SMART: Somatotrophics, Memory, and Aging Research Trial

There is considerable and compelling evidence from both the animal and human literature that
the actions of the somatotrophic hormonal axis (growth hormone releasing hormone/growth
hormone/insulin-like growth factor I) have significant and predictable effects on cognitive
function (memory and reasoning ability). A preliminary study has recently shown that five
months of growth hormone releasing hormone (GHRH) treatment improves cognitive function in
healthy older men and women; there is also preliminary evidence that supports the likelihood
of a similar effect in individuals diagnosed with MCI.

The study sample will include 160 adults, ages 55-90, half of whom will be cognitively
healthy normal adults and half of whom will meet diagnostic criteria for Mild Cognitive
Impairment (MCI). Each of these groups will contain equal numbers of men and women. The
treatment with GHRH will be twenty weeks in duration. In light of the documented interactions
between estrogens and GHRH/GH/IGF-I, each of the two study arms will contain equal
proportions of women not on estrogen replacement therapy (NERT) and women on oral estrogen
replacement therapy (ERT). ERT women will maintain a regular steady dosage of estrogens for
at least seven days preceding each assessment

Cognitive assessments to evaluate treatment-related changes in memory and thinking abilities,
as well as blood collection to evaluate several biomarkers of interest, will be performed at
baseline, 10 and 20 weeks of treatment, and ten weeks post-treatment. In addition there will
be five medication and symptom monitoring visits during the treatment period.

The study hypotheses are:

H1: Healthy, cognitively normal older men and women treated with GHRH will show beneficial
effects in cognitive function, including measures of memory, relative to placebo treated
subjects.

H2: MCI patients treated with GHRH will show beneficial effects in cognitive function,
including measures of memory, relative to placebo treated MCI patients.

H3: Changes in insulin-like-growth factor (IGF-I) will predict changes in cognition both for
normal older adults and for MCI patients treated with GHRH.

Inclusion Criteria:

- Able to give and understand informed consent

- Able to communicate in English

- No exclusionary criteria apply

- Age between 55 and 90 years

- Independent in their daily living abilities

- Living at home with a reliable spouse, significant other or caregiver

- Normal PSA (for men) or mammogram (for women) within one year of study entry

The following inclusion criteria will be applied to identify potential MCI participants:

- Memory complaint that can be corroborated by a study partner

- Memory test scores meeting the diagnostic criteria for MCI

- MMSE score greater than 20

The following inclusion criteria will be applied to identify potential normal control
participants:

- Cognitive testing does not indicate MCI

- MMSE score greater than 28

Exclusion Criteria:

- Use of medications known to affect the GHRH/GH/IGF-I axis, including transdermal
estrogens (use of oral estrogens is not contraindicated)

- Significant medical illness or organ failure, such as uncontrolled hypertension,
diabetes, cardiac disease, cerebrovascular disease, chronic obstructive pulmonary
disease, kidney and liver disease

- Significant neurologic disease that might affect cognition, such as Alzheimer's
disease, stroke, Parkinson's disease, multiple sclerosis, severe head injury with loss
of consciousness for more than 30 minutes or with permanent neurologic sequelae

- Personal or strong family history of cancer (especially colon, breast or melanoma)

- Evidence for pituitary disease by history or physical examination

- Symptoms or history of carpal tunnel or a positive Phalen's Test

- Active arthritis

- Significant current psychiatric illness, such as depression, schizophrenia or an Axis
II diagnosis suggestive of an inability to successfully complete the study protocol

- Current use of an anti-psychotic, anti-depressant, anti-convulsant, anti-coagulant,
anxiolytic or sedative

- Current or planned use of DHEA, testosterone or cognition-enhancing medication (e.g.,
cholinesterase inhibitors, memantine)

- Weight greater than 150% ideal body weight

- Tobacco use, excessive alcohol intake (more than 2 drinks per day), excessive caffeine
intake (more than 4 cups of coffee per day)

- Baseline IGF-I level greater than the mid-range for healthy young adults (250 ng/ml)

- Meets NINCDS/ADRDA criteria for AD