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Effects of growth hormone–releasing hormone on cognitive function in adults with mild cognitive impairment and healthy older adults: results of a controlled trial.

ABSTRACT: 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).To examine the effects of GHRH on cognitive function in healthy older adults and in adults with MCI.Randomized,double-blind,placebo-controlled trial.Clinical Research Center, University of Washington School of Medicine in Seattle.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.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.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.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.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.”clinicaltrials.gov Identifier: NCT00257712

SUBMITTER: Baker LD

PROVIDER: S-EPMC3764914 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Effects of growth hormone–releasing hormone on cognitive function in adults with mild cognitive impairment and healthy older adults: results of a controlled trial.

Baker Laura D LD Barsness Suzanne M SM Borson Soo S Merriam George R GR Friedman Seth D SD Craft Suzanne S Vitiello Michael V MV

Archives of neurology 20121101 11

<h4>Background</h4>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).<h4>Objective</h4>To ...[more]

PMID: 22869065

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Project description: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 ?-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.

Project description:Learning and memory deficits characterize the diagnosis of amnestic mild cognitive impairment (aMCI), which is widely viewed as a clinical precursor to Alzheimer's type dementia. There is a growing interest in non-pharmacologic interventions, such as mnemonic strategies, for improving learning and memory in patients with aMCI as well as for maintaining functioning in healthy older adults. Using an ecologically relevant object-location association paradigm, we conducted a randomized, controlled, single-blind study in which healthy older adults and patients with aMCI were randomized to either mnemonic strategy training or a control group that was matched for stimulus exposure. We previously reported that mnemonic strategy training resulted in significantly greater learning and memory improvements compared to the matched exposure condition, in both aMCI patients and healthy controls. The current study examined changes in neocortical activation during encoding in a subset of participants who underwent functional magnetic resonance imaging (fMRI) scanning both before and after training. To minimize potential confounds in between-group comparisons, we employed non-linear cortex based alignment and included only correctly encoded stimuli in our analyses. When re-encoding stimuli learned during training (i.e., trained stimuli), we found a general enhancement of activation in right prefrontal and parietal regions, possibly reflecting practice-related improvement in coordinate spatial processing in all but the aMCI exposure group. Left hemisphere activation was typically only evident in the mnemonic strategy trained participants, regardless of diagnostic status, with the ventrolateral prefrontal cortex appearing especially important for strategy use. While encoding relatively novel stimuli, both mnemonic strategy groups (aMCI patients and healthy controls) demonstrated increased activation in a subset of regions showing change for the trained stimuli, indicating a mnemonic strategy-induced change in the processing of new information. These findings could not be explained by repeated exposure since there was little to no activation overlap in the respective exposure control groups. The current results reinforce the potential benefits of cognitive interventions in these growing populations and indicate that neuroplastic change in key rostral and lateral prefrontal regions mediate this behavioral change.

Project description:BackgroundRecent evidence from cross-sectional and longitudinal studies supports the hypothesis that sarcopenia is associated with worsening cognitive function. However, primary evidence largely comes from high-income countries, whereas in low- and middle-income countries, this association has been underexplored. This study aimed to estimate the longitudinal association between sarcopenia and mild cognitive impairment in a sample of older Mexican adults.MethodsData come from the three waves of the World Health Organization (WHO) Study on Global AGEing and Adult Health (SAGE) in Mexico (2009, 2014, 2017). Four hundred ninety-six older adults, aged ≥50, were included. Sarcopenia was defined as having low muscle quantity and either/both slow gait speed and weak handgrip strength. Mild cognitive impairment was determined based on the recommendations of the National Institute on Aging-Alzheimer's Association. Cognitive function was evaluated by a composite cognitive score of five different cognitive tests: immediate and delayed recall, forward and backward digit span and semantic verbal fluency. Three-level mixed-effects models (logistic and linear) were used to estimate the longitudinal associations between sarcopenia, mild cognitive impairment and cognitive function.ResultsThe prevalence of mild cognitive impairment (8.9%, 12.9%, 16.0%) and sarcopenia (10.5%, 20.7%, 23.3%) showed a significant temporal increase for Waves 1, 2 and 3 (P-value < 0.01, respectively). The presence of sarcopenia was significantly associated with mild cognitive impairment (OR = 1.74; CI95% 1.02, 2.96; P = 0.04) and worse cognitive function (β = -0.57; CI95% -0.93, -0.21; P < 0.01). We observed significant associations between sarcopenia and immediate verbal recall (β = -0.14; CI95% -0.28, -0.01; P = 0.04), delayed verbal recall (β = -0.12; CI95% -0.23, -0.01; P = 0.03) and semantic verbal fluency (β = -0.17; CI95% -0.28, -0.05; P = 0.01). The prevalence of mild cognitive impairment increased at an annual rate of 0.8% for non-sarcopenic older adults, but nearly 1.5% for sarcopenic adults.ConclusionsSignificant longitudinal associations were observed between sarcopenia, mild cognitive impairment and cognitive function among older Mexican adults. Public health strategies, including policy research and clinical interventions, must be implemented in low- and middle-income countries in order to reduce or delay the onset of sarcopenia and thus improve population-level cognitive health among older adults.

Project description:Previous research has shown that there is considerable overlap in the neural networks mediating successful memory encoding and retrieval. However, little is known about how the relevant human brain regions interact during these distinct phases of memory or how such interactions are affected by memory deficits that characterize mild cognitive impairment (MCI), a condition that often precedes dementia due to Alzheimer's disease. Here we employed multivariate Granger causality analysis using autoregressive modeling of inferred neuronal time series obtained by deconvolving the hemodynamic response function from measured blood oxygenation level-dependent (BOLD) time series data, in order to examine the effective connectivity between brain regions during successful encoding and/or retrieval of object location associations in MCI patients and comparable healthy older adults. During encoding, healthy older adults demonstrated a left hemisphere dominant pattern where the inferior frontal junction, anterior intraparietal sulcus (likely involving the parietal eye fields), and posterior cingulate cortex drove activation in most left hemisphere regions and virtually every right hemisphere region tested. These regions are part of a frontoparietal network that mediates top-down cognitive control and is implicated in successful memory formation. In contrast, in the MCI patients, the right frontal eye field drove activation in every left hemisphere region examined, suggesting reliance on more basic visual search processes. Retrieval in the healthy older adults was primarily driven by the right hippocampus with lesser contributions of the right anterior thalamic nuclei and right inferior frontal sulcus, consistent with theoretical models holding the hippocampus as critical for the successful retrieval of memories. The pattern differed in MCI patients, in whom the right inferior frontal junction and right anterior thalamus drove successful memory retrieval, reflecting the characteristic hippocampal dysfunction of these patients. These findings demonstrate that neural network interactions differ markedly between MCI patients and healthy older adults. Future efforts will investigate the impact of cognitive rehabilitation of memory on these connectivity patterns.

Dataset Information

Effects of growth hormone–releasing hormone on cognitive function in adults with mild cognitive impairment and healthy older adults: results of a controlled trial.

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Effects of growth hormone–releasing hormone on cognitive function in adults with mild cognitive impairment and healthy older adults: results of a controlled trial.

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