Hormone therapy does not modify emotion-induced brain activity in older women.

Sex hormones have actions in brain regions important for emotion, including the amygdala and prefrontal cortex. Previous studies have shown that cyclic sex hormones and hormone therapy after menopause modify responses to emotional events. Thus, this study examined whether hormone therapy modified emotion-induced brain activity in older women. Functional magnetic resonance imaging (fMRI), behavioral ratings (valence and arousal), and recognition memory were used to assess responses to emotionally laden scenes in older women currently using hormone therapy (HT) and women not currently using hormone therapy (NONE). We hypothesized that hormones would affect the amount or persistence of emotion-induced brain activity in the amygdala and ventrolateral prefrontal cortex (VLPFC). However, hormone therapy did not affect brain activity with the exception that NONE women showed a modest increase over time in amygdala activity to positive scenes. Hormone therapy did not affect behavioral ratings or memory for emotional scenes. The results were similar when women were regrouped based on whether they had ever used hormone therapy versus had never used hormone therapy. These results suggest that hormone therapy does not modify emotion-induced brain activity, or its persistence, in older women.

Estrogen modifies arousal but not memory for emotional events in older women.

Emotional arousal and the affective content of events influence memory. These effects shift with age such that older people find negative information less arousing and remember proportionately more positive events compared to the young. The emotional enhancement of memory is mediated by medial temporal lobe limbic structures and the prefrontal cortex, which are both affected by sex hormones. We examined whether hormone use (estrogen or estrogen and progesterone) in older women modulated perceptions of valence and arousal, and subsequent memory for emotional images or stories. Their performance was compared to younger women. Hormone use in older women resulted in higher arousal for negative images and stories but memory was not affected. We hypothesize that estrogen modifies the influence of the amygdala and the prefrontal cortex on emotion, but that age-related changes in the hippocampus prevent the enhancement of emotional memory in older women.

Health status, mood, and cognition in experimentally induced subclinical thyrotoxicosis.

OBJECTIVE: Our objective was to determine whether subclinical thyrotoxicosis alters health status, mood, and/or cognitive function. DESIGN: This was a double-blinded, randomized, cross-over study of usual dose l-T(4) (euthyroid arm) vs. higher dose l-T(4) (subclinical thyrotoxicosis arm) in hypothyroid subjects. PATIENTS: A total of 33 hypothyroid subjects receiving l-T(4) were included in the study. MEASUREMENTS: Subjects underwent measurements of health status, mood, and cognition: Short Form 36 (SF-36); Profile of Mood States (POMS); and tests of declarative memory (Paragraph Recall, Complex Figure), working memory (N-Back, Subject Ordered Pointing, and Digit Span Backwards), and motor learning (Pursuit Rotor). These were repeated after 12 wk on each of the study arms. RESULTS: Mean TSH levels decreased from 2.15 to 0.17 mU/liter on the subclinical thyrotoxicosis arm (P < 0.0001), with normal mean free T(4) and free T(3) levels. The SF-36 physical component summary and general health subscale were slightly worse during the subclinical thyrotoxicosis arm, whereas the mental health subscale was marginally improved. The POMS confusion, depression, and tension subscales were improved during the subclinical thyrotoxicosis arm. Motor learning was better during the subclinical thyrotoxicosis arm, whereas declarative and working memory measures did not change. This improvement was related to changes in the SF-36 physical component summary and POMS tension subscales and free T(3) levels. CONCLUSIONS: We found slightly impaired physical health status but improvements in measures of mental health and mood in l-T(4) treated hypothyroid subjects when subclinical thyrotoxicosis was induced in a blinded, randomized fashion. Motor learning was also improved. These findings suggest that thyroid hormone directly affects brain areas responsible for affect and motor function.

Health status, mood, and cognition in experimentally induced subclinical hypothyroidism.

OBJECTIVE: The objective of the study was to determine whether subclinical hypothyroidism causes decrements in health status, mood, and/or cognitive function. DESIGN: This was a double-blinded, randomized, crossover study of usual dose l-thyroxine (L-T4) (euthyroid arm) vs. lower dose L-T4 (subclinical hypothyroid arm) in hypothyroid subjects. PATIENTS: Nineteen subjects on L-T4 therapy for primary hypothyroidism participated in the study. MEASUREMENTS: Subjects underwent measurements of health status, mood, and cognition using validated instruments: Short Form 36, Profile of Mood States, and tests of declarative memory (paragraph recall, complex figure), working memory (N-back, subject ordered pointing, digit span backward), and motor learning (pursuit rotor). The same measures were repeated after 12 wk on each of the study arms. RESULTS: Mean TSH levels increased to 17 mU/liter on the subclinical hypothyroid arm (P < 0.0001). Mean free T4 and free T3 levels remained within the normal range. The Profile of Mood States fatigue subscale and Short Form 36 general health subscale were slightly worse during the subclinical hypothyroid arm. Measures of working memory (N-back, subject ordered pointing) were worse during the subclinical hypothyroid arm. These differences did not depend on mood or health status but were related to changes in free T4 or free T3 levels. There were no decrements in declarative memory or motor learning. CONCLUSIONS: We found mild decrements in health status and mood in L-T4-treated hypothyroid subjects when subclinical hypothyroidism was induced in a blinded, randomized fashion. More importantly, there were independent decrements in working memory, which suggests that subclinical hypothyroidism specifically impacts brain areas responsible for working memory.

The role of androgens in cognition and brain aging in men.

Losses of working and long-term memory are hallmarks of human aging and may signal impending neurodegenerative disease. The maintenance of neural elements in brain systems that support memory, such as synapse formation in prefrontal cortex and hippocampus, are critical for cognitive health in aging. This paper reviews the biological basis for androgens as neuroprotectants or neuromodulators in aging and the importance of androgens on the brain systems important for memory. We relate biological effects to cognitive outcomes in elderly men under a variety of androgen conditions. In brief, androgen deprivation causes significant loss of synapses in the hippocampus in rodent and nonhuman primates, increases amyloid deposition in human and rodent models and causes changes in neurotransmission in prefrontal cortex in rodent models. Recent work suggests that these changes modify age-related cognitive loss, particularly to memory in men. In addition, the conversion of testosterone to its androgen metabolites or to estradiol may play a special role in the preservation of memory in aging. This paper reviews discrepancies between studies using animal models and studies of human cognition, and suggests new directions that are likely to be fruitful in the future for understanding the role of androgens in brain aging. This review suggests that studies of low androgen levels in older men may not index the same biological mechanisms and behavioral effects as the studies of gonadectomy in animal models.

Selective preservation and degeneration within the prefrontal cortex in aging and Alzheimer disease.

BACKGROUND: The prefrontal cortex (PFC) is a heterogeneous cortical structure that supports higher cognitive functions, including working memory and verbal abilities. The PFC is vulnerable to neurodegeneration with healthy aging and Alzheimer disease (AD). OBJECTIVE: We used volumetric magnetic resonance imaging to determine whether any region within the PFC is more vulnerable to deterioration with late aging or AD. METHODS: Volumetric analysis of PFC regions was performed on younger healthy elderly subjects (n = 26; 14 men and 12 women [mean age, 71.7 years] for aging analysis; 12 men and 14 women [mean age, 71.4 years] for AD analysis), oldest healthy elderly (OHE) subjects (n = 22 [11 men and 11 women]; mean age, 88.9 years), and patients with AD (n = 22 [12 men and 10 women]; mean age, 69.8 years). RESULTS: The OHE subjects had less PFC white matter than did young healthy elderly subjects. The orbital region was selectively preserved relative to other PFC regions in the OHE subjects. Subjects with AD had less total PFC gray matter than did age-matched healthy subjects and significantly less volume in the inferior PFC region only. CONCLUSIONS: Orbital PFC is selectively preserved in OHE subjects. In contrast, degeneration within the PFC with AD is most prominent in the inferior PFC region. Thus, degeneration within the PFC has a regionally distinct pattern in healthy aging and AD.

Growth and development in preterm infants fed long-chain polyunsaturated fatty acids: a prospective, randomized controlled trial.

OBJECTIVES: A randomized, masked, controlled trial was conducted to assess effects of supplementing premature infant formulas with oils containing the long-chain polyunsaturated fatty acids, arachidonic acid (AA; 20:4 n6), and docosahexaenoic acid (DHA; 22:6 n3) on growth, visual acuity, and multiple indices of development. METHODS: Infants (N = 470) with birth weights 750 to 1800 g were assigned within 72 hours of the first enteral feeding to 1 of 3 formula groups with or without long-chain polyunsaturated fatty acids: 1) control (N = 144), 2) AA+DHA from fish/fungal oil (N = 140), and 3) AA+DHA from egg-derived triglyceride (egg-TG)/fish oil (N = 143). Infants were fed human milk and/or Similac Special Care with or without 0.42% AA and 0.26% DHA to term corrected age (CA), then fed human milk or NeoSure with or without 0.42% AA and 0.16% DHA to 12 months' CA. Infants fed exclusively human milk to term CA (EHM-T; N = 43) served as a reference. RESULTS: Visual acuity measured by acuity cards at 2, 4, and 6 months' CA was not different among groups. Visual acuity measured by swept-parameter visual-evoked potentials in a subgroup from 3 sites (45 control, 50 AA+DHA [fish/fungal]; 39 AA+DHA [egg-TG/fish]; and 23 EHM-T) was better in both the AA+DHA (fish/fungal; least square [LS] means [cycle/degree] +/- standard error [SE; octaves] 11.4 +/- 0.1) and AA+DHA (egg-TG/fish; 12.5 +/- 0.1) than control (8.4 +/- 0.1) and closer to that of the EHM-T group (16.0 +/- 0.2) at 6 months' CA. Visual acuity improved from 4 to 6 months' CA in all but the control group. Scores on the Fagan test of novelty preference were greater in AA+DHA (egg-TG/fish; LS means +/- SE, 59.4 +/- 7.7) than AA+DHA (fish/fungal; 57.0 +/- 7.5) and control (57.5 +/- 7.4) at 6 months' CA, but not at 9 months' CA. There were no differences in the Bayley Mental Development Index at 12 months' CA. However, the Bayley motor development index was higher for AA+DHA (fish/fungal; LS means +/- SE, 90.6 +/- 4.4) than control (81.8 +/- 4.3) for infants

Informants' knowledge of reproductive history and estrogen replacement.

BACKGROUND: There has been much interest in assessing estrogen use in healthy older women and those with Alzheimer's disease. However, data for the women with Alzheimer's disease must be obtained from an informant. The aim of this study was to better understand what informants are likely to know about reproductive history and estrogen use. METHODS: Reproductive history data from informants of Alzheimer's patients were modeled by comparing responses from 40 cognitively healthy older women with that of a designated informant. The designated informants were similar in demographics to informants for patients with Alzheimer's disease. RESULTS: Informant data regarding reproductive history was likely to be accurate, when known. However, 30% of the subjects did not identify an informant who had personal knowledge of them. Of those informants who had personal knowledge of the subject, accuracy for those who reported that they knew the information varied depending on the aspect of reproductive history assessed (age of menarche, 29%; age of menopause, 20%; pregnancies, 63%; live births, 92%; hysterectomy, 92%; and postmenopausal estrogen use, 82%). Daughters served as the most likely and most accurate informants in this study. CONCLUSION: This study demonstrates that information obtained from informants for patients with Alzheimer's disease is likely to be accurate for some but not all aspects of reproductive history. Of concern for such studies will be the 30% of patients who do not have an informant with personal knowledge about them.

Hormone replacement therapy and cognition: systematic review and meta-analysis.

CONTEXT: Some observational data suggest that hormone replacement therapy (HRT) may reduce the risk of cognitive decline and dementia but results have been conflicting. OBJECTIVE: To review and evaluate studies of HRT for preventing cognitive decline and dementia in healthy postmenopausal women. DATA SOURCES: Studies with English-language abstracts identified in MEDLINE (1966-August 2000), HealthSTAR (1975-August 2000, PsychINFO (1984-August 2000); Cochrane Library databases; and articles listed in reference lists of key articles. STUDY SELECTION: Randomized controlled trials and cohort studies were reviewed for the effects of HRT on cognitive decline; cohort and case-control studies were reviewed for dementia risk. No randomized controlled trials regarding dementia risk were identified. DATA EXTRACTION: Twenty-nine studies met inclusion criteria and were rated. Two reviewers rated study quality independently and 100% agreement was reached on Jadad scores and 80% agreement was reached on US Preventive Services Task Force quality scores. A final score was reached through consensus if reviewers disagreed. DATA SYNTHESIS: Studies of cognition were not combined quantitatively because of heterogeneous study design. Women symptomatic from menopause had improvements in verbal memory, vigilance, reasoning, and motor speed, but no enhancement of other cognitive functions. Generally, no benefits were observed in asymptomatic women. A meta-analysis of observational studies suggested that HRT was associated with a decreased risk of dementia (summary odds ratio, 0.66; 95% confidence interval, 0.53-0.82). However, possible biases and lack of control for potential confounders limit interpretation of these studies. Studies did not contain enough information to assess adequately the effects of progestin use, various estrogen preparations or doses, or duration of therapy. CONCLUSIONS: In women with menopausal symptoms, HRT may have specific cognitive effects, and future studies should target these effects. The meta-analysis found a decreased risk of dementia in HRT users but most studies had important methodological limitations.

Context processing in older adults: evidence for a theory relating cognitive control to neurobiology in healthy aging.

A theory of cognitive aging is presented in which healthy older adults are hypothesized to suffer from disturbances in the processing of context that impair cognitive control function across multiple domains, including attention, inhibition, and working memory. These cognitive disturbances are postulated to be directly related to age-related decline in the function of the dopamine (DA) system in the prefrontal cortex (PFC). A connectionist computational model is described that implements specific mechanisms for the role of DA and PFC in context processing. The behavioral predictions of the model were tested in a large sample of older (N = 81) and young (N = 175) adults performing variants of a simple cognitive control task that placed differential demands on context processing. Older adults exhibited both performance decrements and, counterintuitively, performance improvements that are in close agreement with model predictions.

Sex steroids modify working memory.

In the last ten years, numerous mechanisms by which sex steroids modify cortical function have been described. For example, estrogen replacement improves verbal memory in women, and animal studies have shown effects of estrogen on hippocampal synaptogenesis and function. Little is known about sex steroid effects on other aspects of memory, such as frontal lobe-mediated working memory. We examined the relationships between working memory and sex steroid concentrations and whether sex steroid supplementation would modify age-related loss of working memory in older men and women. Before hormone supplementation, working memory, tested with the Subject Ordered Pointing Test (SOP), was worse in older subjects than younger subjects, and there was no evidence of gender differences at either age. Testosterone supplementation improved working memory in older men, but a similar enhancement of working memory was not found in older women supplemented with estrogen. In men, testosterone and estrogen effects were reciprocal - with better working memory related to a higher testosterone to estrogen ratio. These results suggest that sex steroids can modulate working memory in men and can act as modulators of cognition throughout life.

Prefrontal gray and white matter volumes in healthy aging and Alzheimer disease.

OBJECTIVES: To quantify the contribution of gray and white matter volumes to total prefrontal volume in healthy aging. To determine if prefrontal tissue volumes distinguish healthy aging from Alzheimer disease (AD). DESIGN: Volumes of total prefrontal cortex, prefrontal gray matter, and prefrontal white matter were compared among young healthy elderly (YHE) (n = 14; mean age, 70 years), old healthy elderly (OHE) (n = 14; mean age, 90 years), and subjects with AD (n = 14; mean age, 70 years) by analysis of variance. Additionally, Pearson correlations were performed between volumes and age. RESULTS: Old healthy elderly and subjects with AD had significantly less total prefrontal volume (approximately 15% less in both groups) and prefrontal white matter volume (approximately 30% less and 20% less in the OHE and AD groups, respectively) than YHE, but there were no differences between the OHE and AD groups. There was a significant difference in gray-white matter volume ratio with OHE having a higher ratio than YHE. Subjects with AD did not differ from YHE or OHE in this ratio. There were significant negative correlations between age and total prefrontal volume and age and prefrontal white matter volume in the healthy subjects. CONCLUSIONS: In the very old, the decline of white matter volume is disproportionately greater than the decline of gray matter volume. In subjects with AD both gray and white matter loss contribute to the decline of prefrontal volume. This is demonstrated by the gray-white matter ratio that does not differ between YHE and subjects with AD. Thus, it is likely that AD is different from accelerated aging.

Sex differences in prefrontal volume with aging and Alzheimer's disease.

We used volumetric magnetic resonance imaging to examine sex differences in prefrontal tissue volumes of healthy aged and patients with Alzheimer's disease (AD). Healthy subjects had greater total prefrontal volume than AD, and men had greater total prefrontal volume than women (ps < or = 0.02). This was true for both gray and white matter volumes. There were no interactions between group and sex for total prefrontal volume. An exploratory analysis of each group suggested that sex differences in both gray and white matter in healthy aging are not sustained in AD.

Formula supplementation with long-chain polyunsaturated fatty acids: are there developmental benefits?

OBJECTIVE: To evaluate the developmental outcomes of children who participated in an augmented randomized clinical trial of supplementing a standard infant formula with long-chain polyunsaturated fatty acids. DESIGN: Randomized clinical trial, augmented with a nonrandomized human milk comparison group. There were three randomized formula groups: standard formula, standard formula containing docosahexaenoic acid (DHA), and standard formula containing DHA and arachidonic acid. SETTING: Three clinical sites serving diverse populations: Kansas City, MO; Portland, OR; and Seattle, WA. PARTICIPANTS: A total of 274 healthy full-term infants were enrolled in the infant-feeding protocol; of these, 197 (72%) participated in assessments of developmental outcome. Formula Supplements. In the randomized trial, one group received a standard formula, another group received a formula that had been supplemented with DHA from fish oil, and a third group received a formula supplemented with both DHA and arachidonic acid from an egg phospholipid. OUTCOME MEASURES: Mental and Motor Scales of the Bayley Scales of Infant Development at 12 months of age; vocabulary and gesture communication scores from the MacArthur Communicative Development Inventories at 14 months of age. RESULTS: There were no statistically significant differences for either the Bayley Mental Scale or the Bayley Motor Scale, neither when the analysis was restricted to the three randomized formula groups nor when the analysis included all four groups. However, the DHA formula group had significantly lower scores on two of the MacArthur scales: the DHA group scored lower than the nonrandomized human milk comparison group on the Vocabulary Comprehension Scale, and the DHA group scored lower than the randomized control formula group on the Vocabulary Production Scale. Moreover, additional analyses both in the formula groups and in the human milk comparison group found significant negative correlations between DHA levels and vocabulary outcomes. CONCLUSION: We believe that additional research should be undertaken before the introduction of these supplements into standard infant formulas.

Estrogen and sequential movement.

Normal movement depends in part on the brain's ability to produce and use dopamine, which regulates basal ganglia function. Behavioral, neuroanatomical, and neurophysiological data suggest that the basal ganglia are critical for the performance of sequential movement. Dopaminergic function is modulated by estrogen in animals and in humans. To test the hypothesis that estrogen modulates sequential movement, this study measured the reaction time (RT) and movement time (MT) of 15 women and 10 men in a choice RT task with sequential responses. Higher levels of estradiol in women's blood were associated with faster total movement time (RT plus MT). Testosterone levels in women's blood were not associated with keypressing performance. Hormone levels in men's blood were unrelated to keypressing performance. These results suggest that women's motor performance was affected by hormone levels, and that estrogen may interact with dopaminergic function in women.

Sex differences in the corpus callosum with aging.

The present study examined sex differences in the area and age-related atrophy of the corpus callosum (CC) of 76 healthy elderly subjects using magnetic resonance imaging. The cerebellum and pons served as noncortical control structures. CC area and its subregions were also related to cognitive performance. Women had a slightly larger posterior sector of the CC than men. Women but not men showed age-related atrophy of the anterior and middle sectors of the CC but not the posterior sector. Cerebellum and pons size was similar in men and women, and neither showed age-related atrophy. CC area was related to visual memory in women but not men; no other significant cognitive to structure area relationships were found. These findings show that selective age related atrophy of the CC differs in men and women late in life.

Atrophy of the corpus callosum in Alzheimer's disease versus healthy aging.

OBJECTIVE: To investigate the specificity of atrophic changes in the corpus callosum (CC) compared with the cerebellum and pons in patients with Alzheimer Disease (AD), healthy elderly subjects (HE), and a sample of prospectively studied subjects who have developed cognitive decline or "incipient dementia" (ID). DESIGN: Cross-sectional comparison by age using quantitative MRI. SETTING: Ambulatory research unit. PARTICIPANTS: Sixty HE subjects (mean age 78.2 years; range 66-95), 20 ID subjects (mean age 88.1 years; range 78-98) and 39 AD subjects (mean age 72.2 years; range 52-91) were enrolled in longitudinal studies of healthy aging or AD. The population was selected for optimal health; all were examined to exclude medical, neurological and psychiatric illness. MEASUREMENTS: Brain atrophy by quantitative MRI. RESULTS: AD subjects had smaller CC than HE or ID subjects, who did not differ from each other. All three sectors of the CC were smaller in AD than in HE or ID subjects. The cross sectional area of the cerebellum and pons did not differ between groups. HE and ID subjects showed a significant decline in CC size with age. No age-related decline was found for AD subjects. The regional atrophy of the CC in AD subjects was significantly related to cognitive function but not to disease duration. CONCLUSIONS: Atrophy of the CC differentiates HE and ID from AD subjects and tracks the cognitive decline of this disease. In addition, optimally healthy subjects show an age-related decline in callosum size. The atrophy is specific to the CC, a cortical projection system, and does not occur in cerebellum or pons.

Asymmetrical memory decline in normal aging and dementia.

We assessed whether age-associated memory impairments and the memory impairment of Alzheimer's disease (AD) is comparable in the verbal and nonverbal domains. Subjects incidentally learned the identity and location of a group of objects and later verbally recalled the objects as well as recalling their previous spatial location. Comparison subject (younger subjects for experiment 1, and older subjects for experiment 2) were tested after retention intervals that equated their performance with that of the index subjects. We found that memory does not change uniformly with age. Verbal memory is more affected than nonverbal memory. This asymmetrical pattern is a feature of normal aging and does not appear to be due to a degenerative process such as Alzheimer's disease.

The role of n-3 fatty acids in visual and cognitive development: current evidence and methods of assessment.

Low levels of dietary n-3 fatty acids during development lead to changes in the electroretinogram and visual acuity in rats, monkeys, and human infants. Additional aspects of vision can be measured in infants and may provide further useful information about the nature of the changes induced by n-3 fatty acid deficiency and their potential long-term relevance for formula-fed human infants. Several tests are available to assess the development of specific cognitive functions such as visual recognition and short-term memory. These measures can provide information that is not now available to test the hypothesis that n-3 fatty acids are important for other aspects of neural function, including intellectual or cognitive development.

Testosterone influences spatial cognition in older men.

Testosterone plays a role in the organization of behavior during development. The authors examined whether testosterone could play a maintenance role in behavior as well. In a double-blind manner, verbal and visual memory, spatial cognition, motor speed, cognitive flexibility, and mood in a group of healthy older men who were supplemented for 3 months with testosterone were assessed. The increase in testosterone levels to 150% of baseline levels resulted in a significant enhancement of spatial cognition, but no change in any other cognitive domain was found. Testosterone supplementation influenced the endogenous production of estradiol, and estradiol was found to have an inverse relationship to spatial cognitive performance. These results suggest that testosterone supplementation can modify spatial cognition in older men; however, it is likely that this occurs through testosterone's influence on estrogen.