Department of Radiology, Seattle Children's Hospital, Seattle, Washington 98105, USA.
JAMA Neurol. 2013 Jul;70(7):883-90. doi: 10.1001/jamaneurol.2013.1425.
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.
To examine the neurochemical effects of GHRH in a subset of participants from the parent trial.
Randomized, double-blind, placebo-controlled substudy of a larger trial.
Clinical research unit at the University of Washington School of Medicine.
Thirty adults (17 with mild cognitive impairment [MCI]), ranging in age from 55 to 87 years, were enrolled and successfully completed the study.
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.
Brain levels of glutamate, inhibitory transmitters γ-aminobutyric acid (GABA) and N-acetylaspartylglutamate (NAAG), and myo-inositol (MI), an osmolyte linked to Alzheimer disease in humans, were measured in three 2 × 2 × 2-cm3 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.
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.
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. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00257712.
生长激素释放激素（GHRH）先前已被证明具有增强认知的作用。通过质子磁共振波谱测量的神经递质变化的作用可能为这种反应的机制提供信息。
在母试验的一部分参与者中检查 GHRH 的神经化学作用。
一项更大试验的随机、双盲、安慰剂对照子研究。
华盛顿大学医学院临床研究单位。
30 名成年人（17 名轻度认知障碍 [MCI]），年龄在 55 至 87 岁之间，入组并成功完成了研究。
参与者在睡前 30 分钟自行皮下注射 tesamorelin（Theratechnologies Inc），一种人 GHRH（1mg/d）的稳定类似物，或安慰剂，持续 20 周。在基线和第 10 周和第 20 周，参与者接受了脑部磁共振成像和光谱学方案以及认知测试，并在禁食后提供了血液样本。参与者还在干预前后进行了葡萄糖耐量测试。
在三个 2×2×2cm3 的左侧大脑区域（背外侧额叶、后扣带回和后顶叶）中测量了谷氨酸、抑制性递质γ-氨基丁酸（GABA）和 N-乙酰天门冬氨酸谷氨酸（NAAG）以及肌醇（MI）的脑水平，一种与人类阿尔茨海默病相关的渗透剂。谷氨酸、GABA 和 MI 水平以肌酸加磷酸肌酸的比值表示，NAAG 以 N-乙酰天门冬氨酸的比值表示。
在 GHRH 给药 20 周后，所有脑区的 GABA 水平均升高（P<0.04），背外侧额叶的 NAAG 水平升高（P=0.03），后扣带回的 MI 水平降低（P=0.002）。在有 MCI 和认知功能正常的老年人中，这些作用相似。未观察到谷氨酸脑水平的变化。在后扣带回，与治疗相关的血清胰岛素样生长因子 1 的变化与 GABA 的变化呈正相关（r=0.47；P=0.001），并且与 MI 的变化呈负相关趋势（r=-0.34；P=0.06）。与母试验的结果一致，在子研究参与者中观察到认知治疗的有利效果（P=0.03）。未观察到治疗相关的神经化学和认知结果之间存在显著关联。外周葡萄糖稳态不受 GHRH 给药的可靠影响，也不能解释治疗的神经化学作用。
20 周的 GHRH 给药增加了所有 3 个脑区的 GABA 水平，增加了额叶的 NAAG 水平，并降低了后扣带回的 MI 水平。据我们所知，这是第一个证据表明 20 周的合成代谢补充剂在临床试验中调节抑制性神经递质和大脑代谢物水平，并为解释 GHRH 对有 MCI 和健康老年人认知的有利影响的一种可能机制提供了初步支持。
clinicaltrials.gov 标识符：NCT00257712。
