Aging and Estrogen on Cortical Function

The broad goal of this proposal is to determine the effect of aging on areas of the brain
whose function is impacted by gonadal steroids in women. The overarching hypothesis is that
aging differentially alters the effects of estrogen on the brain. Our preliminary data
indicated that aging alters the effect of estrogen on brain regions involved in cognition and
thus, the current study focused on the impact of aging on functional changes induced by
estrogen in cortical and subcortical areas associated with verbal working memory and
declarative/episodic memory.

As our model, we will use women in whom the absence of gonadal function makes it possible to
control the duration and amount of estrogen exposure, specifically postmenopausal women who
are younger (45-55) or older (65-80) who receive either oral or transdermal estradiol to
achieve premenopausal early follicular phase estradiol levels.. We evaluate the effects of
low dose estrogen exposure at 48 hr and 1 month to determine whether the short-term changes
in brain regions involved in cognition with low dose estrogen exposure seen in our
preliminary studies are confirmed and whether changes with short-term estrogen exposure
persist with more prolonged exposure, a finding that would have enormous clinical relevance.
These studies, using sophisticated neuroimaging tools (structural and functional magnetic
resonance imaging [MRI] and [18F] 2-fluoro-2-deoxy-D-glucose positron emission tomography
[FDG-PET]), provide a unique window into the brain in women.

Inclusion Criteria:

1. young postmenopausal (age 45-55) or older (age 65-80) postmenopausal women

2. otherwise healthy, non-obese women with normal blood pressure and a history of normal
menopause, defined by the absence of menses for at least 12 months

3. prescription hormone replacement treatment discontinued at least 3 months before study

4. Normal or corrected normal vision

5. Intelligence quotient (IQ) > 70 on the Wechsler Adult Reading Test (WTAR)*

6. Absence of Mild Cognitive Impairment (MCI) and depression on the Mini Mental State
Examination (MMSE)** and Beck Depression Inventory II (BDI-II).***

7. Normal mammogram or breast MRI within the past 2 years

Exclusion Criteria

1. On gonadal hormone replacement medication, herbal supplements and/or over the counter
menopause treatment within three months of study

2. History of radiotherapy or chemotherapy.

3. Absolute contraindications to the use of physiologic replacement doses of estrogen
and/or history of coronary artery disease

4. History of breast cancer, blood clot, pulmonary embolus, hypercoagulability and
stroke.

5. On centrally acting medications

6. History of head trauma and/or neurologic disorder

7. Contraindication to MRI (eg. metal implants) or PET imaging (eg. PET imaging studies
in the previous 12 months)

8. Concurrent participation in research studies involving medications and/or PET scans.

9. Left handedness.

10. Current breast lump(s) or family/genetic history of breast cancer in younger women (<
40 years old).

11. Current smoking