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Evidence suggests that initiation of some forms of hormone therapy (HT) early in the perimenopausal or postmenopausal stage might confer benefit to verbal memory and the neural systems underlying memory, whereas late-life initiation confers no benefit or harm. This "critical window hypothesis" remains a topic of debate. Using functional magnetic resonance imaging (fMRI), we examined the long-term impact of perimenopausal HT use on brain function during performance of verbal and figural memory tasks. Participants were 34 postmenopausal women (mean age 60 years) from the Melbourne Women's Midlife Health Project and included 17 early (perimenopausal) and continuous users of HT and 17 never users matched on age, education, and verbal knowledge. Continuous HT use from the perimenopausal stage versus no use was validated with prospective daily diary records and study visit data. The primary outcome was patterns of brain activation in an a priori region of interest in the medial temporal lobe during verbal encoding and recognition of words. Results indicated that perimenopausal HT users performed better than nonusers on the imaging verbal memory task (p<.05). During verbal recognition, perimenopausal HT users showed increased activation in the left hippocampus and decreased activation in the parahippocampal gyrus bilaterally compared with never users. Each of these patterns of activation was associated with better memory performance on the imaging memory task. These results suggest that perimenopausal use of HT might confer long-term benefits to verbal memory and the brain systems underlying verbal memory. More generally, the results support the critical window hypothesis., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Aging studies consistently show a relationship between decreased gray matter volume and decreased performance on working memory tasks. Few aging studies have investigated white matter changes in relation to functional brain changes during working memory tasks. Twenty-five younger and 25 older adults underwent anatomical magnetic resonance imaging (MRI) scans to measure gray matter volume, diffusion tensor imaging (DTI) to measure fractional anisotropy (FA) as a measure of white matter integrity, and functional magnetic resonance imaging (fMRI) while performing a working memory task. Significant increases in activation (fMRI) were seen in the left dorsal and ventral lateral prefrontal cortex with increased working memory load and with increased age (older showing greater bilateral activation). Partial correlational analyses revealed that even after controlling for age, frontal FA correlated significantly with fMRI activation during performance on the working memory task. These findings highlight the importance of white matter integrity in working memory performance associated with normal aging.

Background: Emerging evidence from clinical trials suggests that oral estrogen and intranasal oxytocin might reduce symptom severity in schizophrenia. Whether increases in endogenous hormones are similarly associated with improved symptoms is unknown. We investigated the effects of menstrual cycle phase and related fluctuations in peripheral hormone levels on clinical symptoms in women with chronic schizophrenia., Method: Twenty-three women with schizophrenia were administered the Positive and Negative Syndrome Scale (PANSS), a measure of clinical symptom severity, at two menstrual cycle phases: 1) early follicular (Days 2-4; low estrogen/progesterone) and 2) midluteal (Days 20-22; high estrogen/progesterone). Twenty-seven males with schizophrenia and 58 controls (31 female) completed testing at comparable intervals. Men were included to examine whether the relationships between clinical symptoms and hormone levels in women generalize to men. Plasma hormone assays of estrogen, oxytocin, progesterone, and testosterone were obtained., Results: Female patients showed less severe symptoms during the midluteal versus early follicular phase (p's<0.01). Oxytocin did not fluctuate across phases, but in female patients (p's<0.01) higher oxytocin levels were associated with less severe positive symptoms and overall psychopathology. In both sexes, higher oxytocin levels were associated with more prosocial behaviors (p<0.05)., Conclusion: Consistent with previous findings in acutely ill patients, our results suggest that clinical symptoms vary across the menstrual cycle in patients with chronic schizophrenia. Similar to recent findings regarding benefits of intranasal oxytocin, these new findings indicate that high levels of endogenous oxytocin might improve positive symptom severity and general psychopathology in women and social behaviors in both sexes., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Women have an increased risk of developing Alzheimer's Dementia (AD) compared to men. It has been postulated that this risk may be modulated by a reduction in the neuroprotective effects of estrogen on the brain in the early postmenopausal period. This view is supported by, for example, findings that ovariectomy in younger women (i.e. prior to menopause) significantly increases the risk for the development of memory problems and AD in later life. However, the biological basis underlying these cognitive changes is still poorly understood. Our aim in the current study was to understand the interactive effects of acute, pharmacological-induced menopause (after Gonadotropin Hormone Releasing Hormone agonist (GnRHa) treatment) and scopolamine (a cholinergic antagonist used to model the memory decline associated with aging and AD) on brain functioning. To this end we used fMRI to study encoding during a Delayed Match to Sample (DMTS) (visual working memory) task. We report a relative attenuation in BOLD response brought about by scopolamine in regions that included bilateral prefrontal cortex and the left parahippocampal gyrus. Further, this was greater in women post-GnRHa than in women whose ovaries were functional. Our results also indicate that following pharmacological-induced menopause, cholinergic depletion produces a more significant behavioural deficit in overall memory performance, as manifest by increased response time. These findings suggest that acute loss of ovarian hormones exacerbate the effects of cholinergic depletion on a memory-related, behavioural measure, which is dependent on fronto-temporal brain regions. Overall, our findings point to a neural network by which acute loss of ovarian function may interact to negatively impact encoding., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Objective: There are significant individual differences in the extent to which mood and cognition change as a function of reproductive stage, menstrual phase, postpartum, and hormone therapy use. This review explores the extent to which variations or polymorphisms in the estrogen receptor alpha gene (ESR1) predict cognitive and mood outcomes., Methods: A literature search was conducted from 1995 to November 2009 through PubMed, Embase, and PsychINFO. Twenty-five manuscripts that summarize investigations of ESR1 in mental health were reviewed., Results: Among studies investigating ESR1 in relation to cognition, 11 of 14 case-control studies reported an association between ESR1 polymorphisms and risk for developing dementia. Three of four prospective cohort studies reported an association between ESR1 polymorphisms and significant cognitive decline. There are inconsistencies between case-control and cohort studies regarding whether specific ESR1 alleles increase or decrease the risk for cognitive dysfunction. The relationships between ESR1 and cognitive impairment tend to be specific to or driven by women and restricted to risk for Alzheimer disease rather than other dementia causes. Three of five studies examining ESR1 polymorphisms in relation to anxiety or depressive symptoms found significant associations. Significant associations have also been reported between ESR1 polymorphisms and childhood-onset mood disorder and premenstrual dysphoric disorder., Conclusions: A strong relationship between ESR1 variants and cognitive outcomes is evident, and preliminary evidence suggests a role of the ESR1 gene in certain mood outcomes. Insights into the discordant results will come from future studies that include haplotype analyses, analyses within specific ethnic/racial populations, and sex-stratified analyses.

Epidemiological and clinic data support the notion that some women may be at higher risk for developing mood and anxiety symptoms and cognitive complaints during certain periods in life that are marked by intense hormone variations and psychosocial stressors. The complexity of the so-called windows of vulnerability poses a particular challenge to professionals involved in the care of female patients. Menopausal transition is perhaps a paramount example; the process itself is marked by progressive, dynamic changes in hormone levels and reproductive function that interact with the aging process, changes in metabolism, sexuality, lifestyle behaviors, and overall health.The putative compounded burden of health challenges associated with this transition has become a main focus of attention of physicians and researchers who aim to identify preventive and/or early intervention strategies to promote healthy aging in midlife women. Recent studies have provided further evidence that the menopausal transition may be not only a window of vulnerability for depression and cognitive impairment but also a critical "window of opportunity" for the success of hormone-based treatments.The need for further investigation and better understanding of common underlying mechanisms seems intuitive. An ultimate goal could include preventive strategies for women presenting with various risk factors for cardiovascular, cognitive, and mood disorders as well as treatments that could be tailored to multiple symptom domains during the menopausal transition.

Objective: The National Institutes of Health and The North American Menopause Society sponsored a symposium to understand the impact of the menopausal transition on mood symptoms and cognitive disorders and to identify research priorities for further investigation., Methods: The symposium was divided into a morning session on depressive symptoms and an afternoon session on cognitive function. There were four speakers per session, and each session covered four methodological approaches, including longitudinal cohort studies, randomized intervention trials, pharmacological challenge studies, and clinical diagnosis. Interactive panel discussions focused on translating research findings to clinical practice., Results: Most women do not experience serious depressive symptoms during the menopausal transition, but a subgroup of women is at increased risk. Slight changes in memory function and processing speed are evident during the menopausal transition, and physiological factors associated with hot flashes may contribute to memory problems. Clinical trial evidence indicates that estradiol therapy can be effective in treating perimenopausal depression. There is some limited evidence of a cognitive benefit with estrogen-alone therapy in younger postmenopausal women and stronger evidence that certain forms of combination hormone therapy produce modest deficits in verbal memory in younger postmenopausal women., Conclusions: Routine evaluation of depressive symptoms in perimenopausal women is warranted by the literature. Quick and valid screening tools for assessing depression in the clinic are available online and free of charge. Identifying a cognitively neutral or beneficial combination therapy for the treatment of menopausal symptoms in naturally postmenopausal women is an important goal for future research.

Objective: To compare the relative effects of conjugated equine estrogens (CEE), raloxifene, and tamoxifen therapies on cognition among women aged > or =65 years., Methods: Annual Modified Mini-Mental State (3MS) examinations were used to assess global cognitive function in the two randomized placebo-controlled clinical trials of CEE therapies of the Women's Health Initiative Memory Study (WHIMS) and the Cognition in the Study of Tamoxifen and Raloxifene (CoSTAR). Analyses were limited to women who had 3MS testing at baseline and the first 3 years of follow-up and, because of potential ethnic-related differences between studies, to Caucasian women (WHIMS n = 6211, CoSTAR n = 250). Covariate adjustment was used to compare the postrandomization mean 3MS scores among the three active therapies with placebo therapy while controlling for differences between groups with respect to dementia risk factors., Results: At baseline, the average (SD) 3MS scores by group were 95.24 (4.28) for placebo, 95.19 (4.33) for CEE, 94.60 (4.76) for raloxifene, and 95.02 (4.03) for tamoxifen. Compared with placebo, each active therapy was associated with a small mean relative deficit in 3MS scores of < or =0.5 units, which was fairly consistent between women with and without prior hysterectomy. Relative deficits were slightly greater for tamoxifen (p = 0.001) and less marked for raloxifene (p = 0.06) and CEE (p = 0.02) therapies. Relative deficits appeared to be greater among women with lower baseline 3MS scores: p = 0.009 (tamoxifen), p = 0.08 (raloxifene), and p = 0.03 (CEE)., Conclusions: Although unmeasured differences between trials may have confounded analyses, these findings raise the possibility that both tamoxifen and raloxifene adversely affect cognitive function in older women; however, the magnitude of the effect is small, and the long-term consequences are unknown.

Background: Clinical trials yield discrepant information about the impact of hormone therapy on verbal memory and executive function. This issue is clinically relevant because declines in verbal memory are the earliest predictor of Alzheimer's disease and declines in executive function are central to some theories of normal, age-related changes in cognition., Methods: We conducted a systematic review of randomized clinical trials of hormone therapy (i.e. oral, transdermal, i.m.) and verbal memory, distinguishing studies in younger (i.e. 65 years; n = 7) women and studies involving estrogen alone versus estrogen plus progestogen. Out of 32 placebo-controlled trials, 17 were included (13 had no verbal memory measures and 2 involved cholinergic manipulations). We also provide a narrative review of 25 studies of executive function (two trials), since there are insufficient clinical trial data for systematic review., Results: There is some evidence for a beneficial effect of estrogen alone on verbal memory in younger naturally post-menopausal women and more consistent evidence from small-n studies of surgically post-menopausal women. There is stronger evidence of a detrimental effect of conjugated equine estrogen plus medroxyprogesterone acetate on verbal memory in younger and older post-menopausal women. Observational studies and pharmacological models of menopause provide initial evidence of improvements in executive function with hormone therapy., Conclusions: Future studies should include measures of executive function and should address pressing clinical questions; including what formulation of combination hormone therapy is cognitively neutral/beneficial, yet effective in treating hot flashes in the early post-menopause.

Context: Different menopausal hormone therapies may have varied effects on specific cognitive functions. We previously reported that conjugated equine estrogens (CEE) with medroxyprogesterone acetate had a negative impact on verbal memory but tended to impact figural memory positively over time in older postmenopausal women., Objective: The objective of the study was to determine the effects of unopposed CEE on changes in domain-specific cognitive function and affect in older postmenopausal women with prior hysterectomy., Design: This was a randomized, double blind, placebo-controlled clinical trial., Setting: The study was conducted at 14 of 40 Women's Health Initiative (WHI) clinical centers., Participants: Participants were 886 postmenopausal women with prior hysterectomy, aged 65 yr and older (mean 74 yr), free of probable dementia, and enrolled in the WHI and WHI Memory Study (WHIMS) CEE-Alone trial for a mean of 3 yr and followed up for a mean of 2.70 yr., Intervention: Intervention was 0.625 mg of CEE daily or placebo., Main Outcome Measures: Annual rates of change in specific cognitive functions and affect, adjusted for time since randomization, were measured., Results: Compared with placebo, unopposed CEE was associated with lower spatial rotational ability (P < 0.01) at initial assessment (after 3 yr of treatment), a difference that diminished over 2.7 yr of continued treatment. CEE did not significantly influence change in other cognitive functions and affect., Conclusions: CEE did not improve cognitive functioning in postmenopausal women with prior hysterectomy. CEE was associated with lower spatial rotational performance after an average of 3 yr of treatment. Overall, CEE does not appear to have enduring effects on rates of domain-specific cognitive change in older postmenopausal women.

Purpose: To compare the effects of two selective estrogen receptor modulators, tamoxifen and raloxifene, on global and domain-specific cognitive function., Patients and Methods: The National Surgical Adjuvant Breast and Bowel Project's Study of Tamoxifen and Raloxifene (STAR) study was a randomized clinical trial of tamoxifen 20 mg/d or raloxifene 60 mg/d in healthy postmenopausal women at increased risk of breast cancer. The 1,498 women who were randomly assigned in STAR were age 65 years and older, were not diagnosed with dementia, and were enrolled onto the Cognition in the Study of Tamoxifen and Raloxifene (Co-STAR) trial, beginning 18 months after STAR enrollment started. A cognitive test battery modeled after the one used in the Women's Health Initiative Study of Cognitive Aging (WHISCA) was administered. Technicians were centrally trained to administer the battery and recertified every 6 months. Analyses were conducted on all participants and on 273 women who completed the first cognitive battery before they started taking their medications., Results: Overall, there were no significant differences in adjusted mean cognitive scores between the two treatment groups across visits. There were significant time effects across the three visits for some of the cognitive measures. Similar results were obtained for the subset of women with true baseline measures., Conclusion: Tamoxifen and raloxifene are associated with similar patterns of cognitive function in postmenopausal women at increased risk of breast cancer. Future comparisons between these findings and patterns of cognitive function in hormone therapy and placebo groups in WHISCA should provide additional insights into the effects of tamoxifen and raloxifene on cognitive function in older women.

Objective: The aim of this study was to characterize the effects of red clover, black cohosh, and combined hormone therapy on cognitive function in comparison to placebo in women with moderate to severe vasomotor symptoms., Methods: In a phase II randomized, double-blind, placebo-controlled study, 66 midlife women (of 89 from a parent study; mean age, 53 y) with 35 or more weekly hot flashes were randomized to receive red clover (120 mg), black cohosh (128 mg), 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (CEE/MPA), or placebo. Participants completed measures of verbal memory (primary outcome) and other cognitive measures (secondary outcomes) before and during the 12th treatment month. A subset of 19 women completed objective, physiological measures of hot flashes using ambulatory skin conductance monitors., Results: Neither of the botanical treatments had an impact on any cognitive measure. Compared with placebo, CEE/MPA led to a greater decline in verbal learning (one of five verbal memory measures). This effect just missed statistical significance (P = 0.057) in unadjusted analyses but reached significance (P = 0.02) after adjusting for vasomotor symptoms. Neither of the botanical treatment groups showed a change in verbal memory that differed from the placebo group (Ps > 0.28), even after controlling for improvements in hot flashes. In secondary outcomes, CEE/MPA led to a decrease in immediate digit recall and an improvement in letter fluency. Only CEE/MPA significantly reduced objective hot flashes., Conclusions: Results indicate that a red clover (phytoestrogen) supplement or black cohosh has no effects on cognitive function. CEE/MPA reduces objective hot flashes but worsens some aspects of verbal memory.

Although the incidence of HIV in the United States is higher among men compared to women, the global proportion of women versus men who are infected has been approximately 50% since the late 1990s. Women have been under-represented in neuropsychological studies of HIV. A small number of studies have reported a significantly higher prevalence of neurocognitive impairment among HIV+ women compared to HIV- controls regardless of symptom status and with or without an AIDS diagnosis. Impairment was most evident on psychomotor tasks. The risk of neuropsychological impairment was increased among HIV+ women not on antiretroviral therapy. Age and depressive symptoms also increase neurocognitive risk. New neurocognitive studies of ovarian steroid hormones, PTSD and other psychiatric conditions are critical for addressing potential female-specific aspects of HIV-Associated Neurocognitive Disorder. Such studies will also address questions regarding involvement of the hippocampus and verbal memory, which may be of particular significance among HIV+ women.

Objective: Neurocognitive studies of HIV typically target executive functions dependent on frontostriatal circuitry. The integrity of medial temporal systems has received considerably less attention despite high hippocampal viral load. Studies also predominately involve HIV+ men, though HIV+ women may be at increased risk for cognitive dysfunction due to the high prevalence of psychosocial/mental health problems and lower educational attainment. Our aim was to conduct a preliminary investigation of episodic memory and its neural correlates in HIV-infected and at-risk uninfected women., Methods: Participants included 54 HIV+ and 12 HIV- women (mean age = 43 years; 86% African American) recruited from the Chicago site of the Women's Interagency HIV Study. Participants completed standardized tests of verbal and visual episodic memory, working memory, and executive function. A subset of 11 women also underwent functional MRI during a delayed verbal episodic memory task., Results: HIV serostatus predicted significantly lower immediate and delayed verbal episodic memory, working memory, and visual memory. Preliminary neuroimaging findings revealed group differences in bilateral hippocampal function, with HIV+ women showing decreased activation during encoding and increased activation during delayed recognition. These alterations correlated with worse episodic verbal memory., Conclusions: Verbal episodic memory deficits are evident in HIV+ women and may be associated with hippocampal dysfunction at both encoding and retrieval.

Use of estrogen therapy in the perimenopausal and postmenopausal periods has been shown in several clinical trials to help women maintain a premenopausal level of cognitive function. What is not yet fully understood is how the neurobiological effects of estrogen contribute to these cognitive effects. This review explores data from two related bodies of human literature that provide compelling evidence in support of the biological plausibility that estrogen treatment can benefit cognition. The first half of the literature review focuses on studies from the estrogen neuroimaging literature, and the second half focuses on pharmacologic challenge studies assessing estrogen-neurotransmitter interactions. We integrate these two bodies of literature by focusing on the neurophysiologic underpinnings of estrogen effects on cognition and linking these clinical studies to preclinical studies. The focus on verbal memory is important because it is a cognitive function that has been shown to change with estrogen treatment and predict Alzheimer's disease risk but is not addressed by preclinical studies. Overall, we conclude that estrogen interacts with cholinergic and serotonergic systems to affect hippocampal and frontal cortical brain areas and thereby enhance memory, particularly at the retrieval stage.

Recent evidence suggests that loss of ovarian function following ovariectomy is a risk factor for Alzheimer's disease (AD); however, the biological basis of this risk remains poorly understood. We carried out an fMRI study into the interaction between loss of ovarian function (after Gonadotropin Hormone Releasing Hormone agonist (GnRHa) treatment) and scopolamine (a cholinergic antagonist used to model the memory decline associated with aging and AD). Behaviorally, cholinergic depletion produced a deficit in verbal recognition performance in both GnRHa-treated women and wait list controls, but only GnRHa-treated women made more false positive errors with cholinergic depletion. Similarly, cholinergic depletion produced a decrease in activation in the left inferior frontal gyrus (LIFG; Brodmann area 45)--a brain region implicated in retrieving word meaning--in both groups, and activation in this area was further reduced following GnRHa treatment. These findings suggest biological mechanisms through which ovarian hormone suppression may interact with the cholinergic system and the LIFG. Furthermore, this interaction may provide a useful model to help explain reports of increased risk for cognitive decline and AD in women following ovariectomy.

Background: Whilst acute loss of ovarian function is associated with memory deficits, the biological basis of this is poorly understood. We have previously reported that acute loss of function during Gonadotropin Hormone Releasing Hormone agonists (GnRHa) treatment is associated with impaired verbal memory and a disruption of corresponding left inferior frontal gyrus (LIFG) during the encoding stage. In the current study, we provide a critical extension to this work by determining whether this memory deficit is reversible following normalization of ovarian function. To do this we carried out a further imaging study using the same verbal memory recognition task after cessation of GnRHa-induced ovarian suppression., Method: We used event-related fMRI to study verbal episodic memory performance and brain activation at the LIFG in 13 healthy pre-menopausal women pre-, during, and post-acute ovarian hormone suppression using GnRHa., Results: Following resolution of acute GnRHa-induced ovarian suppression, verbal recognition scores returned to their initial levels and this restoration was associated with a restored level of left frontal activation during successful encoding of words., Conclusions: Our findings suggest that the memory deficits associated with acute ovarian suppression are reversed following resolution of normal ovarian function and are associated with reversible attenuation of LIFG activation during encoding. These findings lend further support to the hypothesis that memory difficulties reported by some women following acute ovarian hormone withdrawal are reversible and may have a clear neurobiological basis.

Objective: To test the hypothesis that hot flashes specifically relate to verbal memory performance by examining the relationship between objective hot flashes and cognitive test performance in women with moderate to severe vasomotor symptoms., Design: In an observational study, 29 midlife women (mean age, 53 y) with moderate to severe hot flashes provided measures of objective hot flashes with an ambulatory hot flash monitor, subjective hot flashes with a diary and questionnaire, and objective measures of verbal memory and other cognitive functions with standardized neuropsychological tests., Results: The mean number of objective hot flashes was 19.5 per day (range, 6 to 35), including 15.3 (range, 6 to 35) during waking hours and 4.2 (range, 0 to 9) during sleep. The mean sensitivity (ie, subjective detection of objectively measured hot flashes) was 60%. Regression analyses revealed that total number of objective hot flashes, sleep duration, and verbal knowledge were significant predictors of delayed verbal memory. Verbal fluency correlated positively with objective daytime hot flashes. Hot flashes did not predict performance on any of the other secondary cognitive measures (ie, attention, working memory, visual memory), although poor sleep predicted worse performance on several outcome measures., Conclusions: Highly symptomatic women underreport the number of objective hot flashes that they experience by 43%. Verbal memory performance relates significantly to the objective number of hot flashes women experience but not to the number of hot flashes that they report. These findings suggest that physiological factors related to hot flashes, rather than psychological factors, predict poorer verbal memory function.

Surgical or pharmacological suppression of ovarian hormones leads to declines in verbal memory, and estrogen treatment reverses these deficits. In the current study, we investigated the effects of menstrual cycle phase and oral contraceptives on verbal memory, as measured by the California Verbal Learning Test, in two groups of premenopausal women - 16 naturally cycling women and 20 current users of estrogen-based oral contraceptives (OCs). Naturally cycling women were assessed twice - once during the early follicular phase (Days 2-4) and once during the midluteal phase (Days 20-22) of the menstrual cycle. OC users were tested on the same cycle days, corresponding to inactive and active pill phases, respectively. We predicted that naturally cycling women would show improved verbal memory during the midluteal phase, when estradiol levels are high, compared with the follicular phase, when estradiol levels are low. We also predicted that OC users, who show no change in endogenous estradiol across the cycle, would show no change in verbal memory. Contrary to predictions, naturally cycling women showed no changes in verbal memory across the cycle, whereas OC users showed enhanced memory during the active pill phase (p<.05). None of the secondary cognitive outcome measures varied with cycle phase or OC use including measures of visuospatial memory, verbal fluency, visuospatial abilities, and attention. Overall, these results suggest that verbal memory performance in premenopausal women varies across the cycle with OC use, but does not vary systematically with changes in endogenous estradiol.

Gonadotropin Hormone Releasing Hormone agonists (GnRHa) produce an acute decline in ovarian hormone production leading to a 'pseudo' menopause. This is therapeutically useful in the management of a variety of gynaecological conditions but also serves as a powerful model to study the effects of ovarian hormones on cognition. Animal and human behavioral studies report that memory is particularly sensitive to the effects ovarian hormone suppression (e.g. post GnRHa). Further, it has recently been reported that ovariectomy in young women increases the risk of cognitive impairment in later life. However, the underlying brain networks and/or stages of memory processing that might be modulated by acute ovarian hormone suppression remain poorly understood. We used event-related fMRI to examine the effect of GnRHa on visual working memory (VWM). Neuroimaging outcomes from 17 pre-menopausal healthy women were assessed at baseline and 8 weeks after GnRHa treatment. Seventeen matched wait-listed volunteers served as the control group and were assessed at similar intervals during the late follicular phase of the menstrual cycle. We report GnRHa was associated with attenuation of left parahippocampal (BA 35) and middle temporal gyri (BA 21 ,22, 39) activation, with a significant group-by-time interaction at left precuneus (BA 7) and posterior cingulate cortex (PCC) (BA 31) at encoding, and with cerebellar activation at recognition in the context of unimpaired behavioral responses. Our study suggests that acute ovarian hormone withdrawal following GnRHa, and perhaps at other times, (e.g. following surgical menopause and postpartum) alters the neural circuitry underlying performance of VWM.

We extend the investigation of cognitive sex differences in schizophrenia in a novel way by grouping cognitive tests according to the direction of the typical sex difference, an approach used in studies of hormonal effects on behavior in other clinical conditions. Additionally, we explore how performance on these 'male' and 'female' tests changed following antipsychotic treatment. Seventy patients with a first hospitalization for schizophrenia or schizophreniform disorder completed cognitive tests before antipsychotic treatment and approximately 5 weeks after treatment. Thirty-nine healthy comparison subjects completed the tests at similar intervals. Primary outcome variables were composite scores on cognitive tests that in normative studies favor males over females ('male' tests) or favor females over males ('female tests'). Overall, patients performed more poorly than healthy individuals. The expected pattern of sex differences was found on the composite test scores, with an advantage for females on 'female' tests and an advantage for males on 'male' tests. Female patients showed a greater improvement on 'female' tests and a decrease in performance on 'male' tests following treatment. Although male patients did not perform significantly better after treatment on 'female' tests, they did improve on non-motor 'male' tests of visuospatial skills. Future studies of the neurocognitive effects of antipsychotic treatment may need to take potential sex differences in cognitive response into account.

Context: Recent clinical trials of im testosterone in eugonadal men suggest positive effects on verbal memory, but other studies find no effect., Objective: Our objective was to determine whether supraphysiological testosterone influences verbal memory and brain function during a verbal memory task in healthy eugonadal older men., Patients, Design, and Setting: Fifteen cognitively normal men, aged 66-86 yr, participated in a randomized, double-blind, placebo-controlled crossover trial involving 9 months of participation per participant at a hospital-based research facility., Intervention: We used testosterone enanthate (200 mg im every other week for 90 d) crossed over with placebo (sesame oil vehicle im) with a 90-d washout between treatments., Main Outcome Measures: Performance was assessed on a standardized verbal memory test, and brain activity (relative glucose metabolic rates) in medial temporal and frontal regions was measured with positron emission tomography during a verbal memory task., Results: Treatment increased total testosterone by 241%. Behavioral results showed a significant decrease in short-delay verbal memory with treatment (P < 0.05, effect size = 0.59 sd) and a nonsignificant decrease on a composite verbal memory measure (P = 0.09, effect size = 0.48 sd). Positron emission tomography scans revealed decreased relative activity in ventromedial temporal cortex (i.e. right amygdala/entorhinal cortex) and increased relative activity in bilateral prefrontal cortex with treatment., Conclusions: Decreased verbal memory and altered relative activity in medial temporal and prefrontal regions suggest possible detrimental effects of supraphysiological testosterone supplementation in elderly men. The results do not rule out potential benefits with other regimens, cognitive tests, or populations.

Objective: To evaluate the effects of hormone therapy (HT) on cognition and subjective quality of life (QoL) in recently postmenopausal women with cognitive complaints., Methods: Cognitive Complaints in Early Menopause Trial (COGENT) was a randomized, double-blind, placebo-controlled, multicenter, pilot study of 180 healthy postmenopausal women aged 45 to 55 years, randomly assigned to receive either placebo or conjugated equine estrogen 0.625 mg/medroxyprogesterone acetate 2.5 mg for 4 months. Outcome measures included memory, subjective cognition, QoL, sexuality, and sleep, which were assessed at baseline and month 4., Results: The study was terminated before the expected final sample size of 275 due to a decrease in enrollment coinciding with the publication of findings from the Women's Health Initiative. There were no differences between groups on any cognitive or QoL measures, except for an increase in sexual interest and thoughts with HT. Modest negative effects on short- and long-term verbal memory approached significance (p < 0.10). Women with baseline vasomotor symptoms (VMS) showed a decrease in VMS and an improvement in general QoL, but no cognitive benefit vs placebo., Conclusions: With the power to detect an effect size of >or=0.45, this study suggests potential modest negative effects on verbal memory that are consistent with previous hormone therapy trials in older women.

A previous proton magnetic resonance spectroscopy ((1)H MRS) study carried out by our group indicated that post-menopausal women who started taking oestrogen therapy (ET) at or around the menopause had a significantly lower choline (Cho) concentration in the hippocampus and parietal lobe than those who were ET naïve, suggesting that long-term ET positively modulates neuronal/glial membrane turnover in older females. The objective of the current study was to determine whether neuronal membrane turnover is modulated by sex hormones in younger women following a pharmacologic challenge that induced acute ovarian hormone suppression. We carried out an in vivo(1)H MRS study in a group of 10 premenopausal women pre- and post-8 weeks of acute ovarian suppression with a Gonadotrophin Releasing Hormone analogue (GnRHa) (two Zoladex 3.6 mg implants). We report that young women, post-ovarian suppression, had a significant increase in Cho concentration (and Cho/Cr ratio) in the dorsolateral prefrontal cortex (DLPFC). They also showed a trend to a significant increase in Cho concentration in the hippocampus. This supports our previous findings and adds to the evidence that neuronal/glial membrane metabolism is affected by sex hormones in women.

Gonadotropin hormone releasing hormone agonists (GnRHa) are commonly used in clinical practice to suppress gonadal hormone production in the management of various gynaecological conditions and as a treatment for advanced breast and prostate cancer. Animal and human behavioural studies suggest that GnRHa may also have significant effects on memory. However, despite the widespread use of GnRHa, the underlying brain networks and/or stages of memory processing that might be modulated by GnRHa remain poorly understood. We used event-related functional magnetic resonance imaging to examine the effect of GnRHa on verbal encoding and retrieval. Neuroimaging outcomes from 15 premenopausal healthy women were assessed at baseline and 8 weeks after Gonadotrophin Releasing Hormone analogue (GnRHa) treatment. Fifteen matched wait-listed volunteers served as the control group and were assessed at similar intervals during the late follicular phase of the menstrual cycle. GnRHa was associated with changes in brain response during memory encoding but not retrieval. Specifically, GnRHa administration led to a change in the typical pattern of prefrontal activation during successful encoding, with decreased activation in left prefrontal cortex, anterior cingulate, and medial frontal gyrus. Our study suggests that the memory difficulties reported by some women following GnRHa, and possibly at other times of acute ovarian hormone withdrawal (e.g. following surgical menopause and postpartum), may have a clear neurobiological basis; one that manifest during encoding of words and that is evident in decreased activation in prefrontal regions known to sub-serve deep processing of to-be-learned words.

Recent publications describing the results of the Women's Health Initiative (WHI) and other studies reporting the impact of hormone therapy on aging women have spurred reexamination of the broad use of estrogens and progestins during the postmenopausal years. Here, we review the complex pharmacology of these hormones, the diverse and sometimes opposite effects that result from the use of different estrogenic and progestinic compounds, given via different delivery routes in different concentrations and treatment sequence, and to women of different ages and health status. We examine our new and growing appreciation of the role of estrogens in the immune system and the inflammatory response, and we pose the concept that estrogen's interface with this system may be at the core of some of the effects on multiple physiological systems, such as the adipose/metabolic system, the cardiovascular system, and the central nervous system. We compare and contrast clinical and basic science studies as we focus on the actions of estrogens in these systems because the untoward effects of hormone therapy reported in the WHI were not expected. The broad interpretation and publicity of the results of the WHI have resulted in a general condemnation of all hormone replacement in postmenopausal women. In fact, careful review of the extensive literature suggests that data resulting from the WHI and other recent studies should be interpreted within the narrow context of the study design. We argue that these results should encourage us to perform new studies that take advantage of a dialogue between basic scientists and clinician scientists to ensure appropriate design, incorporation of current knowledge, and proper interpretation of results. Only then will we have a better understanding of what hormonal compounds should be used in which populations of women and at what stages of menopausal/postmenopausal life.

Context: Some studies of hormone treatment in postmenopausal women suggest benefits on specific cognitive functions, particularly memory., Objective: The objective of this study was to determine whether hormone therapy influences changes in specific cognitive functions and affect in older women., Design: This study was a randomized, double-blind, placebo-controlled clinical trial., Setting: Participants were women from 14 of 40 clinical centers of the Women's Health Initiative (WHI)., Participants: Postmenopausal women (1416) aged 65 yr and older, free of probable dementia, and enrolled in WHI and the WHI Memory Study (WHIMS) trial of combination estrogen and progestin for a mean of 3 yr and followed for a mean of 1.35 yr, were studied., Intervention: Intervention was conjugated equine estrogen (CEE; 0.625 mg) with 2.5 mg medroxyprogesterone acetate (MPA) in one daily tablet (CEE + MPA) or placebo., Main Outcome Measures: Annual rates of change in specific cognitive functions and affect, adjusted for time since randomization, were measured., Results: CEE + MPA had a negative impact on verbal memory (P

The large majority of women receiving hormone therapy initiate therapy early in life for the treatment of menopausal symptoms. However, the Women's Health Initiative Memory Study, the only randomized clinical trial to date on hormone therapy and dementia, was carried out in women age 65 and older. That trial provided important insights into the detrimental effects of hormone therapy on dementia in women initiating later in life. The generalizability of those findings to the typical hormone therapy user who initiates earlier in life is unknown. To address this important issue, this review focuses on observational trials of hormone therapy and dementia risk, randomized clinical trials of hormone therapy and cognitive function, and basic science studies. These lines of research provide suggestive, but not definitive, evidence that early initiation of hormone therapy may provide cognitive benefits, particularly to verbal memory and other hippocampally mediated functions. Other forms of hormone therapy, other cognitive domains, and cyclic hormone regimens may not conform to this "critical period hypothesis." Further research is needed to test the validity and limits of this hypothesis.

The putative protective effects of hormone therapy (HT) have been cast in doubt by recent findings from the Women's Health Initiative Memory Study showing an increase in dementia and an increased likelihood of impaired cognitive status in women initiating HT after age 65. To explore the external generalizability of those findings to younger postmenopausal women, the medical literature was surveyed for randomized, double-blind, placebo-controlled trials of treatment with either estrogen alone or estrogen plus a progestin on neuropsychological test performance. Findings from trials in younger women (<65 years) are presented separately from those in older women (>or=65 years). This review finds little support for beneficial cognitive effects in older women of estrogen alone or in combination with progestin. However, evidence from younger women suggests potential beneficial effects in select cognitive domains, particularly among symptomatic women and recently menopausal women, and scant evidence of harm. There is a dearth of studies of the cognitive effects of estrogen plus progestin in younger women. Future studies systematically exploring the effect of age and progestin use are needed to better characterize the effects of HT on cognition in younger women. Without firm evidence of benefit to younger women, it is prudent to caution early postmenopausal women about the cognitive risks observed in WHI, recognizing the low likelihood of dementia at that age.

Basic science and clinical studies have investigated the potential neuroprotective effects of estrogen. One apparent area of convergence in these studies is the selective benefits of estrogen on cognitive tasks mediated by the hippocampus and frontal lobes. Findings in non-human primates parallel findings from neuroimaging and behavioral studies in humans and suggest that estrogen might influence memory tasks mediated by the hippocampus as well as working memory tasks mediated by the prefrontal cortex. This evidence provides a framework for the design of future hormone studies, wherein such tasks can serve as primary outcomes. In studies of symptomatic women, hormone therapy can benefit a broader range of cognitive domains, particularly effortful tests that are sensitive to remittance of dysphoria, sleep difficulty, and hot flushes. Serotonin might play a critical role in these potential indirect benefits, and therapies that target these symptoms, even those without estrogenic actions, might have indirect benefits on cognition.

Background: The population of the developed world is ageing; consequently there is an increasing prevalence of age-related neuropsychiatric disorders, such as dementia of any cause and Alzheimer's disease (AD), for which few treatments are available. Observational studies suggested that hormone therapy (HT) might protect postmenopausal women against cognitive decline and AD. However, the results of randomised controlled trials in women age 65 years and older were negative. There has been extensive media coverage of these trials and many doctors are asked whether HT improves or worsens brain function in younger women who are prescribed HT for the treatment of menopausal symptoms., Recent Developments: The Women's Health Initiative Memory Study (WHIMS) was a multicentre, randomised, double-blind, placebo-controlled clinical trial in which a subgroup of women who participated in the Women's Health Initiative study were assessed for the effects of HT on dementia and mild cognitive impairment. There were two study arms, one involving 4532 postmenopausal women who received continuous combined oestrogen (conjugated equine oestrogens [CEE] plus medroxyprogesterone acetate) or placebo, and the other involving 2947 hysterectomised women randomised to continuous unopposed CEE or placebo. All participants were age 65 years or older. CEE with or without medroxyprogesterone acetate, given to women age 65 years and older, does not protect against dementia or cognitive decline, but substantially increases the risk of dementia of any cause and cognitive decline. WHERE NEXT?: WHIMS answered critically important questions about whether HT can protect against dementia in elderly women who start HT some years after menopause. However, several clinically important questions are unanswered, including questions about the generalisability of WHIMS to groups of women for whom HT is an indication-perimenopausal women and those soon after menopause who have menopausal symptoms-and other methods of treatment delivery and treatment regimens.

Prospective observational studies suggest that hormone therapy (HT) might confer protection against the development of Alzheimer's disease. In contrast, recent findings from the Women's Health Initiative Memory Study (WHIMS) indicated a doubling of the risk of all-cause dementia in women randomized to receive HT after age 64. The discrepancy between findings from observational studies and the WHIMS is commonly attributed to the lack of treatment bias in the randomized trial. However, there are other potentially important dfferences between the WHIMS and the observational studies. These include timing of initiation of HT and type of HT regimen used. The present review focuses on the clinical and basic science studies bearing on these clinically important issues. Additional clinical studies are needed to understand the external generalizability of the WHIMS results to populations of women for whom HT remains an indication.

The Women's Health Initiative Study of Cognitive Aging (WHISCA) was a two armed, randomized, placebo controlled, clinical trial designed to assess the efficacy of postmenopausal hormone therapy on age related changes in specific cognitive functions. WHISCA was an ancillary study to the Women's Health Initiative (WHI) and the WHI Memory Study (WHIMS) and enrolled 2302 women aged 66 to 84 years (mean 73.9; standard deviation 3.8) who did not meet criteria for dementia. Women were randomly assigned by the WHI to hormone treatment (unopposed conjugated estrogens (CEE) 0.625 mg/day if they were without a uterus; CEE combined with medroxyprogesterone acetate (MPA) 2.5 mg/day otherwise) or placebo for an average of three years before the first WHISCA assessment. WHISCA investigated the effects of hormone therapy on rates of change over time in memory, other aspects of cognition (language, attention, spatial ability), motor function, and mood. In this paper, we present the study rationale and design, including specific cognitive measures, and the challenges of incorporating WHISCA into an ongoing randomized trial. WHISCA provided a unique opportunity to investigate the potential of hormone therapy to modify age related changes in specific cognitive functions. WHISCA also demonstrated the feasibility of adding a detailed cognitive assessment into an ongoing clinical trial to address an important issue in women's health, despite the challenges of maintaining the integrity of the parent studies, ensuring high retention, and achieving high quality assurance across sites.

Changes in Mini-Mental State Examination (MMSE) scores were examined over a median of 12.8 years in a population of 361 community-dwelling postmenopausal women who had never received estrogen replacement therapy. In a linear regression model that took into account age, education, race, surgical versus natural menopause, use of birth control pills, and MMSE score at baseline, it was found that nulliparous women and women who went through menopause later in life had significantly less cognitive decline. These results suggest that greater lifetime exposure to endogenous estrogen may be associated with less age-related cognitive decline.

Evidence that ovarian steroid hormones such as estrogen and progesterone affect cognition comes from studies of memory in older women receiving estrogen replacement therapy and studies of sexually dimorphic skills in young women across the menstrual cycle. Sixteen women (ages 18-28) completed tests of memory (implicit category exemplar generation, category-cued recall, implicit fragmented object identification) and sexually dimorphic skills (fine motor coordination, verbal fluency, mental rotations) at the early follicular (low estrogen and progesterone) and midluteal (high estrogen and progesterone) phases of the menstrual cycle. Performance on category exemplar generation, a test of conceptual implicit memory, was better at the midluteal than the follicular phase. In contrast, performance on a test of explicit memory, category-cued recall, did not vary across the menstrual cycle. At Session 1, women in the follicular phase performed better on the fragmented object identification task than did those in the midluteal phase. This unexpected finding suggests that high levels of ovarian hormones might inhibit perceptual object priming. Results confirmed previous reports of decreased mental rotations and improved motor skills and fluency in the midluteal phase. Estradiol levels correlated positively with verbal fluency and negatively with mental rotations and perceptual priming, which suggest that estrogen, and not progesterone, was responsible for the observed changes in cognition. Mood did not vary across the cycle phases. Overall, the findings suggest that estrogen may facilitate the automatic activation of verbal representations in memory.

Recent reports suggest that hormone therapy may be associated with a reduced risk for Alzheimer's disease and may offer some protection against age-associated declines in specific cognitive functions. The majority of these reports are based on observational studies, which are confounded by the "healthy user" bias--the tendency for women receiving hormone therapy to be younger, better educated, and have fewer medical problems. In one attempt to address these limitations, we conducted a series of studies examining effects of hormone therapy on cognitive and brain functioning in nondemented postmenopausal women in the Baltimore Longitudinal Study of Aging (BLSA). In this sample, women receiving hormone therapy and women who never received hormone therapy were comparable with respect to educational attainment, general medical health, and performance on a test of verbal knowledge. Despite these similarities, women receiving hormone therapy performed better on tests of verbal and visual memory compared to never-treated women. The two groups also differed in the patterns of regional brain activation evoked during performance of delayed verbal and figural memory tasks. Furthermore, longitudinal comparisons revealed greater relative blood flow increases over two years in women receiving hormone therapy for the hippocampus and other mesial temporal lobe structures that subserve memory. These observational findings from our studies in the BLSA have led to the development of a large-scale randomized clinical trial of hormone therapy and cognitive aging, the ancillary Women's Health Initiative Study of Cognitive Aging (WHISCA), and have important implications for studies of the effects of SERM's on cognitive and brain functioning.

Animal and human studies provide evidence of systematic effects of estrogen on cerebral activity and cognitive function. In this article, we review studies of the activational effects of estrogen on cerebral activity during rest and during the performance of cognitive tasks in pre- and postmenopausal women. The goal is twofold--to better understand evidence suggesting that estrogen influences brain functioning and argue for the importance of considering hormone effects when designing neuroimaging studies. Hormone-related increases in blood flow during the resting state have been documented in healthy elderly women, elderly women with cerebrovascular disease, and middle-aged postmenopausal women with early menopause. There is no reliable influence of estrogen on blood flow during the resting state in women with Alzheimer's disease. Hormone therapy has been associated with changes in brain activation patterns in middle-aged and elderly postmenopausal women during performance of verbal and figural memory tasks, providing critical biological support for the view that estrogen might protect against age-associated changes in cognition and lower the risk of Alzheimer's disease. There is a paucity of studies examining changes in brain activation patterns across the menstrual cycle and a need for randomized studies of hormone therapy in postmenopausal women to confirm findings from observational studies. General procedural guidelines for controlling and investigating hormone effects in neuroimaging studies are discussed.

Objective: This study examined the effects of hormone-replacement therapy on memory and other cognitive abilities in cognitively intact older women., Method: This prospective observational study in nondemented postmenopausal women aged 50-89 from the Baltimore Longitudinal Study of Aging involved study groups consisting of 103 women who were receiving oral or transdermal estrogen-replacement therapy (44 of whom were receiving adjuvant progesterone) and 81 women who had never received such therapy. Groups were naturally matched on education, health status, depressive symptoms, annual income, and general verbal ability. To restrict the study group to cognitively healthy women, prospective clinical data were used to exclude women who developed dementia up to 5 years after assessment. Data were cross-sectional. Multivariate analysis of variance and follow-up univariate analyses of variance were performed to compare those women who were receiving and those who had never received hormone-replacement therapy on measures of verbal memory, figural memory, mental rotations, attention, and working memory., Results: The women receiving hormone-replacement therapy performed significantly better on measures of verbal learning and memory than did those who had never received hormones, but there were no significant differences in scores on other cognitive tests. Specific aspects of memory performance, including encoding and retrieval, were superior among the women receiving hormone therapy., Conclusions: These findings, based on groups of women who were receiving and had never received hormone-replacement therapy and who were naturally matched on health and cognitive status, suggest that hormone-replacement therapy may have a selective beneficial effect on verbal memory in older nondemented women.

The aims of this study were to examine and compare perceptual and conceptual implicit memory (CIM) in Huntington's disease (HD) and to characterize the relationship between tests of frontal lobe functioning and CIM. Sixteen HD patients and 16 normal controls completed structurally parallel tests of perceptual implicit memory and CIM (i.e., rhyme and category exemplar generation), tests of explicit memory, and verbal fluency. HD patients showed intact implicit memory for both rhyme and category exemplars, despite evidence of frontal dysfunction on other tests. An unexpected finding was that patients showed a deficit in cued rhyme generation that correlated with severity of neurological impairment. The authors replicated findings in controls of a correlation between letter fluency and CIM but found no relationship in patients. Frontal dysfunction in HD may lessen the influence of generative strategies on tests of CIM without compromising performance.

Observational studies suggest that estrogen replacement therapy (ERT) may protect against age-related memory decline and lower the risk of Alzheimer's disease (AD). This study aimed to characterize the neural substrates of those effects by comparing 2-year longitudinal changes in regional cerebral blood flow (rCBF) in 12 ERT users and 16 nonusers. Positron emission tomography (PET) measurements of rCBF were obtained under three conditions: rest, and verbal and figural recognition memory tasks. Groups showed different patterns of change in rCBF over time in a number of brain areas. These group differences, for the most part, reflected regions of increased rCBF over time in users compared to nonusers. The greatest differences between ERT users and nonusers were in the hippocampus, parahippocampal gyrus, and temporal lobe, regions that form a memory circuit and that are sensitive to preclinical AD. Across a battery of standardized neuropsychological tests of memory, users obtained higher scores than did nonusers of comparable intellect. Group differences in longitudinal change in rCBF patterns may reflect one way through which hormones modulate brain activity and contribute to enhanced memory performance among ERT users.

In a cross-sectional study of 164 participants aged 21 to 91, the authors examined age differences on two implicit tests, fragmented object identification (FOI) and category exemplar generation (CEG), and on tests of explicit memory, attention, and verbal fluency. FOI results revealed impaired perceptual skill learning in those over 60 and a decrease in perceptual priming across young, middle-aged, and older groups. CEG priming was impaired in those over 80. Regression analysis revealed explicit contamination of priming on both the FOI and CEG tests. Across the three implicit measures, age accounted for 4 to 13% of the variance when explicit memory was controlled. Semantic fluency predicted CEG priming, suggesting possible frontal lobe involvement on the test. Altogether, results indicate that age has a small but reliable influence on implicit memory.

Reports that estrogen may protect against age-associated memory decline and Alzheimer's Disease have kindled interest in the effects of estrogen replacement therapy (ERT) on cognition and brain function. As part of a 9-year study in the Baltimore Longitudinal Study of Aging, we are performing annual magnetic resonance imaging, positron emission tomography (PET), and neuropsychological assessments to examine brain structure and function in individuals aged 55 and older. PET measurements of regional cerebral blood flow (rCBF) are obtained under 3 conditions: rest and verbal and figural delayed recognition memory tasks. Fifteen women receiving ERT (with or without the addition of progesterone) were compared with a matched sample of 17 untreated women. There were no significant differences between groups in regional brain volumes or ventricular size. However, ERT users and nonusers showed significant differences in PET-rCBF relative activation patterns during the memory tasks. During verbal memory processing, there were significant interactions in rCBF activations for the right parahippocampal gyrus, right precuneus, right frontal regions, and left hypothalamus. During figural memory processing, significant interactions were observed for right parahippocampal and inferior parietal regions and for left visual association and anterior thalamic regions. ERT users also showed better performance on neuropsychological tests of figural and verbal memory and on some aspects of the PET activation tests, although the two groups did not differ in education, overall verbal ability, or performance on other neuropsychological tests. These findings confirm our previous observation of the beneficial effects of ERT on figural memory. Moreover, differences in rCBF activation patterns between ERT users and nonusers suggest an area for future research to examine mechanisms through which ERT may influence memory and other cognitive abilities., (Copyright 1998 Academic Press.)

Symptoms consistent with dysfunction of the frontal lobes can occur following traumatic brain injury (TBI) or other types of acquired brain injury (stroke, aneurysm). These symptoms can include problems with short-term memory, attention, planning, problem solving, impulsivity, disinhibition, poor motivation, and other behavioral and cognitive deficits ("frontal lobe syndrome"). These symptoms may respond to certain drugs, such as dopaminergic agents. This case series describes results of using amantadine in 7 patients with this type of symptom profile (6 with TBI, 1 with meningitis following sinus surgery). Patients received neuropsychiatric examinations and serial neuropsychological testing. All patients showed some degree of positive response. One had side effects that resolved upon discontinuation of drug. The rationale for using dopaminergics is discussed, and pertinent literature is reviewed.