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Original Investigation |

Growth Hormone–Releasing Hormone Effects on Brain γ-Aminobutyric Acid Levels in Mild Cognitive Impairment and Healthy Aging

Seth D. Friedman, PhD1; Laura D. Baker, PhD3,5,8; Soo Borson, MD3; J. Eric Jensen, PhD7; Suzanne M. Barsness, RN, MSN3; Suzanne Craft, PhD3,5,9; George R. Merriam, MD4,6; Randolph K. Otto, MD1; Edward J. Novotny, MD2; Michael V. Vitiello, PhD3
[+] Author Affiliations
1Department of Radiology, Seattle Children’s Hospital, Seattle, Washington
2Department of Neurology, Seattle Children’s Hospital, Seattle, Washington
3Departments of Psychiatry and Behavioral Science, University of Washington School of Medicine, Seattle
4Department of Medicine, University of Washington School of Medicine, Seattle
5Geriatric Research, Education, and Clinical Center,Veterans Affairs Puget Sound Health Care System, Seattle, Washington
6Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, Washington
7Harvard University, Mclean Hospital, Belmont, Massachusetts
8now with the Department of Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina
9now with the Department of Internal Medicine and the Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
JAMA Neurol. 2013;70(7):883-890. doi:10.1001/jamaneurol.2013.1425.
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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 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.

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.

Trial Registration  clinicaltrials.gov Identifier: NCT00257712.

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Figure 1.
Magnetic Resonance Image of the Brain

Voxel locations (white boxes) in the posterior cingulate (A), dorsolateral frontal (B), and parietal (C) regions.

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Figure 2.
γ-Aminobutyric Acid to Creatine Plus Phosphocreatine Ratio by Treatment Group

Mean (SE) baseline to week 20 change in the ratio of γ-aminobutyric acid (GABA) to creatine plus phosphocreatine (Cr) by treatment group (placebo vs growth hormone–releasing hormone [GHRH]), expressed as residualized change scores. WM, white matter. aP < .05.

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Figure 3.
N-acetylaspartylglutamate to N-acetylaspartate Ratio by Treatment Group

Mean (SE) baseline to week 20 change in the ratio of N-acetylaspartylglutamate (NAAG) to N-acetylaspartate (NAA)  by treatment group (placebo vs growth hormone–releasing hormone [GHRH]), expressed as residualized change scores. WM, white matter. aP < .05.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.
Myo-inositol to Creatine Plus Phosphocreatine Ratio by Treatment Group

Mean (SE) baseline to week 20 change in the ratio of myo-inositol (MI) to creatine plus phosphocreatine (Cr) by treatment group (placebo vs growth hormone–releasing hormone [GHRH]), expressed as residualized change scores. WM indicates white matter. aP < .05.

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