IMPORTANCE Growth hormone-releasing hormone (GHRH) has been previously shown to have cognition-enhancing effects. The role of neurotransmitter changes, measured by proton magnetic resonance spectroscopy, may inform the mechanisms for this response.OBJECTIVE To examine the neurochemical effects of GHRH in a subset of participants from the parent trial.DESIGN Randomized, double-blind, placebo-controlled substudy of a larger trial.SETTING Clinical research unit at the University of Washington School of Medicine.PARTICIPANTS Thirty adults (17 with mild cognitive impairment [MCI]), ranging in age from 55 to 87 years, were enrolled and successfully completed the study.INTERVENTIONS Participants self-administered daily subcutaneous injections of tesamorelin (Theratechnologies Inc), a stabilized analogue of human GHRH (1 mg/d), or placebo 30 minutes before bedtime for 20 weeks. At baseline and weeks 10 and 20, participants underwent brain magnetic resonance imaging and spectroscopy protocols and cognitive testing and provided blood samples after fasting. Participants also underwent glucose tolerance tests before and after intervention.MAIN OUTCOMES AND MEASURES Brain levels of glutamate, inhibitory transmitters.-aminobutyric acid (GABA) and N-acetylaspartylglutamate (NAAG), and myo-inositol (MI), an osmolyte linked to Alzheimer disease in humans, were measured in three 2 x 2 x 2-cm(3) left-sided brain regions (dorsolateral frontal, posterior cingulate, and posterior parietal). Glutamate, GABA, and MI levels were expressed as ratios to creatine plus phosphocreatine, and NAAG was expressed as a ratio to N-acetylaspartate.RESULTS After 20 weeks of GHRH administration, GABA levels were increased in all brain regions (P < .04), NAAG levels were increased (P = .03) in the dorsolateral frontal cortex, and MI levels were decreased in the posterior cingulate (P = .002). These effects were similar in adults with MCI and older adults with normal cognitive function. No changes in the brain levels of glutamate were observed. In the posterior cingulate, treatment-related changes in serum insulin-like growth factor 1 were positively correlated with changes in GABA (r = 0.47; P = .001) and tended to be negatively correlated with MI (r = -0.34; P = .06). Consistent with the results of the parent trial, a favorable treatment effect on cognition was observed in substudy participants (P = .03). No significant associations were observed between treatment-related changes in neurochemical and cognitive outcomes. Glucose homeostasis in the periphery was not reliably affected by GHRH administration and did not account for treatment neurochemical effects.CONCLUSIONS Twenty weeks of GHRH administration increased GABA levels in all 3 brain regions, increased NAAG levels in the frontal cortex, and decreased MI levels in the posterior cingulate. To our knowledge, this is the first evidence that 20 weeks of somatotropic supplementation modulates inhibitory neurotransmitter and brain metabolite levels in a clinical trial, and it provides preliminary support for one possible mechanism to explain favorable GHRH effects on cognition in adults with MCI and in healthy older adults.

Previously, we reported cognition-enhancing effects of growth hormone-releasing hormone (GHRH) in mild cognitive impairment (MCI) and in healthy older adults. GHRH, growth hormone, and insulin-like growth factor-I (IGF-I) have potent effects on brain function, decline with advancing age, and likely play a role in Alzheimer's disease (AD) pathogenesis. One mechanism to support cognition-enhancing GHRH effects may involve IGF-I modulation of inhibitory neurotransmitter activity, a key regulator in learning and memory processing. Regulation of inhibitory control in brain by gamma-amino butyric acid (GABA) has been identified as a possible therapeutic target in AD, particularly since the GABAergic system is relatively spared in this disease. In the parent randomized, double-blind placebo-controlled study, older adults with MCI or normal cognitive status (55–87 yrs old) received 1 mg/d subcutaneous human GHRH (Tesamorelin®, Theratechnologies Inc.) or placebo 30 min before bedtime for 20 weeks. For a subset of participants (n=30; 17 with MCI), magnetic resonance spectroscopy (MRS) examined treatment effects on glutamate and the inhibitory transmitters GABA and N-acetylaspartylglutamic acid (NAAG) in three left brain regions (dorsolateral frontal cortex, posterior cingulate, and posterior parietal white matter). Glutamate and GABA were expressed as ratios of creatine (Cr), and NAAG as a ratio of N-acetylaspartate (NAA). Outcomes collected in the parent study included serum IGF-I and cognitive measures of executive function and memory. Following 20 weeks of GHRH administration, GABA/Cr increased in all brain regions (p<0.04), with comparable effects in MCI and healthy adults. In frontal cortex, GHRH also increased NAAG/NAA (p=0.03) for both subject groups. No changes in the excitatory neurotransmitter glutamate were observed. In the posterior cingulate, a region sensitive to early changes of AD pathology, GHRH effects on GABA/Cr and serum IGF-I were positively correlated (r=0.47, p=0.01). There were no associations between treatment-induced changes in MRS and cognitive outcomes likely due to sample size limitations. Twenty weeks of GHRH administration increased GABA in all brain regions, and increased NAAG in frontal cortex. This is the first evidence that somatotropic supplementation modulates inhibitory neurotransmitter levels in humans, and provides preliminary support for a potential mechanism to account for positive GHRH effects on cognition.

specificity/90% accuracy. By modified intent-to-treat analysis, which included results from two patients in whom the diagnosis of GHD was not confirmed (MITT, n = 52 AGHD, 48 controls), these cutoffs provided 86% sensitivity/85% specificity/86% accuracy in lean/overweight subjects and 83% sensitivity/96% specificity/90% accuracy in the obese group. The areas under the curve for receiver operating characteristic (ROC) analysis also increased with BMI adjustment–from 0.923 unadjusted to 0.925 adjusted in the PP groups, and from 0.912 to 0.918 in the MITT groups.

BACKGROUND:Growth hormone–releasing hormone(GHRH), growth hormone, and insulin like growth factor 1 have potent effects on brain function, their levels decrease with advancing age, and they likely play a role in the pathogenesis of Alzheimer disease. Previously, we reported favorable cognitive effects of short-term GHRH administration in healthy older adults and provided preliminary evidence to suggest a similar benefit in adults with mild cognitive impairment (MCI).OBJECTIVE:To examine the effects of GHRH on cognitive function in healthy older adults and in adults with MCI.DESIGN:Randomized,double-blind,placebo-controlled trial.SETTING:Clinical Research Center, University of Washington School of Medicine in Seattle.PARTICIPANTS:A total of 152 adults (66 with MCI) ranging in age from 55 to 87 years (mean age, 68 years); 137 adults (76 healthy participants and 61 participants with MCI) successfully completed the study.INTERVENTION:Participants self-administered daily subcutaneous injections of tesamorelin (Theratechnologies Inc),a stabilized analog of human GHRH (1 mg/d), or placebo 30 minutes before bedtime for 20 weeks. At baseline, at weeks 10 and 20 of treatment, and after a 10-week washout(week 30), blood samples were collected, and parallel versions of a cognitive battery were administered. Before and after the 20-week intervention, participants completed an oral glucose tolerance test and a dual-energy x-ray absorptiometry scan to measure body composition.MAIN OUTCOME MEASURES:Primary cognitive outcomes were analyzed using analysis of variance and included 3 composites reflecting executive function, verbal memory, and visual memory. Executive function was assessed with Stroop Color-Word Interference,Task Switching, the Self-Ordered Pointing Test, and Word Fluency, verbal memory was assessed with Story Recall and the Hopkins Verbal Learning Test,and visual memory was assessed with the Visual-Spatial Learning Test and Delayed Match-to-Sample.RESULTS:The intent-to-treat analysis indicated a favorable effect of GHRH on cognition (P=.03), which was comparable in adults with MCI and healthy older adults.The completer analysis showed a similar pattern, with a more robust GHRH effect (P=.002). Subsequent analyses indicated a positive GHRH effect on executive function (P=.005) and a trend showing a similar treatment-related benefit in verbal memory(P=.08). Treatment with GHRH increased insulin like growth factor 1 levels by 117 %(P.001), which remained within the physiological range, and reduced percent body fat by 7.4%(P.001). Treatment with GHRH increased fasting insulin levels within the normal range by 35%in adults with MCI (P.001) but not in healthy adults. Adverse events were mild and were reported by 68%of GHRH treated adults and 36% of those who received placebo.CONCLUSIONS:Twenty weeks of GHRH administration had favorable effects on cognition in both adults with MCI and healthy older adults. Longer-duration treatment trials are needed to further examine the therapeutic potential of GHRH administration on brain health during normal aging and “pathological aging.”TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT00257712

Animal and clinical studies show that the somatotrophic axis, which modulates circulating levels of growth hormone, growth hormone-releasing hormone (GHRH), and insulin-like growth factor I (IGF-I), has potent effects on brain function. Age- and disease-related changes in this axis set the stage for targeted therapeutic interventions to improve cognitive function. In an earlier pilot study, we demonstrated that six months of GHRH treatment had positive effects on cognition for healthy older men and women. These results also provided preliminary evidence that similar benefits might be observed for adults with mild cognitive impairment (MCI). Using a double-blind, randomized, placebo-controlled study design, 124 subjects (55-87 yrs old, 59% women) received subcutaneous injections of tesamorelin, a stabilized analogue of human GHRH (1 mg/d, provided by Theratechnologies Inc.) or placebo 30 min before bedtime for 20 weeks. Sixty subjects (n=27 amnestic MCI) in the tesamorelin group and 64 subjects (n=28 amnestic MCI) in the placebo group completed the study. Prior to enrollment, study candidates received a neuropsychological assessment with diagnostic adjudication and medical screening. At baseline and week 20, cognitive function was assessed including tests of executive function and episodic memory, oral glucose tolerance tests were performed, and blood was collected for assay of IGF-I, glucose, insulin, and lipids. Tesamorelin significantly increased plasma levels of IGF-I over baseline (p < 0.0001) but remained within physiological range. Both for healthy older adults and adults with MCI, tesamorelin improved performance on executive function tests of response inhibition (p=0.009, Stroop Color Word Interference test) and set-shifting (p=0.01, Task Switching), and a statistical trend also suggested tesamorelin-related improvements in working memory (p=0.07, Self-ordered Pointing Test). On tests of memory, tesamorelin significantly improved delayed verbal recall for adults with MCI but not for healthy older adults (MANOVA tx*dx interaction, p=0.05). General cognitive status (MMSE), visual memory, word fluency, and processing speed were not affected by treatment. This study is the first to demonstrate that short-term tesamorelin administration improves executive function for healthy and memory-impaired older adults, and has a favorable effect on verbal memory for adults with MCI who are at high risk of progression to Alzheimer's dementia.

Insomnia is a commonly reported clinical problem with as many as 50% of older adults reporting difficulty in falling and/or remaining asleep. Valerian ( Valeriana officinalis ) is a commonly used herb that has been advocated for promoting sleep. Valerenic acid is used as a marker for quantitative analysis of valerian products with evidence of pharmacological activity relevant to the hypnotic effects of valerian. The objective of this study was to determine the pharmacokinetics of valerenic acid in a group of elderly women after receiving a single nightly valerian dose and after 2 weeks of valerian dosing. There was not a statistically significant difference in the average peak concentration ( C max ), time to maximum concentration ( T max ) area under the time curve ( AUC ), elimination half‐life ( T 1/2 ) and oral clearance after a single dose compared with multiple dosing. There was considerable inter‐ and intra‐subject variability in the pharmacokinetic parameters. C max and AUC deceased and T 1/2 increased with increased body weight. The variability between the capsules was extremely low: 2.2%, 1.4% and 1.4%, for hydroxyvalerenic acid, acetoxyvalerenic acid and valerenic acid, respectively. In conclusion, large variability in the pharmacokinetics of valerenic acid may contribute to the inconsistencies in the effect of valerian as a sleep aid. Copyright © 2010 John Wiley & Sons, Ltd.

Objective: To test the effects of nightly valerian (Valeriana officinalis) extract to improve sleep of older women with insomnia.Methods: Participants in this phase 2 randomized, double-blind, crossover controlled trial were 16 older women (mean age = 69.4 +/- 8.1 years) with insomnia. Participants took 300 mg of concentrated valerian extract or placebo 30 min before bedtime for 2 weeks. Sleep was assessed in the laboratory by self-report and polysomnography (PSG) at baseline and again at the beginning and end of each treatment phase (total of nine nights in the laboratory) and at home by daily sleep logs and actigraphy.Results: There were no statistically significant differences between valerian and placebo after a single dose or after 2 weeks of nightly dosing on any measure of sleep latency, wake after sleep onset (WASO), sleep efficiency, and self-rated sleep quality. In comparing each treatment to baseline in separate comparisons, WASO significantly increased (+ 17.7 +/- 25.6 min., p = .02) after 2 weeks of nightly valerian, but not after placebo (+6.8 +/- 26.4 min, NS). Side effects were minor and did not differ significantly between valerian and placebo.Conclusion: Valerian did not improve sleep in this sample of older women with insomnia. Findings from this study add to the scientific evidence that does not support use of valerian in the clinical management of insomnia. (C) 2008 Elsevier B.V. All rights reserved.