Epidemiological studies suggest that hormone therapy might lower the incidence of Alzheimer’s disease and delay its onset (Tang et al.
1996; Kawas et al. 1997). Behavioral studies suggest that hormone therapy might also protect against age-related declines in memory and other cognitive abilities in individuals who are free of dementia (Resnick et al. 1997; Kampen and Sherwin 1994; Robinson et al.
1994), in part by enhancing encoding while learning new information (Maki et al. 2001). Biological support for these findings comes from animal studies showing beneficial effects of estrogen on neuronal survival and connectivity in regions of the brain subserving memory, in particular, the hippocampus (McEwen et al. 1997). Evidence that estrogen influences brain function in humans comes from neuro- imaging studies. In this chapter, we review studies of the effects of hormone therapy on cerebral blood flow, cerebral glucose meta- bolism, and patterns of brain activity during performance of cog- nitive tasks. A greater understanding of the effects of hormone therapy on brain function is valuable, because neurophysiological studies offer unique insights into the biological plausibility of the epidemiological and behavioral findings.
Studies of the effects of hormone therapy on resting cerebral blood flow and metabolism preceded neuroimaging studies using cognitive challenge paradigms. In the mid-1980s, Namba and Sokoloff (1984) demonstrated that acute administration of high doses of estrogen resulted in significant increases in glucose metabolism in ovariecto- mized rats. Subsequent studies of cerebral blood flow during the resting state in middle-aged postmenopausal women demonstrated estrogen-related increases at the level of the convexity corresponding to the cerebral vasculature (Greene 2000), in cerebellar and whole brain blood flow (Ohkura et al. 1995), and more specifically across
Effects of Hormone Therapy on Patterns of Brain Activation during Cognitive Activity:
A Review of Neuroimaging Studies
Pauline M. Maki and Susan M. Resnick
right lower frontal regions, bilateral middle and upper frontal regions, bilateral medial and upper temporal regions, bilateral caudate and thalamus, bilateral parietal regions, bilateral lower occipital regions, left upper occipital regions, and bilateral precentral regions (Ohkura et al. 1996). Estrogen-related increases in global blood flow have been reported in older women with a history of cerebrovascular disease (Funk et al. 1991), and in relative blood flow in healthy older women in the right middle/superior temporal gyrus, the right inferior tem- poral gyrus, and the left middle temporal gyrus (Maki and Resnick 2000). Additional evidence of hormone effects on cerebral activity comes from demonstrations of changes in regional glucose meta- bolism in female rats across the estrous cycle (Nehlig et al. 1985) and in premenopausal women across the menstrual cycle (Reimann et al.
1996). These studies suggest that hormone therapy increases resting cerebral blood flow and glucose metabolism.
Recent advances in functional neuroimaging studies allow for direct assessments of the effects of hormone therapy on regional patterns of brain activity during cognitive test performance. Two primary neuroimaging techniques have been used. One, positron emission tomography (PET), involves a radiolabeled tracer or radio- isotope. One of the more commonly used radioisotopes is H215O, or radiolabeled water, which is used to measure cerebral blood flow.
H215O has a short radioactive half-life (2 min.), enabling researchers to perform successive neuroimaging scans under different cognitive instructions. Another commonly used radioisotope is 18-F-Fluoro- deoxyglucose (18-F-FDG) radiolabeled glucose, which is used to measure glucose metabolism. 18-F-FDG is used less commonly in cognitive studies than H215O, because 18-F-FDG has a longer half-life (110 min) and is more difficult to use for sequential assessments of different cognitive states. In cognitive studies, the radioisotope is typically injected into an arm vein very shortly after the participant begins to perform a particular cognitive task. The isotope then distri- butes throughout the brain depending upon where blood flow or energy metabolism is greatest and emits positrons as it decays. Under typical conditions, regional cerebral blood flow and metabolism are thought to be closely coupled and reflect the underlying neural activity.
The second neuroimaging approach, functional magnetic reso- nance imaging (fMRI), uses MRI technology to measure functional processes in the brain. This technique measures particular magnetic
signal changes called blood oxygen level dependent (BOLD) signal changes that occur with neural activity. BOLD changes reflect two factors – first, that there are local changes in the amount of oxygen in active neural tissue, and second, that deoxygenated hemoglobin is magnetic whereas oxygenated hemoglobin is not (Cohen 1996). To detect the change in the magnetic properties of brain regions, the fMRI technique involves serial imaging of brain tissue during active and rest states. A brain region with more oxygenated blood will show up more intense on certain MRI images compared to when there is less oxygenated blood. fMRI has better spatial and temporal resolution than PET, but may have limited resolution in inferior temporal and frontal areas due to airway (i.e., sinus) artifacts. To date, of the functional neuroimaging studies on hormone therapy and brain activation, one used fMRI (Shaywitz 1999), three used PET and H215O (Maki and Resnick 2000; Berman et al. 1997; Resnick et al.
1998), and one used PET and 18-F-FDG (Eberling et al. 2000). Both PET and fMRI techniques have been sensitive to the effects of hor- mone therapy on patterns of brain activation during performance of cognitive tests.
Berman and colleagues (1997) were the first to investigate the effects of ovarian steroid hormones on regional cerebral blood flow during performance of a cognitive task. In an add-back design, they used PET and H215O in 11 young premenopausal women as they performed a modified version of a common test of executive functioning and a control test during ovarian hormone suppression with Lupron (i.e., lowered estrogen and progesterone). In a rando- mized manner, they then repeated the tests during treatment with Lupron plus transdermal estradiol to isolate the effects of estradiol alone, and during treatment with Lupron plus progesterone to isolate the effects of progesterone alone. With Lupron, the young women showed suppression of the activation pattern typically obtained during the test, which is activation of the prefrontal cortex, inferior parietal lobule, and other cortical regions. With add-back estrogen and add-back progesterone, they showed the normal pattern of activation and showed increased activity in parietal and temporal regions. There was greater hippocampal activation in the estrogen add-back condition than in the progesterone add-back condition.
This study provides evidence that estrogen and progesterone influence patterns of brain activation during performance of an executive task in premenopausal women. The add-back design in
premenopausal women has been proposed as a model for estrogen replacement and progesterone replacement in postmenopausal wo- men, although potential differences between acute and chronic hormone depletions warrant caution.
Five studies of the effects of hormone therapy on regional brain activation patterns in postmenopausal women followed Berman’s seminal study in premenopausal women. Three of those were obser- vational studies (also called naturalistic studies) (Maki and Resnick 2000; Resnick et al. 1998; Eberling et al. 2000), which compared women who chose to receive hormone therapy to those who did not choose to receive such therapy. Observational studies of hormone therapy can be limited by the healthy user bias, the tendency for women who choose to receive hormone therapy to be younger, healthier, and better educated than women who do not choose to receive hormone therapy (Matthews et al. 1996). One approach to minimizing these confounds is to match the study groups for age and education (Maki and Resnick 2000; Resnick et al. 1998). Another approach is to covary for group differences in confounding factors (Eberling et al. 2000); however, the validity of such techniques, parti- cularly in small samples, is questionable.
In the first of the observational studies, we conducted a cross- sectional investigation in postmenopausal women participating in the Longitudinal Neuroimaging Study of the Baltimore Longitudinal Study of Aging (BLSA) (Resnick et al. 2000). Our goal was to build on our findings that postmenopausal BLSA participants receiving hormone therapy performed better on tests of verbal (Maki et al.
2001) and figural (Resnick et al. 1997) memory than did participants who were not receiving hormones. To this end, we used PET and H215O to measure patterns of brain activity during performance of delayed verbal and figural recognition memory tasks (Golski et al.
1998) and also during rest in two groups of older women differing in hormone use. The study involved 15 women who were receiving hormone therapy (typically, Premarin 0.625 mg/day) and 17 who were receiving no therapy. The two groups were matched in age (mean age 66 years), education, and general verbal knowledge (Resnick et al. 1998). Women receiving hormone therapy and those receiving no hormone therapy showed different patterns of brain activation during the tasks (Fig. 1).
Comparisons between the verbal memory and resting conditions revealed group differences in the right parahippocampal gyrus,
precuneus, inferior frontal cortex, and dorsal frontal gyrus. Compar- isons between the figural memory and resting conditions revealed group differences in the right inferior parietal region, right parahip- pocampal gyrus, left visual association area, left anterior thalamus, and a region proximal to the right mammilary body. These group differences do not indicate that one group shows consistently greater activation of specific brain regions, but rather they reveal greater relative activation by one or the other group for some regions, whereas in other regions the pattern is in the opposite direction. We focused on regional patterns rather than directions of differences, because greater regional cerebral blood flow response to a task has been associated with both better performance (Nyberg et al. 1996) and less efficient processing (Grady et al. 1995). Although the group receiving hormone therapy did not show a clear advantage on the activation task, they showed superior memory on standardized neuropsychological tests of verbal and figural memory, suggesting that the group differences in regional cerebral blood flow during performance of memory tasks were indicative of a beneficial effect of estrogen on brain function. This study points to the parahippo- campal gyrus, frontal cortex, and inferior parietal lobule as regions that may modulate the beneficial effects of hormone therapy on verbal and figural memory.
In a follow-up study, we examined longitudinal changes in re- gional cerebral blood flow to determine whether women who re- ceived hormone therapy and those who received no such therapy showed different patterns of brain aging over time (Maki and Resnick
Fig. 1. Hormone therapy is associated with changes in activity in the right parahippocampal gyrus and inferior frontal regions during performance
of a delayed verbal memory task (Source: Resnick et al. 1998)
Fig. 2. Women who receive hormone replacement therapy show greater longitudinal increases in blood flow in the hippocampus over a 2-year interval
compared with women who receive no hormone replacement (Source: Maki and Resnick 2000)
Axial Slice
superimposed on structural MRI
R L
2000). We compared patterns of change over a 2-year interval in 28 of the women who participated in the previous cross-sectional analysis and maintained the same group assignment during that interval. In this study, we focused primarily on the change over time across the three conditions combined (i.e., rest and figural and verbal memory) to maximize statistical power. Results indicated significant differences in the patterns of blood flow changes over time, with most changes indicating areas of increased blood flow in women receiving hormone therapy. Notably, the largest of these differences were in the right hippocampus, entorhinal cortex, middle temporal gyrus, and parahippocampal gyrus (Fig. 2).
These are the same regions that show hypoperfusion in indivi- duals at increased risk for Alzheimer’s disease (Kennedy et al. 1995;
Reiman et al. 1996; Johnson et al. 1998). This demonstration that estrogen modulates hippocampal functioning in humans lends support to the biological plausibility that estrogen may protect against age-associated declines in memory and may lower the risk of Alzheimer’s disease.
Sagittal Coronal Axial
Zvalue
6 4 3 2 1 0
A recent observational study used PET and 18-F-FDG to measure regional glucose metabolism during performance of a continuous recognition memory task for words (Eberling et al. 2000). Compared with women with Alzheimer’s disease (n = 13), nondemented, post- menopausal women receiving hormone therapy (n = 8) showed grea- ter relative metabolism, adjusted for whole brain values, in dorsola- teral frontal, middle temporal, and inferior parietal cortex. In con- trast, nondemented women receiving no hormone therapy (n = 5) did not differ from women with Alzheimer’s disease in glucose meta- bolism. The difference in metabolism between nondemented women receiving hormone therapy and those not receiving hormone therapy was evident only indirectly, in reference to patients with Alzheimer’s disease. The failure to find hormone-related differences in glucose metabolism among the neurologically normal women may have been due to insufficient statistical power.
To date, there has been one published randomized, placebo-con- trolled intervention trial of the effects of hormone therapy on brain activation patterns (Shaywitz et al. 1999). In intervention studies, women are treated with hormone therapy for the purpose of the study. Intervention studies have a notable advantage over observa- tional trials – they are not susceptible to the healthy user bias, because treatment is decided by investigators or by random assign- ment. The use of a placebo control group in intervention studies allows for estimations of placebo effects and of the effects of repeated assessments on outcomes. Shaywitz and colleagues conducted a double-blind, placebo-controlled, crossover intervention study of short-term estrogen therapy (i.e., 1.25 mg conjugated equine estro- gen/day for 21 days) on activation patterns during figural and verbal working memory tests in 46 middle-aged, postmenopausal women (mean age 51 years). Working memory involves the temporary maintenance of information in memory. To examine the effects of hormones on different aspects of working memory, functional MRI imaging scans were acquired under three conditions – encoding (i.e., study), storage (i.e., a 20-s delay), and retrieval (i.e., forced choice recognition) – for each of the two memory tasks (i.e., figural and verbal). There was no change in performance on the tests with treatment, but there were changes in the patterns of brain activation during task performance. Across the two tests combined, estrogen therapy was associated with an exaggeration of the typical pattern observed during encoding and retrieval, namely, increased
activation in the left superior frontal gyrus during encoding and right superior frontal gyrus during retrieval. During storage of verbal material there were estrogen-related increases in anterior frontal regions and the inferior parietal lobule bilaterally, and decreases in the inferior parietal lobule (at a level lower than the area of increased inferior parietal activation), left central sulcus, and right superior temporal gyrus. During storage of nonverbal material, there was decreased activation in the inferior parietal lobule at the same level at which activations increased during storage of verbal material.
This study demonstrates that hormones modulate brain activity during working memory tasks in middle-aged, postmenopausal women.
In summary, observational, intervention, and add-back studies indicate that hormone therapy modulates brain activity during per- formance of a variety of cognitive tasks (Maki and Resnick 2000;
Shaywitz et al. 1999; Berman et al. 1997; Resnick et al. 1998). Studies of hormone effects on brain activity during memory tests are of parti- cular interest, given that hormone therapy appears to exert the most consistent beneficial effects on memory, particularly verbal memory.
Although not all studies have shown a beneficial effect of hormone therapy on verbal memory (Barrett-Connor and Kritz-Silverstein 1993; Szklo et al. 1996), we argue that the failure to find such effects reflects the particular type of memory tests selected for use in those studies. In a recent study, women receiving hormone therapy showed enhanced encoding of words (Maki et al. 2001), suggesting that the beneficial effects of hormone therapy on verbal recall may in part reflect enhanced encoding. In studies involving memory tests that maximize the encoding of words by directing rehearsal of unrecalled words (Barrett-Connor and Kritz-Silverstein 1993; Szklo et al. 1996), no beneficial effects of hormone therapy are seen. In contrast, where studies include memory tests involving no such rehearsal, a bene- ficial effect on memory is observed (Maki et al. 2001; Kampen and Sherwin 1994; Robinson et al. 1994; Resnick et al. 1998). If estrogen influences memory in part by enhancing encoding, then rehearsing items until they are well learned may obscure the beneficial effects of estrogen on memory.
The fact that verbal memory has shown the most consistent improvement with hormone therapy (Maki et al. 2001; Kampen and Sherwin 1994; Robinson et al. 1994; Sherwin 1988; Sherwin and Phillips 1990; Phillips and Sherwin 1992) has led to the view that the
beneficial effects of estrogen may be limited to verbal memory (Sher- win 1997). However, the beneficial effects of hormone therapy on figural memory are evident in some behavioral studies (Resnick et al. 1997; Duka et al. 2000) and supported by three neuroimaging studies (Maki and Resnick 2000; Shaywitz et al. 1999; Resnick et al.
1998). Recent observational data from our laboratory showed bene- ficial effects of hormone therapy on both verbal and figural memory performance, with only those for verbal memory reaching statistical significance in a moderate sized sample (Maki et al. 2001). Several lines of evidence demonstrate significant effects of estrogen on the hippocampus, an area critical for encoding and retrieval of both words and figures (Schacter and Wagner 1999; Schacter et al. 1999). Animal studies show beneficial effects of estrogen on dendritic spine density (Gould et al. 1990) and synaptic excitability (Wong and Moss 1992) in hippocampal neurons. Evidence of increased hippocampal blood flow over time in women receiving hormone therapy (Maki and Resnick 2000) provides support for hormone-related enhancements in hippocampal functioning in humans.
Neuroimaging studies point to hormone-related changes in a number of extra-hippocampal brain areas that subserve distinct memory processes. A review of the evidence of hormone-related ef- fects on encoding, storage, and retrieval may help to highlight the particular brain regions that are sensitive to hormone therapy.
Greater left hemisphere activation during encoding and greater right hemisphere activation during retrieval is the typical pattern observed in imaging studies of memory processes (Tulving et al. 1994).
Estrogen therapy influences activation in left frontal regions during encoding (Shaywitz et al. 1999) and right frontal areas during retrieval (Shaywitz et al. 1999; Resnick et al. 1998). During storage of verbal material, estrogen therapy is associated with increased activity in the anterior frontal and inferior parietal lobule (Shaywitz et al. 1999).
Hormone therapy is associated with decreased activation in the inferior parietal lobule during storage of nonverbal material (Shay- witz et al. 1999) and during recognition of figures (Resnick et al.
1998). PET studies revealed hormone-associated increases in activity in the hippocampus and parahippocampal cortex in association with performance on delayed memory tasks (Maki and Resnick 2000;
Resnick et al. 1998) and executive tasks (Berman et al. 1997). Due to airway artifacts that cause distortions in imaging some regions, some fMRI techniques may have limited sensitivity for detection of hor-
mone effects in particular inferior frontal and anterior temporal lobe regions.
Hormone therapy influences patterns of brain activity on cog- nitive tests that do not typically show beneficial effects in behavioral outcomes, including tests of executive function (Berman et al. 1997) and working memory (Shaywitz et al. 1999). This suggests that neu- roimaging techniques may be more sensitive than behavioral tech- niques in detecting beneficial effects of hormones on brain function associated with a number of cognitive activities. The argument that any estrogen-related effect on neural activity is reflective of a meaningful change in cognition is bolstered by concurrent demon- strations of beneficial effects on standardized neuropsychological tests.
In summary, results of neurophysiological studies add to the bio- logical plausibility of epidemiological and behavioral findings of a protective effect of hormone therapy on age-related changes in cognition and Alzheimer’s disease. Studies suggest that hormone therapy affects neural substrates of several cognitive functions in young, middle-aged, and older women. Randomized, double-blind, placebo-controlled studies of hormone effects on neuroimaging outcomes during cognitive tasks are underway to determine whether these effects can be generalized to older women in a randomized trial.
Although we are hopeful that observational findings (Crawford 1996;
Simpkins et al. 1997) will replicate in randomized trials, we must be cautious in attributing differences in brain functioning among women receiving hormone therapy to the physiological properties of the hormones. Findings from ongoing neuroimaging studies and large-scale, randomized trials of hormone therapy on cognitive out- comes will provide data necessary for determining whether hormone therapy is a useful preventative treatment for minimizing age-related declines in brain function in postmenopausal women.
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