None listed
Conditions
Brief summary
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory loss, impairments in behaviour, language and visuo-spatial skills and is ultimately fatal. In the majority of cases, AD onset occurs after the age of 65 (late onset) and is sporadic in origin. Only approximately 5-10% of cases have a disease onset before the age of 65 (early onset). These are often familial forms but only a few that are caused by autosomal dominant mutations in certain AD linked genes. One of the major pathological hallmarks of AD is the presence of neuritic plaques in the brain. These plaques are formed from the build-up of a peptide known as beta-amyloid (AB). There is now evidence to show that sex hormones play an important role in reducing AB levels and so has the potential to protect individuals against developing the disease. Our laboratory was the first to demonstrate clinically in men a reduction in testosterone levels following chemical castration resulted in increased plasma beta AB levels and subsequently showed that in elderly men a decrease in testosterone levels was associated with increased plasma AB levels. However, the question remains whether changes in plasma testosterone result in changes in AB in the CSF and the brain. In addition, recent research has shown that high levels of the gonadotropin, Luteinizing Hormone (LH), are associated with AD and modulate AB production. However, the relative contribution of LH and testosterone in the pathogenesis of AD remains to be elucidated. The current study tests the efficacy of testosterone on cognition in high risk men by employing a randomized placebo controlled double blind study and to determine associations with a number of key blood and brain biomarkers. These findings will serve as the basis for the establishment of a larger, multicentre trial for the prevention of AD.
Interventions
Arm 1: Treatment Group - Testosterone treatment for 24 weeks followed by a wash out period of 4 weeks. Following this step, the participant groups were “crossed over”, such that the testosterone group received placebo and vice versa for a further 24 weeks.
For the testosterone treatment group (n=22), testosterone (50 mg in the form of Andromen(Registered Trademark) 5% FORTE cream obtained from Lawley Pharmaceuticals, Perth, Western Australia) was applied daily to the scrotum, thus using a trans
Arm 1: Treatment Group - Testosterone treatment for 24 weeks followed by a wash out period of 4 weeks. Following this step, the participant groups were “crossed over”, such that the testosterone group received placebo and vice versa for a further 24 weeks. For the testosterone treatment group (n=22), testosterone (50 mg in the form of Andromen(Registered Trademark) 5% FORTE cream obtained from Lawley Pharmaceuticals, Perth, Western Australia) was applied daily to the scrotum, thus using a transdermal route (topically), for 24 weeks. For all participants, there were a total of 11 clinic visits to Siloam Hospital within the 52-week study period. During the first visit, the participants’ blood pressure, height, weight, body fat percentage and body mass index (BMI) were checked and blood drawn for a baseline reading of blood counts, chemistries, serum testosterone level, LH and SHBG, DHT (dihydrotestosterone) and estradiol, cholesterol, lipid concentrations and plasma beta amyloid levels. The participants’ APOE genotype was also determined. The baseline neuropsychological testing, brain imaging (MRI/MRS) and a CSF sample (for those participants who consented) were collected. CSF samples were collected by lumbar puncture. At each of the six remaining clinic visits i.e. at 4, 8, 12, 16, 20 and 24 weeks during the first treatment period, blood pressure, weight, body fat percentage and body mass index (BMI) were checked and blood drawn for blood counts, chemistries, measurement of serum testosterone, LH, SHBG, albumin, PSA, DHT, estradiol, insulin, cholesterol, lipid and glucose concentrations and plasma AB levels, while neuropsychological testing were only included at 8, 16 and 24 weeks. At the end of 24 weeks a second CSF sample was collected (from those participants that consented) and MRI/MRS performed, followed by a 4-week washout period. The placebo and testosterone treatment arms of the study were then crossed-over for a further 24-week treatment period. During this period, the participants were examined every eight weeks (three bleeds in total i.e. at weeks 8, 16 and 24 of the cross-over period); blood collected for analysis as described above and neuropsychological testing performed on all occasions. At the end of the 24-week cross-over period (i.e. week 52 overall, the completion of the trial) a third CSF sample was collected (from those participants that consented) and MRI/MRS performed. Thus, visits mainly lasted for a maximum of 1.5 hours mainly due to the cognitive testing. Monitoring adherence mainly comprised of ensuring participants were applying the cream as per the protocol during each of the monitoring visits.
Sponsors
McCusker Alzheimer's Research Foundation
Study design
Allocation
Randomised controlled trial
Intervention model
Crossover
Primary purpose
Prevention
Masking
Blinded (masking used) (Subject, Caregiver)
Eligibility
Sex/Gender
Male
Age
50 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
Male participants: needed to 1) be 50 years of age or older, and have 2) a memory complaint, 3) testosterone levels between 300-600 ng/dL (~10.4 - 20.8 nmol/L), 4) normal levels of PSA, 5) blood pressure within normal limits, 6) no signs of diabetes mellitus, 7) normal liver and kidney enzyme function, and 8) No history of major head injury. The diagnosis of subjective memory loss (complaint of memory loss but not meeting the criteria for dementia) was reached after a full clinical evaluation including a review of medical and drug history and a physical examination.
Exclusion criteria
Any participants meeting the criteria for Dementia were excluded from the study.
Outcome results
None listed