontal cortex activity in women who had recovered from AN in comparison to controls when negatively rated images were presented during the working memory task. DISCUSSION: These results suggest that recovery from AN is not achieved by dampening an amygdala mediated emotional response to bodies, but instead by developing compensatory neural mechanisms that prevent emotional responses from disturbing cognition.

Risk, reward, and economic decision making in aging.

OBJECTIVES: Older adults' decision quality is considered to be worse than that of younger adults. This age-related difference is often attributed to reductions in risk tolerance. Little is known about the circumstances that affect older adults' decisions and whether risk attitudes directly influence economic decisions. We measure the influence of risk attitudes on age-related differences in decision making in both nonsocial and social contexts. METHODS: Risk attitudes and economic decision making were measured in 30 healthy older adults and 29 healthy younger adults. RESULTS: Older adults report being less impulsive, sensation seeking and risk tolerant than younger adults. Age did not affect a measure of nonsocial economic decision making. Older adults were more likely to reject unfair divisions of money during an economic social-bargaining game and more likely to make equitable divisions of money during social-giving game. These age-related differences were determined in part by individuals' self-reported risk taking. DISCUSSION: We conclude that age-related differences in decision making are domain specific and that some social economic decision making is influenced by risk attitudes. Older adults are more risk avoidant, but this does not alter their willingness to wait for reward in a nonsocial context. Perceiving more risk is associated with an unwillingness to accept an unfair offer in social economic contexts and ultimately leads to poorer outcomes for older adults.

More is less: emotion induced prefrontal cortex activity habituates in aging.

Several recent studies have documented age-related changes in brain activity--less amygdala activity and higher prefrontal activity in response to emotional stimuli. Using functional magnetic resonance imaging (fMRI), we examined whether aging also affects the maintenance of activity to emotional stimuli and whether maintenance differs by the valence (negative, neutral and positive) of the pictures. Younger participants had a larger volume of activity in the amygdala but less in the prefrontal cortex than the old. The old showed more habituation to highly arousing negative but not positive or neutral stimuli in prefrontal cortex as compared to younger participants. Thus prefrontal cortex activity indexes emotion in the elderly, but not the young. Amplified prefrontal activity suggests elderly increase cognitive control for negative, highly arousing emotional stimuli, but it is not maintained. Taken together, age-related increases in prefrontal activity and reduced amygdala activity may underlie observed affective changes in aging.

Assessment of body image in younger and older women.

Body image was compared in younger versus older women using questionnaires and women's responses to fatter and thinner images of their own bodies versus responses to line drawings of bodies in the Figure Ratings Scale. We found that younger and older women have similar body dissatisfaction but that younger women have a higher drive for thinness and experience more societal influence on their body image. Using images of one's own body versus line drawings did not result in different body dissatisfaction in younger versus older women. These data suggest that age affects some facets of body image but not others and that ratings of body image do not differ in normal, healthy younger and older women when personalized measures are used.

Cognition is not modified by large but temporary changes in sex hormones in men.

CONTEXT: Little is known about the role of testosterone and estradiol on cognition in healthy older men. OBJECTIVE: The cognitive effects of increasing or lowering testosterone or estradiol were examined. DESIGN: Cognition was assessed before and after 6 wk of double-blind placebo-controlled hormone modification. SETTING: The study was conducted at an academic medical center. PARTICIPANTS: Healthy older (ages 60-80 yr) and younger men (ages 25-35 yr) were recruited from the community. INTERVENTION: Men were randomized to one of four treatments: 1) maintain testosterone and estradiol at eugonadal levels for young men (GnRH agonist + testosterone gel); 2) block testosterone's conversion to estradiol (GnRH agonist + testosterone gel + aromatase inhibitor); 3) induce hypogonadism (GnRH agonist alone); and 4) all placebo. MAIN OUTCOME MEASURES: Measures of executive function, memory, and spatial cognition were obtained before and after treatment. Hormone levels were obtained 10 times over the course of the study. RESULTS: Counter to expectations, hormone treatment did not affect cognition (P > 0.10). Free testosterone was positively related to spatial cognition in older men after treatment and controlling for age and estradiol level or exclusion of the hypogonadal men (P = 0.02). Estradiol was negatively associated with working memory controlling for the same variables (P = 0.01). Blinding to treatment assignment was maintained, with the exception of the hypogonadal group. CONCLUSIONS: A significant change in sex hormone status, including complete hypogonadism, does not modify cognition in men. These findings, along with studies that show a risk for neurodegenerative disease in those with low testosterone, suggest that sex hormone status may be important for neuroprotection in aging but not modulation of normal day-to-day cognitive function.

Association between sex steroids and cognition in elderly men.

OBJECTIVE: To examine the association of cognitive function with sex steroid and sex hormone binding globulin (SHBG) levels among elderly men. DESIGN: Prospective cohort study, The Osteoporotic Fractures in Men Study (MrOS), consisting of 5995 US community dwelling men of 65 years or older. PATIENTS: One thousand six hundred and two men were chosen randomly from MrOS cohort for sex steroid level measurements by Mass Spectrometry (MS) at baseline. Two thousand six hundred and twenty-three MrOS participants with sex steroids measured using RIA were also examined. MEASUREMENTS: Baseline and follow-up (4.5 years later) performance on two cognitive tests: Trails B (executive function and motor speed) and 3MS (global cognitive function). Baseline total testosterone and oestradiol were measured by MS. Free testosterone (free-T) and free oestradiol (free-E) were calculated. SHBG was measured by radioimmunoassay. Data were analysed using linear regression. RESULTS: Baseline free-T and free-E levels were not associated with cognitive performance or change in cognition, following adjustment for age, education, race, health status and alcohol use. Baseline SHBG levels were inversely associated with follow-up trails B (P = 0.03) and 3MS performance (P = 0.02). Higher SHBG was associated with an increased risk of cognitive decline. Total sex steroid levels were not associated with cognitive performance. CONCLUSIONS: Despite large numbers of participants and rigorous sex steroid measurements, we did not observe an association between cognition and either testosterone or oestradiol levels. We conclude that endogenous sex steroids in the normal range are not related to executive function or global cognitive function in elderly men. High SHBG deserves further examination as a risk factor for cognitive decline.

Age differences in perception and awareness of emotion.

We investigated the effects of age and gender on emotional perception and physiology using electrodermal skin conductance response (SCR) and examined whether SCR is related to subjective perceptions of emotional pictures. Older adults found pictures to be more positive and arousing than younger participants. Older women rated pictures more extremely at both ends of the valence continuum: they rated positive pictures more positively and negative pictures more negatively. Elders were less likely to show measurable SCRs. However, magnitude of SCRs when a response occurred did not differ between young and old. Subjective ratings of emotion correlated with physiological responses in younger participants, but they were unrelated in older participants. Thus, in older adults the perception of emotional events was disconnected from the physiological state induced by emotion.

Estrogen, testosterone, and sequential movement in men.

Behavioral and physiological data suggest that the striatal dopaminergic system is important in the production and execution of sequential movements. Striatal function is also modulated by sex hormones, and previous studies show that estradiol is related to sequential movement in women. The authors examined whether sex hormones are involved in the production of sequential movement in healthy older and younger men. Testosterone was modified for a 6-week period such that levels in older men matched those of younger men, the conversion of testosterone to estradiol was blocked, the production of testosterone was blocked, or the men received no treatment (placebo). Sequential movement was measured before and after hormone treatment. Older men were slower and more accurate than younger men on the sequential movement task pre- and posttreatment. Hormone manipulation had no effect on movement speed. Hormone levels were not correlated with sequential movement performance in either older or younger men, suggesting that sex hormones do not modulate sequential movement in men, and hormone replacement may not restore a loss of sequential movement ability in elderly men or men with Parkinson's disease.

Health status, psychological symptoms, mood, and cognition in L-thyroxine-treated hypothyroid subjects.

OBJECTIVE: Many hypothyroid subjects receiving L-thyroxine (L-T4) complain of psychological symptoms or cognitive dysfunction. However, there is limited validated information on these self-reports. DESIGN: Cross-sectional comparison of 20 euthyroid and 34 treated hypothyroid subjects, aged 20-45 years, with normal thyroid-stimulating hormone (TSH) levels. Subjects underwent the following validated measures: Short Form 36 (SF-36); Symptom Checklist 90-Revised (SCL-90-R); Profile of Mood States (POMS); and tests of declarative memory (Paragraph Recall, Complex Figure), working memory (N-Back, Subject Ordered Pointing, Digit Span Backwards), and motor learning (Pursuit Rotor). MAIN OUTCOMES: L-T4-treated subjects had higher mean TSH and free T4 levels, but free triiodothyronine (T3) levels were comparable to controls. L-T4-treated subjects had decrements on SF-36 and SCL-90-R summary scales and subscales. These subjects performed slightly worse on N-Back and Pursuit Rotor tests. Neither TSH nor thyroid hormone levels were associated with performance on psychological or cognitive measures. CONCLUSIONS: This group of L-T4-treated subjects had decrements in health status, psychological function, working memory, and motor learning compared to euthyroid controls. Higher mean TSH levels suggest this may be related to suboptimal treatment, although there were no correlations between TSH levels and outcomes. These findings are limited by potential selection bias, and randomized studies targeting different TSH levels and memory subdomains would clarify these issues.

Preliminary evidence that long-term estrogen use reduces white matter loss in aging.

Despite numerous studies showing neurotrophic and neuroprotective effects of estrogen in animal models, the long-term effects of estrogen use on brain morphology in older women are not known. Thus, we compared ventricular, cerebrospinal fluid, white matter, and grey matter volumes estimated from magnetic resonance images of postmenopausal women with more than 20 years exposure to unopposed estrogen, women who were not on estrogen, and young healthy women. Estrogen users had significantly smaller ventricles and greater white matter volumes than non-users, but hormone exposure did not affect grey matter volumes. Young healthy women had significantly smaller ventricles, less cerebrospinal fluid and more grey matter than both groups of older women. However, they had comparable white matter volumes to older women on estrogen. These findings suggest that long-term estrogen protects against white matter loss in aging. This adds to findings from other studies suggesting estrogen is neuroprotective of the hippocampus and other regions in older women.

Hot flashes and estrogen therapy do not influence cognition in early menopausal women.

OBJECTIVE: To examine how menopausal symptoms and estrogen therapy (ET)-induced symptom relief affect cognition in early menopause. DESIGN: There were two components. Part 1 was a cross-sectional study of 37 healthy, recently postmenopausal women with diverse menopausal symptoms. Women were categorized as having low (n=20) or high symptoms (n=17) based on a validated symptom questionnaire. Women completed mood and sleep questionnaires and underwent cognitive testing, which included verbal memory, visual memory, emotional memory, and verbal fluency. Thirty-two of these women went on to part 2 of the study. Fourteen were randomly assigned to receive ET and 18 to receive placebo for 8 weeks. Before treatment and at 4 and 8 weeks, women completed the same measures as in part 1 of the study. RESULTS: High symptom women had more negative mood (P=0.01) and lower quality sleep (P<0.001) than low symptom women. Despite suffering from more menopausal symptoms, worse mood, and poorer sleep, women in the high symptom group performed the same on cognitive testing as women in the low symptom group. Women receiving ET had greater improvements in menopausal symptoms and sleep compared with those receiving the placebo (P

Thinking with your gonads: testosterone and cognition.

Sex hormones play a crucial role during brain development, but do they modulate or maintain cognition throughout life? Despite several million prescriptions annually for testosterone supplementation, we do not really know the answer. Here I review recent evidence that testosterone alters neural activity essential for learning and memory, and plays an important role as a neuroprotective agent in aging. In particular, testosterone deprivation is associated with poor memory in men and replacement can enhance memory and spatial cognition. However, there is little evidence that testosterone selectively affects only those cognitive domains where sex differences in performance have been found. There are also gaps in our knowledge surrounding the individual cognitive processes altered by testosterone, their neural basis, and the degree to which testosterone affects cognitive performance in women.

Testosterone loss and estradiol administration modify memory in men.

PURPOSE: Little is known about the effect of androgen deprivation therapy on the brain despite the fact that sex steroid receptors are abundant in cortical brain regions that mediate memory and other cognitive functions. We characterized the impact of androgen deprivation and of subsequent estradiol therapy on the long-term and working memory of patients with prostate cancer. MATERIALS AND METHODS: Long-term memory (immediate and delayed paragraph recall tests), working memory (SOP and Trails tests) and Profile of Mood States were assessed at baseline and 4 weeks later in 18 patients with androgen independent prostate cancer beginning second line hormonal therapy with transdermal estradiol 0.6 mg/24 hours. The same assessments were performed in 2 age matched control groups of 18 patients with prostate cancer undergoing androgen deprivation continuing on hormonal therapy and 17 community dwelling healthy men. RESULTS: Immediate and delayed verbal memory were significantly worse in patients with prostate cancer on androgen deprivation than in age matched healthy controls. In addition, men with prostate cancer took more time to complete the Trails A task, indicating slower processing speed, but did not differ significantly from healthy controls in working memory tasks. In individual repeated measures analyses, verbal memory performance improved with estradiol therapy but did not change in the 2 control groups. CONCLUSIONS: Sex steroid loss and replacement have effects on specific cognitive processes in older men. Furthermore, estrogen has the potential to reverse the neurotoxic effects on memory performance caused by androgen deprivation.

Use of functional MRI to guide decisions in a clinical stroke trial.

BACKGROUND AND PURPOSE: An investigational trial examined safety and efficacy of targeted subthreshold cortical stimulation in patients with chronic stroke. The anatomical location for the target, hand motor area, varies across subjects, and so was localized with functional MRI (fMRI). This report describes the experience of incorporating standardized fMRI into a multisite stroke trial. METHODS: At 3 enrollment centers, patients moved (0.25 Hz) the affected hand during fMRI. Hand motor function was localized at a fourth center guiding intervention for those randomized to stimulation. RESULTS: The fMRI results were available within 24 hours. Across 12 patients, activation site variability was substantial (12, 23, and 11 mm in x, y, and z directions), exceeding stimulating electrode dimensions. CONCLUSIONS: Use of fMRI to guide decision-making in a clinical stroke trial is feasible.

Androgen deprivation impairs memory in older men.

Androgen deprivation leads to a profound loss of synaptic density in the hippocampus and changes in learning and memory in animal models. The authors examined group differences in verbal memory between men on androgen deprivation therapy (ADT), a commonly used treatment for prostate cancer, and healthy men. The authors found that men on ADT have a specific impairment of retention but normal encoding and retrieval processes on a word list-learning task. Speed and accuracy for both perceptual and semantic encoding, as well as retrieval at a very short retention interval, were not affected; however, recognition fell to chance after a 2-min retention interval in men on ADT. Healthy men showed only moderate forgetting, and performance was still above chance at 12 min. This pattern of preserved encoding and retrieval but impaired retention suggests that androgens play a role in hippocampally mediated memory processes, possibly having a specific affect on consolidation.

Age related changes in emotional memory.

Studies have found that emotionally evocative stimuli are better remembered than neutral stimuli, an effect called "emotional enhancement". Researchers have also found that the elderly experience an overall decline in memory relative to the young. We hypothesized that the elderly may experience diminished emotional enhancement, and that this may be one factor contributing to overall memory decline in the elderly. We tested elderly and young subjects on tasks of emotional memory for words and faces. In both the elderly and young, a shift in memory favoring positive stimuli (as opposed to negative and neutral stimuli) was evident, this effect being slightly more marked in the elderly. We suggest that the effects seen in both groups may be due to a shift from the amygdala-hippocampal system to the prefrontal cortex over time. We suggest that the more marked response in the elderly may be due to age-related changes in these brain systems, causing a further shift towards memory for positive material.