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PSYCHOGERIATRICS 2013; 13: 170–174
doi:10.1111/psyg.12023
ORIGINAL ARTICLE
Higher serum insulin-like growth factor-1 is associated with better cognitive performance in persons with mild cognitive impairment Dayana CALVO,1 John GUNSTAD,1,2 Lindsay A. MILLER,1 Ellen GLICKMAN1 and Mary Beth SPITZNAGEL1,2
1
Department of Psychology, Kent State University, Kent, 2Summa Health System, Akron City Hospital, Akron, OH, USA Correspondence: Dr Mary Beth Spitznagel PhD, Department of Psychology, Kent State University, Kent, OH 44242, USA. Email: [email protected] Received 16 December 2012; revision received 22 April 2013; accepted 8 May 2013.
Key words: cognitive functioning, insulin-like growth factor, mild cognitive impairment.
Abstract Background: Serum insulin-like growth factor-1 (IGF-1) is a mitogenic peptide involved in the regulation of cell proliferation, differentiation, and apoptosis in a wide variety of cells and tissues. Recent research suggests higher circulating levels of IGF-1 are associated with better cognitive performance in healthy older adults and in early stages of Alzheimer’s disease, although the cognitive profile associated with elevated IGF-1 has not been examined in persons with mild cognitive impairment. Methods: Thirty-one participants (age: 83.71 1 3.59 years; 58% women) with mild cognitive impairment completed neuropsychological testing and 12-hour fasting blood draw to assess serum IGF-1. Results: Partial correlations between serum IGF-1 and neuropsychological measures were conducted, adjusting for insulin, body mass index, and age. Higher IGF-1-values were associated with better global cognition (Modified Mini Mental State Exam: r = 0.39, P = 0.04) and verbal list learning (Hopkins Verbal Learning Test learning: r = 0.38, P = 0.05), Hopkins Verbal Learning Test free recall (r = 0.41, P = 0.03), and Hopkins Verbal Learning Test recognition discriminability (r = 0.46, P = 0.01). A similar trend emerged for executive function as tested by the Frontal Assessment Battery (r = 0.33, P = 0.09). Conclusion: Results suggest higher levels of serum IGF-1 are associated with better cognitive performance in persons with mild cognitive impairment, particularly on tests of learning and memory. These findings suggest IGF-1 may be neuroprotective not only in healthy older adults, but also in adults in the earliest stages of Alzheimer’s disease. Further investigation is needed to clarify the nature of this relationship, particularly prospective studies.
INTRODUCTION Serum insulin-like growth factor-1 (IGF-1) is a mitogenic peptide involved in the regulation of cell proliferation, differentiation, and apoptosis in a wide variety of cells and tissues.1 IGF-1 is actively transported across the blood–brain barrier and is likely produced locally in the brain.2 It plays an important role in nervous system homeostasis, including metabolic, neurotrophic, neuromodulatory, and neuroendocrine actions, and in brain development and stimulation of neuritic growth.3 170
Extensive literature suggests that IGF-1 may have neuroprotective effects.4 Animal and in vitro studies show that IGF-1 enhances neuronal survival and inhibits apoptosis via suppression and stimulation of specific proteins related to these phenomena.1 It also exerts neurotrophic activities in the hippocampus and prefrontal cortex.5 Neural injuries, such as insult due to asphyxia, result in changes in brain IGF-1; administration of IGF-1 immediately after these injuries reduces secondary neuronal loss.4 It has been suggested that the disruption of IGF-1 leads to © 2013 The Authors Psychogeriatrics © 2013 Japanese Psychogeriatric Society
Serum IGF-1 and cognition
amyloid-β accumulation and plaque formation, and enhances tau phosphorylation, in turn increasing neurofibrillary tangles.5 Recent work implicates IGF-1 deficiency in the neurodegenerative process of Alzheimer’s disease.6 Additionally, IGF-1 has been found to oppose the amyloid-β process and hyperphosphorylated tau toxicity,7,8 processes implicated in the development and progression of Alzheimer’s disease. Consistent with these findings, a link between IGF-1 and cognitive decline has been observed on global screening measures over time in large cohorts of older adults.9–11 In studies examining cognitive patterns on neuropsychological testing, reduced cognition is associated with lower IGF-1 in healthy older adults on measures of global cognition as well as within several areas of verbal fluency, attention,12 and executive function, including working memory, selective attention and executive control.13 These studies suggest a robust relationship between IGF-1 and cognition, and that IGF-1 may exert a protective action for cognition in older adults. Despite these clear links between IGF-1, Alzheimer’s disease, and cognition, only a single study has examined the relationship between mild cognitive impairment (MCI) and IGF, noting a relationship between a global cognitive screening measure and lower levels of IGF-1 in men. Specifically, individuals diagnosed with Alzheimer’s disease demonstrated lower IGF-1 levels than those with MCI and healthy controls, although the latter two groups did not differ significantly from each other; the relationship was not detected in women.6 However, a thorough neurocognitive investigation of the role of IGF-1 in the early stages of Alzheimer’s disease (i.e. MCI) has not been conducted. Further research on the involvement of IGF-1 in Alzheimer’s disease and MCI may help identify potentially modifiable risk factors involved in cognitive decline associated with this pathology. Based on past research, we expected that higher levels of IGF-1 would be associated with better cognitive performance in the current study.
METHODS Participants Study participants consisted of 31 English-speaking residents of a structured living facility in north-eastern Ohio, USA that offered assisted and independent living arrangements. All participants included in the © 2013 The Authors Psychogeriatrics © 2013 Japanese Psychogeriatric Society
Table 1 Participant demographic and clinical characteristics Demographic characteristics Age, mean 1 SD (years) Education, mean 1 SD (years) Women Clinical characteristics Body mass index, mean 1 SD Insulin, mean 1 SD (μU/mL) Hypertension Coronary artery bypass graft Myocardial infarction Type 2 diabetes mellitus
83.71 1 3.59 15.70 1 3.34 58.1% 26.80 1 4.97 15.74 1 8.54 41.9% 9.7% 12.9% 6.5%
study had a global Clinical Dementia Rating of 0.5 (questionable dementia or MCI), as determined by an experienced neuropsychologist, and were receiving some level of assistance in activities of daily living. Table 1 shows characteristics of the sample. Prospective participants were excluded if they demonstrated a Clinical Dementia Rating above or below 0.5, were younger than 55 years of age, or could not independently provide informed consent. Measures Participants completed a battery of well-validated measures of global cognition, memory, executive function, attention, and language functions. Modified Mini-Mental State Examination14 This test is a brief screening measure of global cognitive function. It is comprised of several short tasks, including orientation, similarities, animal fluency, learning and brief and delayed recall of a short list of target words, and copy of a simple geometric figure. Trail Making Test A and B15 In Trail Making Test A, participants are asked to connect a series of 25 numbered dots in ascending order as quickly as they can (i.e. 1-2-3 and so on). Trail Making Test B adds a set-shifting component and requires participants to alternate between numbers and letters in ascending order (i.e. 1-A-2-B and so on). Frontal Assessment Battery16 This test employs several short tasks to assess frontal systems functions. More specifically, participants are asked to identify similarities among two words (e.g. automobile, boat), name as many words as they can that start with a target letter (e.g. words that begin 171
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with M), complete frontal-motor hand movements, and tap patterns with their right and left hands. Hopkins Verbal Learning Test-Revised (HVLT-R)17 The HVLT-R requires participants to learn and remember a list of 12 words. Participants are read the list of words and asked to recall as many as they can. After a 20-minute delay during which other tasks are completed, participants are asked to recall as many words from the list as possible. Finally, they are asked to identify the words from a list of targets and foils. Animal naming18 This test is a measure of semantic verbal fluency. Participants are asked to name as many different kinds of animals as they can in 60 seconds. Boston Naming Test19 This test is a measure of confrontation naming and language abilities. Participants are shown pictures and asked to name the depicted item. Item difficulty increases from high-frequency objects (e.g. bed) to lower frequency objects (e.g. trellis). Blood collection and analysis A certified phlebotomist performed all blood draws via venepuncture using serum separator tubes with a Vacutainer needle (BD, Franklin Lakes, NJ, USA). Samples were then centrifuged at 25°C for 15 min and serum allocated into 2 mL Nunc CryoTubes (Thermo Fisher Scientific, Rochester, NY, USA). Serum IGF-1 levels were quantified in an ELISA technique performed at the Cleveland Clinic Reference Laboratory (Cleveland, OH, USA). The quantification was performed with IMMULITE 2000 IGF-1 kits (Siemens, Los Angeles, CA, USA); this kit has a sensitivity of 20 ng/mL. Procedure All participants provided informed consent before beginning any study activity. Participants typically completed the neuropsychological test battery and blood draws on the same day or within one week, if same day completion could not be arranged.
RESULTS Consistent with their diagnosis, this sample of persons with MCI exhibited reduced global cognitive function on testing with an average Modified 172
Mini-Mental State Examination score of 90.10 1 7.03. Partial correlations between serum IGF-1 and neuropsychological measures were conducted, with adjustments for insulin, body mass index, and age because of the known relationships between these variables and cognitive function and/or IGF-1. Higher IGF-1 values were associated with better global cognition (Modified Mini-Mental State Examination: r = 0.39, P = 0.04), verbal list learning (HVLT learning: r = 0.38, P = 0.05), HVLT free recall (r = 0.41, P = 0.03), and HVLT recognition discriminability (r = 0.46, P = 0.01). These values represent medium to large effect sizes. A similar trend emerged for executive function (Frontal Assessment Battery: r = 0.33, P = 0.09). See Table 2 below for correlations between IGF-1 and cognitive tests.
DISCUSSION The current study examined the relationship between serum IGF-1 levels and cognition in individuals with MCI who reside in a structured living facility. Consistent with past work, participants with higher levels of IGF-1 demonstrated better cognitive performance in multiple domains. Several aspects of these findings warrant brief discussion. Results demonstrate that higher IGF-1 levels are associated with better performance on tests of global cognitive functioning, verbal list learning, free recall, and recognition discriminability, with a trend towards better frontal systems index performance in this sample of older adults with MCI. Similar findings (i.e. reduced complex attention and executive function) have been previously found in healthy older adults.13
Table 2 Descriptive statistics and correlations of cognitive tests with IGF-1 levels Cognitive test 3MS HVLT, learn HVLT, recall HVLT, discrimination Trail Making Test A Trail Making Test B Frontal Assessment Battery Animal naming Boston Naming Test
Mean 1 SD
IGF-1 correlation
Pvalue
90.10 1 7.03 19.19 1 5.73 6.00 1 3.22 8.68 1 2.96 50.58 1 26.70 139.93 1 68.28 14.39 1 1.93 17.42 1 6.21 53.52 1 5.85
0.39* 0.38 0.41* 0.46* −0.07 −0.19 0.33 0.22 0.09
0.04* 0.05* 0.03* 0.01** 0.73 0.33 0.09† 0.30 0.67
*P < 0.05. **P < 0.01. †Indicates a trend at the P < 0.10 level. 3MS, Modified Mini-Mental State Examination; HVLT, Hopkins Verbal Learning Test; IGF-1, insulin-like growth factor-1.
© 2013 The Authors Psychogeriatrics © 2013 Japanese Psychogeriatric Society
Serum IGF-1 and cognition
One recent study found a similar link between IGF-1 and cognition across men with Alzheimer’s disease, MCI, and healthy controls,6 although the authors only employed a measure of global cognition rather than a battery examining multiple cognitive domains. The current results extend prior work by demonstrating that the specific cognitive domains positively associated with IGF-1 reflect abilities that are frequently impaired in the early stages of Alzheimer’s disease.20 These findings suggest that within an MCI sample, elevated IGF-1 may prove neuroprotective in the aspects of cognition most affected in early Alzheimer’s disease. Given the possible role of IGF-1 in Alzheimer’s disease, studies involving samples with MCI may be helpful for determining key risk factors in the progression of MCI to Alzheimer’s disease. Pinpointing such risk factors may allow for discovery of methods to improve cognition and possibly deter further cognitive decline. One such method may be physical exercise, which has been shown to both improve cognition in those with MCI as well as raise levels of IGF-1.21,22 The exact mechanism for the relationships between IGF-1 and cognitive domains associated with early cognitive decline in MCI is not entirely clear. One possibility is moderation of homeostasis within the brain; IGF-1 facilitates brain homeostasis, and its disruption may alter cognitive function.23 Evidence of IGF-1 receptors in the hippocampus and prefrontal cortex as well as the increase in hippocampal neurogenesis associated with intracerebroventricular IGF-1 infusion and increased learning via enhancement of excitatory synaptic transmission in the hippocampus may further explain the mechanism by which IGF-1 promotes cognitive performance in individuals with MCI.24–28 The current findings are consistent with prior literature suggesting neurotrophic activities of IGF-1 in the hippocampus and prefrontal cortex.5 Specifically, given the role of the hippocampus in learning and memory,29 it is not surprising that IGF-1 was robustly related to HVLT learning and memory performance. Similarly, in light of the involvement of the prefrontal cortex in executive and frontal systems functioning,29 the trend towards a significant relationship between IGF-1 and frontal systems performance on the FAB might also be expected. Prospective studies examining the association between IGF-1 and cognitive function are much needed, particularly studies that follow persons from © 2013 The Authors Psychogeriatrics © 2013 Japanese Psychogeriatric Society
at-risk status to MCI to Alzheimer’s disease. Such studies may facilitate early detection in the future and possibly lay the foundation for a preventive approach to pathological cognitive ageing. The current findings are limited in several ways. The sample size for this study was small, and future studies with larger and more diverse samples are needed. Also, although the Frontal Assessment Battery demonstrated a trend towards significance, other indices of frontal systems functioning (e.g. Trail Making Test B) did not. The current sample was large enough to capture the medium to large effect sizes for the relationship between IGF-1 and memory indices, possibly because memory indices show greater impairment relative to other cognitive domains in early stages of Alzheimer’s disease.29 However, it may be that in this earliest stage of cognitive decline, prior to significant decline of executive function,30 effect sizes for the relationship between IGF-1 and frontal systems functioning are more modest. As such, we recommend that future research utilizing indices of frontal systems functioning in the examination of IGF-1 levels anticipate small effect sizes in MCI or employ a sample that shows further clinical progression. However, the robust correlations between IGF-1 levels and several aspects of cognitive performance suggest that these effects reflect a meaningful relationship that will likely generalize across studies, particularly for indices of memory and learning. Another limitation is that we examined a single assay of IGF. Future research should consider assessment of growth hormone-releasing hormone, the overarching hormone that mediates IGF-1, which also decreases in the ageing process. Growth hormone-releasing hormone has been linked to cognitive decline, specifically in age-related declines of spatial memory.23 It may also be of benefit to consider the neurocognitive profile associated with IGF binding protein 3, which regulates the bioavailability of IGF.6,31 Prior work links IGF binding protein 3 to diabetes, cognitive decline, and lack of overall health; these biomarkers in combination may better account for cognitive function than IGF-1 alone. Finally, given past research demonstrating that exercise can increase IGF-1,22 as well as potentially improve cognitive function in MCI,21 future studies should consider examining the connection between cognitive function and IGF following exercise. In brief summary, the current study found that IGF-1 levels are positively associated with several 173
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domains of cognitive performance, particularly learning and memory, in older adults with MCI. These findings suggest that IGF-1 may have a neuroprotective effect on the cognitive domains that typically show the greatest impact of the early stages of pathological cognitive decline in Alzheimer’s disease, although prospective studies are needed to clarify this possibility.
ACKNOWLEDGMENTS Data collection was supported by the Extendicare Foundation (Milwaukee, WI, USA). Work was completed at Kent State University (Kent, OH, USA) and Summa Health System (Akron, OH, USA). The authors have no conflicts of interest to report.
REFERENCES 1 Yu H, Rohan T. Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst 2000; 92: 1472–1489. 2 Pan W, Nyberg F, Kastin AJ. Interactions of growth hormone, insulin-like growth factor-1 and ghrelin with the blood-brain barrier. Open Endocrinol J 2012; 6: 22–26. 3 Watanabe T, Miyazaki A, Katagiri T, Yamamoto H, Idei T, Iguchi T. Relationship between serum like insulin-growth factor-1 levels and Alzheimer’s disease and vascular dementia. J Am Geriatr Soc 2005; 53: 1748–1753. 4 Gluckman J, Guan C, Williams A et al. Asphyxial brain injury – the role of the IGF system. Mol Cell Endocrinol 1998; 140: 95–99. 5 Vardy E, Rice PJ, Bowie P, Holmes JD, Grant PJ, Hooper NM. Increased circulating insulin-like growth factor-1 in lateonset Alzheimer’s disease. J Alzheimers Dis 2007; 12: 285– 290. 6 Duron E, Funalot B, Brunel N et al. Insulin-like growth factor-i and insulin-like growth factor binding protein-3 in Alzheimer’s disease. J Clin Endocrinol Metab 2012; 97: 4673–4681. doi: 10.1210/jc.2012-2063. 7 Caro E, Trejo JL, Gomez-Isla T, LeRoith D, Torres-Aleman I. Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nat Med 2002; 8: 1390–1397. 8 Hong M, Lee VM. Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons. J Biol Chem 1997; 272: 19547–19543. 9 Dik MG, Pluijm SM, Jonker C, Deeg DJ, Lomecky MZ, Lips P. Insulin-like growth factor I (IGF-I) and cognitive decline in older persons. Neurobiol Aging 2003; 24: 573–581. 10 Kalmijn S, Janssen JA, Pols HA, Lamberts SW, Breteler MM. A prospective study on circulating insulin-like growth factor I (IGFI), IGF-binding proteins, and cognitive function in the elderly. J Clin Endocrinol Metab 2000; 85: 4551–4555. 11 Aleman A, Verhaar HJ, De Haan EH et al. Insulin-like growth factor-i and cognitive function in healthy older men. J Clin Endocrinol Metab 1999; 84: 471–475.
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12 Wael KA, Muhlen D, Barrett-Connor E. IGF-1 and IGFBP-1 and cognitive function in older men and women. J Am Geriatr Soc 2009; 57: 1441–1446. 13 Bellar D, Glickman E, Juvancic-Heltzel J, Gunstad J. Serum insulin like growth factor-1 is associated with working memory, executive function and selective attention in a sample of healthy, fit older adults. Neuroscience 2011; 178: 133–137. 14 Teng E, Chui H. The modified mini-mental (3MS) examination. J Clin Psychiatry 1987; 48: 314–318. 15 Reitan R. Validity of the Trail Making Test as an indicator of organic brain damage. Percept Mot Skills 1958; 8: 271–276. 16 Dubois B, Slacheysky A, Livan I, Pillon B. The FAB: a frontal assessment battery at bedside. Neurology 2000; 55: 1621– 1626. 17 Brandt J. The Hopkins Verbal Learning Test: development of a new memory test with six equivalent forms. Clin Neuropsychol 1991; 5: 125–142. 18 Eslinger P, Damasio A, Benton A. The Iowa Screening Battery for Mental Decline. Iowa City, IA: University of Iowa, 1984. 19 Kaplan E, Goodglass H, Weintraub S. The Boston Naming Test. Philadelphia, PA: Lea and Febiger, 1983. 20 Lambon RM, Patterson K, Graham N, Dawson K, Hodges JR. Homogeneity and heterogeneity in mild cognitive impairment and Alzheimer’s disease: A cross-sectional and longitudinal study of 55 cases. Brain 2003; 126: 2350–2362. 21 Sofi F, Valecchi D, Bacci D et al. Physical activity and risk of cognitive decline: a meta-analysis of prospective studies. J Intern Med 2011; 269: 107–117. 22 Rojas Vega S, Knicker A, Hollman W, Bloch W, Struder HK. Effect of resistance exercise on serum levels of growth factors in humans. Horm Metab Res 2010; 42: 982–986. 23 Aleman A, Torres-Aleman I. Circulating insulin-like growth factor I and cognitive function: Neuromodulation throughout the lifespan. Prog Neurobiol 2009; 89: 256–265. 24 van Dam PS, Aleman A. Insulin-like growth factor-I, cognition and brain aging. Eur J Pharmacol 2004; 490: 87–95. 25 Lichtenwalner RJ, Forbes ME, Bennett SA, Lynch CD, Sonntag WE, Riddle DR. Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience 2001; 107: 603–613. 26 Harada N, Narimatsu N, Kurihara H, Nakagata N, Okajima K. Stimulation of sensory neurons improves cognitive function by promoting the hippocampal production of insulin-like growth factor-I in mice. Transl Res 2009; 154: 90–102. 27 Ramsey MM, Adams MM, Ariwodola OJ, Sonntag WE. Functional characterization of des-IGF-1 action at excitatory synapses in the CA1 region of rat hippocampus. J Neurophysiol 2005; 94: 247–254. 28 Aberg MA, Aberg ND, Hedbacker H, Oscarsson J, Eriksson PS. Peripheral infusion of IGF-1 selectivity induces neurogenesis in the adult rat hippocampus. J Neurosci 2000; 20: 2896–2903. 29 Lezak MD, Howieson DB, Loring DW. Neuropsychological Assessment, 4th edn. New York: Oxford University Press, 2004. 30 Perry RJ, Watson P, Hodges JR. The nature and staging of attention dysfunction in early (minimal and mild) Alzheimer’s disease: relationship to episodic and semantic memory impairment. Neuropsychologia 2000; 38: 252–271. 31 Paolisso G, Ammendola S, Del Buono A et al. Serum levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 in healthy centenarians: relationship with plasma leptin and lipid concentrations, insulin action, and cognitive function. J Clin Endocrinol Metab 1997; 82: 2204–2209.
© 2013 The Authors Psychogeriatrics © 2013 Japanese Psychogeriatric Society
PSYCHOGERIATRICS 2013; 13: 170–174
doi:10.1111/psyg.12023
ORIGINAL ARTICLE
Higher serum insulin-like growth factor-1 is associated with better cognitive performance in persons with mild cognitive impairment Dayana CALVO,1 John GUNSTAD,1,2 Lindsay A. MILLER,1 Ellen GLICKMAN1 and Mary Beth SPITZNAGEL1,2
1
Department of Psychology, Kent State University, Kent, 2Summa Health System, Akron City Hospital, Akron, OH, USA Correspondence: Dr Mary Beth Spitznagel PhD, Department of Psychology, Kent State University, Kent, OH 44242, USA. Email: [email protected] Received 16 December 2012; revision received 22 April 2013; accepted 8 May 2013.
Key words: cognitive functioning, insulin-like growth factor, mild cognitive impairment.
Abstract Background: Serum insulin-like growth factor-1 (IGF-1) is a mitogenic peptide involved in the regulation of cell proliferation, differentiation, and apoptosis in a wide variety of cells and tissues. Recent research suggests higher circulating levels of IGF-1 are associated with better cognitive performance in healthy older adults and in early stages of Alzheimer’s disease, although the cognitive profile associated with elevated IGF-1 has not been examined in persons with mild cognitive impairment. Methods: Thirty-one participants (age: 83.71 1 3.59 years; 58% women) with mild cognitive impairment completed neuropsychological testing and 12-hour fasting blood draw to assess serum IGF-1. Results: Partial correlations between serum IGF-1 and neuropsychological measures were conducted, adjusting for insulin, body mass index, and age. Higher IGF-1-values were associated with better global cognition (Modified Mini Mental State Exam: r = 0.39, P = 0.04) and verbal list learning (Hopkins Verbal Learning Test learning: r = 0.38, P = 0.05), Hopkins Verbal Learning Test free recall (r = 0.41, P = 0.03), and Hopkins Verbal Learning Test recognition discriminability (r = 0.46, P = 0.01). A similar trend emerged for executive function as tested by the Frontal Assessment Battery (r = 0.33, P = 0.09). Conclusion: Results suggest higher levels of serum IGF-1 are associated with better cognitive performance in persons with mild cognitive impairment, particularly on tests of learning and memory. These findings suggest IGF-1 may be neuroprotective not only in healthy older adults, but also in adults in the earliest stages of Alzheimer’s disease. Further investigation is needed to clarify the nature of this relationship, particularly prospective studies.
INTRODUCTION Serum insulin-like growth factor-1 (IGF-1) is a mitogenic peptide involved in the regulation of cell proliferation, differentiation, and apoptosis in a wide variety of cells and tissues.1 IGF-1 is actively transported across the blood–brain barrier and is likely produced locally in the brain.2 It plays an important role in nervous system homeostasis, including metabolic, neurotrophic, neuromodulatory, and neuroendocrine actions, and in brain development and stimulation of neuritic growth.3 170
Extensive literature suggests that IGF-1 may have neuroprotective effects.4 Animal and in vitro studies show that IGF-1 enhances neuronal survival and inhibits apoptosis via suppression and stimulation of specific proteins related to these phenomena.1 It also exerts neurotrophic activities in the hippocampus and prefrontal cortex.5 Neural injuries, such as insult due to asphyxia, result in changes in brain IGF-1; administration of IGF-1 immediately after these injuries reduces secondary neuronal loss.4 It has been suggested that the disruption of IGF-1 leads to © 2013 The Authors Psychogeriatrics © 2013 Japanese Psychogeriatric Society
Serum IGF-1 and cognition
amyloid-β accumulation and plaque formation, and enhances tau phosphorylation, in turn increasing neurofibrillary tangles.5 Recent work implicates IGF-1 deficiency in the neurodegenerative process of Alzheimer’s disease.6 Additionally, IGF-1 has been found to oppose the amyloid-β process and hyperphosphorylated tau toxicity,7,8 processes implicated in the development and progression of Alzheimer’s disease. Consistent with these findings, a link between IGF-1 and cognitive decline has been observed on global screening measures over time in large cohorts of older adults.9–11 In studies examining cognitive patterns on neuropsychological testing, reduced cognition is associated with lower IGF-1 in healthy older adults on measures of global cognition as well as within several areas of verbal fluency, attention,12 and executive function, including working memory, selective attention and executive control.13 These studies suggest a robust relationship between IGF-1 and cognition, and that IGF-1 may exert a protective action for cognition in older adults. Despite these clear links between IGF-1, Alzheimer’s disease, and cognition, only a single study has examined the relationship between mild cognitive impairment (MCI) and IGF, noting a relationship between a global cognitive screening measure and lower levels of IGF-1 in men. Specifically, individuals diagnosed with Alzheimer’s disease demonstrated lower IGF-1 levels than those with MCI and healthy controls, although the latter two groups did not differ significantly from each other; the relationship was not detected in women.6 However, a thorough neurocognitive investigation of the role of IGF-1 in the early stages of Alzheimer’s disease (i.e. MCI) has not been conducted. Further research on the involvement of IGF-1 in Alzheimer’s disease and MCI may help identify potentially modifiable risk factors involved in cognitive decline associated with this pathology. Based on past research, we expected that higher levels of IGF-1 would be associated with better cognitive performance in the current study.
METHODS Participants Study participants consisted of 31 English-speaking residents of a structured living facility in north-eastern Ohio, USA that offered assisted and independent living arrangements. All participants included in the © 2013 The Authors Psychogeriatrics © 2013 Japanese Psychogeriatric Society
Table 1 Participant demographic and clinical characteristics Demographic characteristics Age, mean 1 SD (years) Education, mean 1 SD (years) Women Clinical characteristics Body mass index, mean 1 SD Insulin, mean 1 SD (μU/mL) Hypertension Coronary artery bypass graft Myocardial infarction Type 2 diabetes mellitus
83.71 1 3.59 15.70 1 3.34 58.1% 26.80 1 4.97 15.74 1 8.54 41.9% 9.7% 12.9% 6.5%
study had a global Clinical Dementia Rating of 0.5 (questionable dementia or MCI), as determined by an experienced neuropsychologist, and were receiving some level of assistance in activities of daily living. Table 1 shows characteristics of the sample. Prospective participants were excluded if they demonstrated a Clinical Dementia Rating above or below 0.5, were younger than 55 years of age, or could not independently provide informed consent. Measures Participants completed a battery of well-validated measures of global cognition, memory, executive function, attention, and language functions. Modified Mini-Mental State Examination14 This test is a brief screening measure of global cognitive function. It is comprised of several short tasks, including orientation, similarities, animal fluency, learning and brief and delayed recall of a short list of target words, and copy of a simple geometric figure. Trail Making Test A and B15 In Trail Making Test A, participants are asked to connect a series of 25 numbered dots in ascending order as quickly as they can (i.e. 1-2-3 and so on). Trail Making Test B adds a set-shifting component and requires participants to alternate between numbers and letters in ascending order (i.e. 1-A-2-B and so on). Frontal Assessment Battery16 This test employs several short tasks to assess frontal systems functions. More specifically, participants are asked to identify similarities among two words (e.g. automobile, boat), name as many words as they can that start with a target letter (e.g. words that begin 171
D. Calvo et al.
with M), complete frontal-motor hand movements, and tap patterns with their right and left hands. Hopkins Verbal Learning Test-Revised (HVLT-R)17 The HVLT-R requires participants to learn and remember a list of 12 words. Participants are read the list of words and asked to recall as many as they can. After a 20-minute delay during which other tasks are completed, participants are asked to recall as many words from the list as possible. Finally, they are asked to identify the words from a list of targets and foils. Animal naming18 This test is a measure of semantic verbal fluency. Participants are asked to name as many different kinds of animals as they can in 60 seconds. Boston Naming Test19 This test is a measure of confrontation naming and language abilities. Participants are shown pictures and asked to name the depicted item. Item difficulty increases from high-frequency objects (e.g. bed) to lower frequency objects (e.g. trellis). Blood collection and analysis A certified phlebotomist performed all blood draws via venepuncture using serum separator tubes with a Vacutainer needle (BD, Franklin Lakes, NJ, USA). Samples were then centrifuged at 25°C for 15 min and serum allocated into 2 mL Nunc CryoTubes (Thermo Fisher Scientific, Rochester, NY, USA). Serum IGF-1 levels were quantified in an ELISA technique performed at the Cleveland Clinic Reference Laboratory (Cleveland, OH, USA). The quantification was performed with IMMULITE 2000 IGF-1 kits (Siemens, Los Angeles, CA, USA); this kit has a sensitivity of 20 ng/mL. Procedure All participants provided informed consent before beginning any study activity. Participants typically completed the neuropsychological test battery and blood draws on the same day or within one week, if same day completion could not be arranged.
RESULTS Consistent with their diagnosis, this sample of persons with MCI exhibited reduced global cognitive function on testing with an average Modified 172
Mini-Mental State Examination score of 90.10 1 7.03. Partial correlations between serum IGF-1 and neuropsychological measures were conducted, with adjustments for insulin, body mass index, and age because of the known relationships between these variables and cognitive function and/or IGF-1. Higher IGF-1 values were associated with better global cognition (Modified Mini-Mental State Examination: r = 0.39, P = 0.04), verbal list learning (HVLT learning: r = 0.38, P = 0.05), HVLT free recall (r = 0.41, P = 0.03), and HVLT recognition discriminability (r = 0.46, P = 0.01). These values represent medium to large effect sizes. A similar trend emerged for executive function (Frontal Assessment Battery: r = 0.33, P = 0.09). See Table 2 below for correlations between IGF-1 and cognitive tests.
DISCUSSION The current study examined the relationship between serum IGF-1 levels and cognition in individuals with MCI who reside in a structured living facility. Consistent with past work, participants with higher levels of IGF-1 demonstrated better cognitive performance in multiple domains. Several aspects of these findings warrant brief discussion. Results demonstrate that higher IGF-1 levels are associated with better performance on tests of global cognitive functioning, verbal list learning, free recall, and recognition discriminability, with a trend towards better frontal systems index performance in this sample of older adults with MCI. Similar findings (i.e. reduced complex attention and executive function) have been previously found in healthy older adults.13
Table 2 Descriptive statistics and correlations of cognitive tests with IGF-1 levels Cognitive test 3MS HVLT, learn HVLT, recall HVLT, discrimination Trail Making Test A Trail Making Test B Frontal Assessment Battery Animal naming Boston Naming Test
Mean 1 SD
IGF-1 correlation
Pvalue
90.10 1 7.03 19.19 1 5.73 6.00 1 3.22 8.68 1 2.96 50.58 1 26.70 139.93 1 68.28 14.39 1 1.93 17.42 1 6.21 53.52 1 5.85
0.39* 0.38 0.41* 0.46* −0.07 −0.19 0.33 0.22 0.09
0.04* 0.05* 0.03* 0.01** 0.73 0.33 0.09† 0.30 0.67
*P < 0.05. **P < 0.01. †Indicates a trend at the P < 0.10 level. 3MS, Modified Mini-Mental State Examination; HVLT, Hopkins Verbal Learning Test; IGF-1, insulin-like growth factor-1.
© 2013 The Authors Psychogeriatrics © 2013 Japanese Psychogeriatric Society
Serum IGF-1 and cognition
One recent study found a similar link between IGF-1 and cognition across men with Alzheimer’s disease, MCI, and healthy controls,6 although the authors only employed a measure of global cognition rather than a battery examining multiple cognitive domains. The current results extend prior work by demonstrating that the specific cognitive domains positively associated with IGF-1 reflect abilities that are frequently impaired in the early stages of Alzheimer’s disease.20 These findings suggest that within an MCI sample, elevated IGF-1 may prove neuroprotective in the aspects of cognition most affected in early Alzheimer’s disease. Given the possible role of IGF-1 in Alzheimer’s disease, studies involving samples with MCI may be helpful for determining key risk factors in the progression of MCI to Alzheimer’s disease. Pinpointing such risk factors may allow for discovery of methods to improve cognition and possibly deter further cognitive decline. One such method may be physical exercise, which has been shown to both improve cognition in those with MCI as well as raise levels of IGF-1.21,22 The exact mechanism for the relationships between IGF-1 and cognitive domains associated with early cognitive decline in MCI is not entirely clear. One possibility is moderation of homeostasis within the brain; IGF-1 facilitates brain homeostasis, and its disruption may alter cognitive function.23 Evidence of IGF-1 receptors in the hippocampus and prefrontal cortex as well as the increase in hippocampal neurogenesis associated with intracerebroventricular IGF-1 infusion and increased learning via enhancement of excitatory synaptic transmission in the hippocampus may further explain the mechanism by which IGF-1 promotes cognitive performance in individuals with MCI.24–28 The current findings are consistent with prior literature suggesting neurotrophic activities of IGF-1 in the hippocampus and prefrontal cortex.5 Specifically, given the role of the hippocampus in learning and memory,29 it is not surprising that IGF-1 was robustly related to HVLT learning and memory performance. Similarly, in light of the involvement of the prefrontal cortex in executive and frontal systems functioning,29 the trend towards a significant relationship between IGF-1 and frontal systems performance on the FAB might also be expected. Prospective studies examining the association between IGF-1 and cognitive function are much needed, particularly studies that follow persons from © 2013 The Authors Psychogeriatrics © 2013 Japanese Psychogeriatric Society
at-risk status to MCI to Alzheimer’s disease. Such studies may facilitate early detection in the future and possibly lay the foundation for a preventive approach to pathological cognitive ageing. The current findings are limited in several ways. The sample size for this study was small, and future studies with larger and more diverse samples are needed. Also, although the Frontal Assessment Battery demonstrated a trend towards significance, other indices of frontal systems functioning (e.g. Trail Making Test B) did not. The current sample was large enough to capture the medium to large effect sizes for the relationship between IGF-1 and memory indices, possibly because memory indices show greater impairment relative to other cognitive domains in early stages of Alzheimer’s disease.29 However, it may be that in this earliest stage of cognitive decline, prior to significant decline of executive function,30 effect sizes for the relationship between IGF-1 and frontal systems functioning are more modest. As such, we recommend that future research utilizing indices of frontal systems functioning in the examination of IGF-1 levels anticipate small effect sizes in MCI or employ a sample that shows further clinical progression. However, the robust correlations between IGF-1 levels and several aspects of cognitive performance suggest that these effects reflect a meaningful relationship that will likely generalize across studies, particularly for indices of memory and learning. Another limitation is that we examined a single assay of IGF. Future research should consider assessment of growth hormone-releasing hormone, the overarching hormone that mediates IGF-1, which also decreases in the ageing process. Growth hormone-releasing hormone has been linked to cognitive decline, specifically in age-related declines of spatial memory.23 It may also be of benefit to consider the neurocognitive profile associated with IGF binding protein 3, which regulates the bioavailability of IGF.6,31 Prior work links IGF binding protein 3 to diabetes, cognitive decline, and lack of overall health; these biomarkers in combination may better account for cognitive function than IGF-1 alone. Finally, given past research demonstrating that exercise can increase IGF-1,22 as well as potentially improve cognitive function in MCI,21 future studies should consider examining the connection between cognitive function and IGF following exercise. In brief summary, the current study found that IGF-1 levels are positively associated with several 173
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domains of cognitive performance, particularly learning and memory, in older adults with MCI. These findings suggest that IGF-1 may have a neuroprotective effect on the cognitive domains that typically show the greatest impact of the early stages of pathological cognitive decline in Alzheimer’s disease, although prospective studies are needed to clarify this possibility.
ACKNOWLEDGMENTS Data collection was supported by the Extendicare Foundation (Milwaukee, WI, USA). Work was completed at Kent State University (Kent, OH, USA) and Summa Health System (Akron, OH, USA). The authors have no conflicts of interest to report.
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