Hormone and Information Processing Study

Natural age related declines in testosterone (T) are associated with decreases in cognitive abilities independent of health status. Low T levels over time are associated with increased risk for developing Alzheimer's disease (AD). These findings suggest that men with low T levels are most at risk for age-related cognitive decline and AD and therefore most likely to benefit from T supplementation to prevent the development of AD or age-associated cognitive decline. The current study will assess cognition, mood, and cerebral spinal fluid (CSF) biomarker response to T supplementation in older men with mild cognitive impairment (MCI) and low T levels.

Participants will be randomized to either receive T treatment or a placebo for six months. Participants will come in for about five visits within the span of six months where they will complete cognitive \& memory tests, fill out mood questionnaires, and have their blood drawn to monitor the medication level. A sample of blood will also be taken at one visit to test for apolipoprotein E (APOE), which is a genetic risk factor associated with AD. Participants will have the option to get a spinal tap in order to measure biological markers associated with Alzheimer's disease including beta-amyloid 1-40, 42, total-tau, and phosphorylated-tau-181-231. This will require an additional two visits.

• testosterone gel (Drug), also known as Solvay Testosterone Gel: 50-100mg applied topically daily for six months
• placebo gel (Drug): applied topically daily for six months

Primary outcomes

• Behavioral & Mood Measure: Profile of Mood States (POMS) [Baseline, 3 and 6 months]: Values represent self evaluation of vigor-activity. The scale compares t-scores of participants to published norms (range 0-100), and higher scores indicate elevated emotion in subscale. Higher t-scores in vigor-activity subscale are considered favorable. Month 3 and Month 6 values display change from baseline.
• Cognitive Changes Measured by Neuropsychological Tests: Rey Auditory Verbal Learning Test [Baseline, 3 and 6 months]: Values represent total score in Long Delay Word List Recall. Higher score indicates higher level of functioning (range 0-15). Month 3 and Month 6 indicate change from baseline.
• Geriatric Depression Scale (GDS) [Baseline, Month 3, Month 6]: Values represent self evaluation of depression (range 0-30). Higher scores indicate a more depressed mood. Month 3 and Month 6 indicate change from baseline.
• Short-Form Health Survey (SF-36) [Baseline, Month 3, Month 6]: Self assessment of Physical Functioning in Health Survey. Higher scores indicate a higher level of functioning (range 0-100). Month 3 and 6 values represent change from baseline in subscale.

Sex: Male, ages: 60 Years to 90 Years

Inclusion Criteria:

* Male 60-90 years of age
* Diagnosis of mild cognitive impairment (MCI)
* Low testosterone level
* Primary language is English
* Availability of an informant who knows the participant well enough to answer questions
* Stable medications for the previous 3 months
* Normal complete blood count (CBC), and no clinically significant blood chemistry
* American Urological Association (AUA) symptom score less than or equal to 19
* Body Mass Index (BMI) less than 33 and stable weight in the previous year

Exclusion Criteria:

* Prior history of prostate cancer or prostate specific antigen level greater than 4.0ng/ml
* Peripheral or vascular disease
* Significant history of alcohol abuse, current alcohol abuse (more than 2 drinks per day), or other substance abuse
* History of severe head injury (with loss of consciousness greater than 30 minutes)
* Significant neurological illness, such as Parkinson's disease, seizure disorder, multiple sclerosis, major stoke
* Smokes cigarettes
* Major psychiatric illness, such as schizophrenia or bipolar disorder

Prohibited Medications:

* Anti-convulsants
* Anti-psychotics
* Sedating antihistamines
* Sedative/hypnotics
* Benzodiazepines
* Hormone or testosterone regimens
* Gonadotropin-releasing hormone (GNRH) antagonists
* Flutamide
* Anti-depressants and/or anti-cholinesterase inhibitors, but acceptable if on stable dose for 3 months or more

Participant flow

Outcome results

• Behavioral & Mood Measure: Profile of Mood States (POMS) (Primary), Mean, units on a scale: Treatment Group 57.7 +/- 2.2; Placebo Group 55.5 +/- 2.0
• Cognitive Changes Measured by Neuropsychological Tests: Rey Auditory Verbal Learning Test (Primary), Mean, units on a scale: Treatment Group 6.2 +/- 1.1; Placebo Group 4.9 +/- 1.0
• Geriatric Depression Scale (GDS) (Primary), Mean, units on a scale: Treatment Group 7.2 +/- 1.3; Placebo Group 4.1 +/- 1.2
• Short-Form Health Survey (SF-36) (Primary), Mean, units on a scale: Treatment Group 70.7 +/- 10.4; Placebo Group 85.6 +/- 2.3

Adverse events

Other adverse events by term

• Cherrier MM, Asthana S, Plymate S, Baker L, Matsumoto AM, Peskind E, Raskind MA, Brodkin K, Bremner W, Petrova A, LaTendresse S, Craft S. Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology. 2001 Jul 10;57(1):80-8. doi: 10.1212/wnl.57.1.80. PMID 11445632
• Cherrier MM, Matsumoto AM, Amory JK, Ahmed S, Bremner W, Peskind ER, Raskind MA, Johnson M, Craft S. The role of aromatization in testosterone supplementation: effects on cognition in older men. Neurology. 2005 Jan 25;64(2):290-6. doi: 10.1212/01.WNL.0000149639.25136.CA. PMID 15668427
• Cherrier MM, Matsumoto AM, Amory JK, Asthana S, Bremner W, Peskind ER, Raskind MA, Craft S. Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment. Neurology. 2005 Jun 28;64(12):2063-8. doi: 10.1212/01.WNL.0000165995.98986.F1. PMID 15985573
• Cherrier MM, Matsumoto AM, Amory JK, Johnson M, Craft S, Peskind ER, Raskind MA. Characterization of verbal and spatial memory changes from moderate to supraphysiological increases in serum testosterone in healthy older men. Psychoneuroendocrinology. 2007 Jan;32(1):72-9. doi: 10.1016/j.psyneuen.2006.10.008. Epub 2006 Dec 4. PMID 17145137
• Lu PH, Masterman DA, Mulnard R, Cotman C, Miller B, Yaffe K, Reback E, Porter V, Swerdloff R, Cummings JL. Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. Arch Neurol. 2006 Feb;63(2):177-85. doi: 10.1001/archneur.63.2.nct50002. Epub 2005 Dec 12. PMID 16344336

• Monique Cherrier, PhD, Principal investigator, University of Washington

NIH grants: R01AG027156