***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Memory performance by four age groups ( 30 - 45 years , 46 - 60 years , 61 - 75 years , and 76 - 90 years ) was compared on a multi-trial verbal recall task with 20-minute and 1-day delay free recall and recognition trials . The rate of acquisition across 5 learning trials was similar for all ages except the youngest group whose performance was constrained by a ceiling effect . The level of acquisition achieved was less in the two oldest groups . Words gained across trials and words lost across trials made similar contributions to the shape of the learning curve for the acquisition trials . Subjective organization decreased with age , but remained strongly related to the number of words recalled during acquisition for all age groups . The two oldest age groups demonstrated significant declines in words recalled on the 20-minute and 1-day delay trials . A subset of the oldest group demonstrated more rapid forgetting at the 1-day delay when participants from all age conditions were matched on acquisition . Thus , many aspects of free recall were impaired with age , and variance measurement of recall showed greater inter-individual differences with increasing age . This increase in individual differences could reflect a single form of age-related memory impairment , or it could indicate that memory impairment in the elderly is due to multiple processes . The importance of testing across the life span and using tests that examine a variety of memory components and processes for establishing norms and clarifying age-related deficits are discussed This study describes the neural circuitry underlying temporally separated components of working memory ( WM ) performance-stimulus encoding , maintenance of information during a delay , and the response to a probe . While other studies have applied event-related fMRI to separate epochs of WM tasks , this study differs in that it employs a methodology that does not make any a priori assumptions about the shape of the hemodynamic response ( HDR ) . This is important because no one model of the HDR is valid across the range of activated brain regions and stimulus types . Systematic modeling inaccuracies may lead to the misattribution of activity to adjacent events . Twelve healthy subjects performed a numerical version of the Sternberg Item Recognition Paradigm adapted for rapid presentation event-related fMRI . This paradigm emphasized maintenance rather than manipulative WM processes and used a subcapacity WM load . WM trials with different delay lengths were compared to fixation . The HDR of the entire WM trial for each trial type was estimated using a finite impulse response ( FIR ) . Regional activity associated with the Encode , Delay , and Probe epochs was identified using contrasts that were based on the FIR estimates and by examining the HDRs . Each epoch was associated with a distinct but overlapping pattern of regional activity . Activation of the dorsolateral prefrontal cortex , thalamus , and basal ganglia was exclusively associated with the probe . This suggests that frontostriatal neural circuitry participates in selecting an appropriate response based on the contents of WM Estrogen Therapy ( ET ) may protect against age-related cognitive decline and neuropsychiatric disorders ( e.g. Alzheimer 's disease ) . The biological basis for this putative neuroprotective effect is not fully understood , but may include modulation of cholinergic systems . Cholinergic dysfunction has been implicated in age-related memory impairment and Alzheimer 's disease . However , to date no one has investigated the effect of long-term ET on brain cholinergic muscarinic receptor aging , and related this to cognitive function . We used Single Photon Emission Tomography ( SPET ) and (R , R)[(123)I]-I-QNB , a novel lig and with high affinity for m(1)/m(4 ) muscarinic receptors , to examine the effect of long-term ET and age on brain m(1)/m(4 ) receptors in healthy females . We included 10 younger premenopausal subjects and 22 postmenopausal women ; 11 long-term ET users ( all treated following surgical menopause ) and 11 ET never-users ( surgical menopause , n=2 ) . Also , verbal memory and executive function was assessed in all postmenopausal subjects . Compared to young women , postmenopausal women ( ET users and never-users combined ) had significantly lower muscarinic receptor density in all brain regions examined . ET users also had higher muscarinic receptor density than ET never-users in all the brain regions , and this reached statistical significance in left striatum and hippocampus , lateral frontal cortex and thalamus . Moreover , in ET users , (R , R)[(123)I]-I-QNB binding in left hippocampus and temporal cortex was significantly positively correlated with plasma estradiol levels . We also found evidence for improved executive function in ET users as compared to ET never-users . However , there was no significant relationship between receptor binding and cognitive function within any of the groups . In healthy postmenopausal women use of long-term ET is associated with reduced age-related differences in muscarinic receptor binding , and this may be related to serum estradiol levels Estradiol has been shown to interact with the cholinergic system to affect cognition in postmenopausal women . This study further investigated the interaction of estradiol and cholinergic system functioning on verbal memory and attention in two groups of healthy younger ( ages 50 - 62 ) and older ( ages 70 - 81 ) postmenopausal women . Twenty-two postmenopausal women were r and omly and blindly placed on 1 mg of 17-beta estradiol orally for 1 month then 2 mg for 2 months or matching placebo pills after which they participated in three anticholinergic challenge sessions when verbal memory and attention were assessed . Subjects were administered either the antimuscarinic drug scopolamine ( SCOP ) , the antinicotinic drug mecamylamine ( MECA ) , or placebo . After the first challenge phase , they were crossed over to the other hormone treatment for another 3 months and repeated the challenges . Results showed that estradiol pretreatment significantly attenuated the anticholinergic drug-induced impairments on a test of episodic memory ( the Buschke Selective Reminding Task ) for the younger group only , while estradiol treatment impaired performance of the older group . The results suggest that younger subjects may experience more cholinergic benefit from estradiol treatment than older subjects , supporting the concept of a critical period for postmenopausal estrogen use CONTEXT Postmenopausal women have a greater risk than men of developing Alzheimer disease , but studies of the effects of estrogen therapy on Alzheimer disease have been inconsistent . On July 8 , 2002 , the study drugs , estrogen plus progestin , in the Women 's Health Initiative ( WHI ) trial were discontinued because of certain increased health risks in women receiving combined hormone therapy . OBJECTIVE To evaluate the effect of estrogen plus progestin on the incidence of dementia and mild cognitive impairment compared with placebo . DESIGN , SETTING , AND PARTICIPANTS The Women 's Health Initiative Memory Study ( WHIMS ) , a r and omized , double-blind , placebo-controlled clinical trial , began enrolling participants from the Women 's Health Initiative ( WHI ) estrogen plus progestin trial in May 1996 . Of the 4894 eligible participants of the WHI study , 4532 ( 92.6 % ) postmenopausal women free of probable dementia , aged 65 years or older , and recruited from 39 of 40 WHI clinical centers were enrolled in the WHIMS . INTERVENTION Participants received either 1 daily tablet of 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate ( n = 2229 ) , or a matching placebo ( n = 2303 ) . MAIN OUTCOME MEASURES Incidence of probable dementia ( primary outcome ) and mild cognitive impairment ( secondary outcome ) were identified through a structured clinical assessment . RESULTS The mean ( SD ) time between the date of r and omization into WHI and the last Modified Mini-Mental State Examination ( 3MSE ) for all WHIMS participants was 4.05 ( 1.19 ) years . Overall , 61 women were diagnosed with probable dementia , 40 ( 66 % ) in the estrogen plus progestin group compared with 21 ( 34 % ) in the placebo group . The hazard ratio ( HR ) for probable dementia was 2.05 ( 95 % confidence interval [ CI ] , 1.21 - 3.48 ; 45 vs 22 per 10 000 person-years ; P = .01 ) . This increased risk would result in an additional 23 cases of dementia per 10 000 women per year . Alzheimer disease was the most common classification of dementia in both study groups . Treatment effects on mild cognitive impairment did not differ between groups ( HR , 1.07 ; 95 % CI , 0.74 - 1.55 ; 63 vs 59 cases per 10 000 person-years ; P = .72 ) . CONCLUSIONS Estrogen plus progestin therapy increased the risk for probable dementia in postmenopausal women aged 65 years or older . In addition , estrogen plus progestin therapy did not prevent mild cognitive impairment in these women . These findings , coupled with previously reported WHI data , support the conclusion that the risks of estrogen plus progestin outweigh the benefits UNLABELLED The aim of the double-blind , placebo-controlled study was to investigate the effects of a continuous combined estrogen-progestogen treatment ( Climodien , Lafamme ) as compared with estrogen alone on vigilance in insomniac postmenopausal syndrome patients , objectified by EEG mapping . METHODS In a 3-arm , 2-month parallel group design phase , patients received a combination of estradiol valerate 2 mg and the novel progestogen dienogest 3 mg ( Climodien 2/3 ) or estradiol valerate 2 mg alone or placebo . In a subsequent open-label phase , all patients received estradiol valerate 2 mg+dienogest 2 mg ( Climodien 2/2 ) . EEG mapping was carried out before and after the 2-month double-blind phase as well as after the 2-month open-label treatment . RESULTS As compared with placebo , Climodien 2/3 induced a marked and highly significant increase in absolute power in all frequency b and s , specifically in alpha-2 activity . Moreover , a significant increase in relative alpha-2 power , a decrease in relative delta and beta power as well as an acceleration of the dominant frequency and of the delta and alpha centroids suggested a marked improvement in vigilance . In contrast , under estradiol valerate 2 mg alone , only a slight augmentation of alpha and attenuation of relative delta and beta power occurred , suggesting only a slight vigilance improvement as compared with placebo . Thus , dienogest 2 mg increased the estrogen effect , which was also confirmed by a statistical evaluation of the differences between Climodien 2/3 and estradiol valerate alone ( augmentation of alpha-2 , attenuation of relative beta , acceleration of the dominant frequency ) . Moreover , Climodien 2/2 also markedly increased alpha-2 power , decreased relative beta-2 power and accelerated the alpha centroid . Finally , comparing Climodien 2/3 with Climodien 2/2 , there was even a dose-efficacy relation . CONCLUSIONS Estradiol valerate 2 mg improves vigilance slightly , thereby confirming previous findings . The additional administration of dienogest does not minimize the effect of estrogen , but on the contrary increases it , which makes the combination superior to both placebo and estradiol valerate alone . Vigilance improvement may be of great therapeutic benefit to menopausal syndrome patients at a time when increased adaptability is needed to adjust to increasing sexual , marital , occupational and social difficulties known to occur specifically in this period of life Recent research in rodents suggests that extended and chronic hormone therapy can exacerbate memory impairments and irreversibly damage cells . However , aerobic fitness regimens have been shown to spare brain tissue and cognitive function . In addition , interactions between estrogen treatment and exercise have been reported in rodents . However , whether aerobic fitness and hormone treatments show interactive effects on human brain tissue and cognition has yet to be determined . Here we report two unique and important results : ( a ) HRT treatment up to 10 years in duration spares gray matter in prefrontal cortex and is associated with better performance on measures of executive function , whereas HRT treatment beyond 10 years in duration increases the degree of prefrontal deterioration and amplifies the decline on measures of executive functioning ( b ) higher fitness levels augment the effects of shorter duration s of hormone treatment and ameliorate the declines associated with prolonged hormone treatment 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 reciprocalwith better working memory related to a higher testosterone to estrogen ratio . 
    Output:
    
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 .
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