Dement Geriatr Cogn Disord 2015;39:251–256 DOI: 10.1159/000371510 Accepted: December 9, 2014 Published online: January 31, 2015
© 2015 S. Karger AG, Basel 1420–8008/15/0396–0251$39.50/0 www.karger.com/dem
Original Research Article
Plasma Insulin-Like Growth Factor 1 Is Associated with Cognitive Impairment in Parkinson’s Disease Jianfang Ma Qianwen Jiang Jing Xu Qian Sun Yuan Qiao Wei Chen Yiwen Wu Ying Wang Qin Xiao Jun Liu Huidong Tang Shengdi Chen Department of Neurology and Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
Key Words Insulin-like growth factor 1 · Cognitive function · Parkinson’s disease · Essential tremor Abstract Objective: The aim of this study was to test plasma insulin-like growth factor 1 (IGF-1) change in Parkinson’s disease (PD) and essential tremor (ET), and assess the association of plasma IGF1 level with motor and nonmotor symptoms in PD and ET. Methods: Plasma IGF-1 was measured in 100 PD patients, 40 ET patients, and 76 healthy controls. Motor and nonmotor symptoms were assessed by different scales. Spearman correlation test and linear logistic model were used to analyze the correlation of plasma IGF-1 with motor and nonmotor symptoms of PD and ET. Results: The plasma IGF-1 level was significantly increased in PD compared to healthy controls and ET patients. In addition, low plasma IGF-1 was correlated with low MiniMental State Examination (MMSE) scores in PD patients. However, no correlation was found between plasma IGF-1 and MMSE scores in ET patients. Conclusion: Plasma IGF-1 increased significantly in PD but remained unchanged in ET. A low plasma IGF-1 level was associated © 2015 S. Karger AG, Basel with poor cognitive performance in PD but not in ET patients.
Introduction
Shengdi Chen Department of Neurology and Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine Shanghai 200025 (PR China) E-Mail chen_sd @ medmail.com.cn
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Insulin-like growth factor 1 (IGF-1) is a neurotrophic factor exerting a protective role in neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) [1–3]. The elevation of plasma IGF-1 in neurodegenerative diseases was considered a compensation mechanism to protect neurons from degeneration [2]. In addition, IGF-1 was also
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Dement Geriatr Cogn Disord 2015;39:251–256 DOI: 10.1159/000371510
© 2015 S. Karger AG, Basel
Ma et al.: Plasma Insulin-Like Growth Factor 1 Is Associated with Cognitive Impairment in Parkinson’s Disease
found associated with the risk of cognitive decline in PD and Huntington’s disease (HD) [4, 5]. These data demonstrated an important role of IGF-1 in the pathogenesis of PD and related cognitive dysfunctions. Apart from the association of cognitive dysfunction, however, the relationship of plasma IGF-1 with other nonmotor symptoms of PD has never been examined. The mechanism of nonmotor symptoms in PD remained largely unknown, involving different neurotransmitter dysfunctions and more diffuse neurodegeneration. Therefore, it will be helpful to examine the change of IGF-1 in other nonmotor symptoms to further reveal the function of IGF-1 in PD. Essential tremor (ET) is a neurological disease characterized by bilateral postural tremor, which shares some similarity with PD symptoms. Recently, some studies demonstrated that cognitive impairment was not uncommon in ET patients, indicating that ET may be a slowly progressive neurodegenerative disease [6–8]. IGF-1 was increased in several neurodegenerative diseases, such as PD, AD, and HD. However, the relationship of plasma IGF-1 and ET has never been examined. In addition, it is not known whether IGF-1 is also associated with cognitive dysfunction in ET. Answering these two questions will further contribute to our understanding of the role of IGF-1 in neurodegenerative disorders. In the present study, we investigated plasma IGF-1 in PD, ET, and healthy people to study (1) the change of plasma IGF-1 in PD and ET, and (2) whether IGF-1 is associated with motor and nonmotor symptoms of PD and ET. Materials and Methods Study Population Our study population was recruited from two samples: (1) outpatient clinics of the Neurology Department of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine (from January 28, 2013 to September 30, 2013), and (2) an epidemiological study targeted on people ≥50 years old in the Malu suburb of Shanghai, China (from October 9, 2012 to October 18, 2013). All PD patients from the outpatient clinic and epidemiological samples, and all ET patients from the epidemiological study were recruited if they met the enrollment criteria and were willing to participate in our study. Healthy controls who were willing to participate in our study were randomly selected from the epidemiological sample. PD and ET patients were diagnosed by movement disorder specialists from the Neurology Department of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine. Diagnosis of PD was based on United Kingdom PD Society Brain Bank Diagnostic Criteria, excluding secondary causes or other parkinsonism-related diseases. Diagnosis of ET was based on the consensus statement of the Movement Disorder Society on Tremor, excluding other causes of tremor. Demographic information, PD and ET features (age of onset, duration, motor and nonmotor function), concurrent diseases, and medications were recorded. The total equivalent levodopa dosage was calculated for each patient with PD medications. After considering the confounding factors for IGF-1 (body mass index >30, diabetes, cancer, thyroid and pituitary diseases, medications including β-blocker, corticosteroid, neuroleptic drugs, hormone replacement), 13 idiopathic PD patients were excluded from our study. Finally, 100 idiopathic PD patients, 40 ET patients, and 76 healthy controls were enrolled in our study. All recruited people were informed of our study and asked to sign the consent forms. Approval for this study was obtained from the Ethics Committee of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine.
Assessment of Motor and Nonmotor Function of PD and ET Patients All PD patients were assessed in their ‘on’ state by the Unified Parkinson’s Disease Rating Scale part III (UPDRS-III) and Hoehn-Yahr Staging Scale (H-Y) for motor function. Nonmotor symptoms of all PD and ET
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Plasma Sampling and Measurement Overnight fasting blood samples were collected from all participants, immediately centrifuged, and stored at –70 ° C until analysis. The plasma IGF-1 levels were quantified by an IGF-1 enzyme-linked immunosorbent assay kit (BE504112, RB Corporation).
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Dement Geriatr Cogn Disord 2015;39:251–256 DOI: 10.1159/000371510
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Ma et al.: Plasma Insulin-Like Growth Factor 1 Is Associated with Cognitive Impairment in Parkinson’s Disease
Table 1. Demographic features and plasma IGF-1 of PD and ET patients and healthy controls
PD Patients Age, years Sex Male Female IGF-1, ng/l 1
100 67.84 ± 9.89 67 (67.0) 33 (33.0) 183.50 ± 38.611, 3
ET
Healthy controls
40 70.85 ± 11.39
76 67.75 ± 8.55
24 (60.0) 16 (40.0) 158.38 ± 32.472, 3
45 (59.2) 31 (40.8) 154.91 ± 36.09
p value 0.203a 0.520b 0.000a
Values are given as mean ± SD or n (%). a ANOVA test; b χ2 test; multiple comparison (Bonferroni). p = 0.000 between PD and controls; 2 p = 1.000 between ET and controls; 3 p = 0.001 between ET and PD.
patients were assessed by the Non-Motor Symptoms Questionnaire (NMSQ), Mini-Mental State Examination (MMSE), Scales for Outcomes in Parkinson’s Disease – Autonomic (SCOPA-AUT), Hamilton Depression Rating Scale, and Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire (RBDSQ). All scales used in this study had been validated in Chinese PD patients [9, 10]. Statistical Analysis Statistical analysis was performed using SPSS 19.0. Demographic data were compared among the three groups by the ANOVA and χ2 tests. Plasma IGF-1 was compared among the three groups by the ANOVA test, and multiple comparison analysis was performed by the Bonferroni test. The Spearman correlation test and linear logistic regression model were used to analyze the correlation between plasma IGF-1 level and disease duration, motor and nonmotor variables, educational background, and equivalent levodopa dosage in PD and ET patients. All tests were 2-tailed, and the results were considered statistically significant at p < 0.05.
Demographic features were comparable among PD, ET, and healthy control groups (table 1). Plasma IGF-1 was significantly increased in PD patients (183.50 ± 38.61 ng/l) compared to healthy controls (154.91 ± 36.09 ng/l, p = 0.000) and ET patients (158.38 ± 32.47 ng/l, p = 0.001) (table 1; fig. 1). However, no difference of plasma IGF-1 level was found between ET and controls (p = 1.000). Among the PD group, 23 patients were drug naïve and 77 were on antiparkinson medications. PD medications included levodopa/benseraside or carbidopa, dopamine agonists, amantadine, and trihexyphenidyl. There was no difference between drug-naïve and medication-treated PD patients in terms of demographic features and plasma IGF-1 level (table 2). Further Spearman correlation analysis did not found any association between plasma IGF-1 level and duration [Spearman’s rank correlation coefficient (r) = 0.075, p = 0.460], or levodopa equivalent dosage (r = –0.045, p = 0.658). In PD patients, plasma IGF-1 was positively correlated with MMSE scores (r = 0.222, p = 0.026). Further linear logistic regression also showed that plasma IGF-1 was correlated with MMSE scores (p = 0.001; fig. 1). However, no correlation was found between plasma IGF-1 and UPDRS-III scores (r = 0.094, p = 0.354), H-Y stage (r = 0.067, p = 0.510), SCOPA-AUT (r = 0.129, p = 0.201), Hamilton depression scores (r = 0.144, p = 0.153), NMSQ scores (r = 0.112, p = 0.266), and RBDSQ scores (r = 0.063, p = 0.535). In ET patients, no correlation was found between plasma IGF-1 and MMSE scores (r = 0.264, p = 0.145), SCOPA-AUT (r = –0.036, p = 0.847), Hamilton depression scores (r = –0.009, p = 0.959), NMSQ scores (r = –0.209, p = 0.196), RBDSQ scores (r = –0.077, p = 0.675), and disease duration (r = 0.231, p = 0.195).
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Results
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Dement Geriatr Cogn Disord 2015;39:251–256 © 2015 S. Karger AG, Basel
DOI: 10.1159/000371510
Ma et al.: Plasma Insulin-Like Growth Factor 1 Is Associated with Cognitive Impairment in Parkinson’s Disease
200
*
IGF-1 (ng/l)
150 100 50 0 Control
a
PD Group
ET
400
IGF-1 (ng/l)
300 200 100
Table 2. Demographic features and plasma IGF-1 of drug-naïve and medication-treated PD patients
0
b
40
30
20 MMSE score
Drug naïve Patients Age, years Sex Male Female Age of onset, years LED, mg Duration, years UPDRS-III H-Y MMSE NMSQ SCOPA-AUT Hamilton RBDSQ IGF-1, ng/l
10
Medication treated
23 67.84 ± 9.89
77 70.85 ± 11.39
23 (56.5) 10 (43.5) 66.87 ± 11.12 – 2.34 ± 1.75 13.30 ± 8.97 1.30 ± 0.45 26.00 ± 5.31 4.22 ± 2.59 7.70 ± 4.41 4.61 ± 2.82 2.00 ± 2.17 185.64 ± 11.58
54 (70.1) 23 (29.9) 62.39 ± 9.06 274.76 ± 253.44 5.04 ± 4.21 20.47 ± 12.15 1.78 ± 0.76 25.75 ± 5.21 7.54 ± 5.05 11.01 ± 7.40 5.77 ± 4.29 3.10 ± 2.73 182.86 ± 37.90
0
p value 0.449a 0.312b
0.764a
Values are given as mean ± SD or n (%). LED = Levodopa dosage. a ANOVA test; b χ2 test.
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Fig. 1. a Plasma IGF-1 change among the 3 groups. b Correlation of plasma IGF-1 with MMSE scores in PD.
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Ma et al.: Plasma Insulin-Like Growth Factor 1 Is Associated with Cognitive Impairment in Parkinson’s Disease
Several studies have already reported that plasma IGF-1 was increased in PD [1, 4]. Our study confirmed the elevation of plasma IGF-1 in Chinese PD patients. Most studies suggested that IGF-1 increases as a compensation to protect neurodegeneration of dopaminergic neurons. This hypothesis was supported by animal model studies which showed that IGF-1 supplement prevented the loss of dopaminergic neurons [11]. In an AD model, IGF-1 also showed a protective effect on hippocampus degeneration [12], further supporting the protective role of IGF-1 in neurodegenerative diseases. However, we did not find any change of plasma IGF-1 in ET patients in our study. Although ET presents some similar clinical features to PD, these results indicated a probably different pathogenesis involved in ET, such as Purkinje neuron dysfunction [13, 14]. Moreover, we found that plasma IGF-1 was significantly increased in PD but did not change in ET patients. As we know, a differential diagnosis of tremulous PD and ET could be very difficult in certain circumstances because both diseases may share some similarity with regard to clinical features. Also, tremulous PD usually has a poor response to levodopa treatment and a favorable prognosis, making a differential diagnosis even more difficult. So it will be interesting to further investigate whether plasma IGF-1 could be used as a potential biomarker to differentiate PD from ET. However, we did not directly compare tremulous PD with ET, and the disease duration of ET in our study was about 15 years, which was quite longer than the PD duration of 4 years. We do not know how plasma IGF-1 changed during the entire course of PD or ET. Therefore, further well-designed studies are needed to answer this question. Our retrospective study also showed that plasma IGF-1 was associated with cognitive dysfunction in PD defined by MMSE scores. The association of plasma IGF-1 with cognitive impairment had already been reported in AD, PD, and HD [3–5]. However, the results were contradictory in some studies [3, 15, 16]. Our results supported the notion that low plasma IGF-1 was associated with poor cognitive performance, which is in agreement with the finding of the study by Pellecchia et al. [4]. As mentioned above, IGF-1 was protective for hippocampus and dopaminergic neuronal degeneration. A low level of plasma IGF-1 might be less protective than a high level, thus being associated with poor cognitive impairment in PD. Although the mechanism of cognitive impairment in PD is not the same as in AD, our results, together with those of other studies, suggested that both diseases might share some common pathway, such as the IGF-1 pathway. However, no association of plasma IGF-1 with cognitive impairment was found in ET patients, further indicating that the pathogenesis involved in cognitive dysfunction in ET is different from that in PD and AD, for example cerebellar dysfunction or tauopathy [17–19]. We also did not find any association between plasma IGF-1 with other nonmotor symptoms, including autonomic dysfunction and depression, which probably again suggested a different mechanism of neurodegeneration for these nonmotor symptoms in PD. There are some limitations of our study: (1) we did consecutive but not random sampling, so our sample might not be representative; (2) most of our study samples are from Shanghai (a certain area of China), so our results cannot be generalized to the whole country; (3) disease duration of PD was different between the drug-naïve and medication groups, and the sample of drug-naïve PD patients was small. So it is not sure whether disease course and medication have any effect on the change of IGF-1 in PD patients. Further studies with larger samples in different cities of China will overcome these drawbacks. In conclusion, our study found that plasma IGF-1 increased significantly in PD but remained unchanged in ET. Furthermore, low plasma IGF-1 was associated with cognitive impairment in PD but not in ET.
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Discussion
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Dement Geriatr Cogn Disord 2015;39:251–256 DOI: 10.1159/000371510
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Ma et al.: Plasma Insulin-Like Growth Factor 1 Is Associated with Cognitive Impairment in Parkinson’s Disease
Acknowledgements This study was supported by grants from the National Program of Basic Research (2010CB945200, 2011CB504104) of China, National Natural Science Fund (81371407), and National Nature Science for Youth (81200979). We thank Dr. Lifang Zhu and the other doctors from Malu Medical Center for their support of our epidemiology study.
References
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Godau J, Herfurth M, Kattner B, Gasser T, Berg D: Increased serum insulin-like growth factor 1 in early idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 2010;81:536–538. Godau J, Knauel K, Weber K, Brockmann K, Maetzler W, Binder G, Berg D: Serum insulinlike growth factor 1 as possible marker for risk and early diagnosis of Parkinson disease. Arch Neurol 2011;68:925–931. Westwood AJ, Beiser A, Decarli C, Harris TB, Chen TC, He XM, Roubenoff R, Pikula A, Au R, Braverman LE, Wolf PA, Vasan RS, Seshadri S: Insulin-like growth factor-1 and risk of Alzheimer dementia and brain atrophy. Neurology 2014;82:1613–1619. Pellecchia MT, Santangelo G, Picillo M, Pivonello R, Longo K, Pivonello C, Vitale C, Amboni M, De Rosa A, Moccia M, Erro R, De Michele G, Santoro L, Colao A, Barone P: Insulin-like growth factor-1 predicts cognitive functions at 2-year follow-up in early, drug-naïve Parkinson’s disease. Eur J Neurol 2014;21:802–807. Saleh N, Moutereau S, Azulay JP, Verny C, Simonin C, Tranchant C, El Hawajri N, Bachoud-Levi AC, Maison P; Huntington French Speaking Group: High insulinlike growth factor I is associated with cognitive decline in Huntington disease. Neurology 2010;75:57–63. Bermejo-Pareja F: Essential tremor – a neurodegenerative disorder associated with cognitive defects? Nat Rev Neurol 2011;7:273–282. Benito-Leon J, Louis ED, Sanchez-Ferro A, Bermejo-Pareja F: Rate of cognitive decline during the premotor phase of essential tremor: a prospective study. Neurology 2013;81:60–66. Bermejo-Pareja F, Louis ED, Benito-Leon J; Neurological Disorders in Central Spain Study Group: Risk of incident dementia in essential tremor: a population-based study. Mov Disord 2007;22:1573–1580. Chen W, Xu ZM, Wang G, Chen SD: Non-motor symptoms of Parkinson’s disease in China: a review of the literature. Parkinsonism Relat Disord 2012;18:446–452. Chen W, Tan YY, Hu YY, Zhan WW, Wu L, Lou Y, Wang X, Zhou Y, Huang P, Gao Y, Xiao Q, Chen SD: Combination of olfactory test and substantia nigra transcranial sonography in the differential diagnosis of Parkinson’s disease: a pilot study from China. Transl Neurodegener 2012;1:25. Guan J, Krishnamurthi R, Waldvogel HJ, Faull RL, Clark R, Gluckman P: N-terminal tripeptide of IGF-1 (GPE) prevents the loss of TH positive neurons after 6-OHDA induced nigral lesion in rats. Brain Res 2000; 859: 286–292. Miltiadous P, Stamatakis A, Stylianopoulou F: Neuroprotective effects of IGF-I following kainic acid-induced hippocampal degeneration in the rat. Cell Mol Neurobiol 2010;30:347–360. Babij R, Lee M, Cortés E, Vonsattel JP, Faust PL, Louis ED: Purkinje cell axonal anatomy: quantifying morphometric changes in essential tremor versus control brains. Brain 2013;136:3051–3061. Grimaldi G, Manto M: Is essential tremor a purkinjopathy? The role of the cerebellar cortex in its pathogenesis. Mov Disord 2013;28:1759–1761. van Exel E, Eikelenboom P, Comijs H, Deeg DJ, Stek ML, Westendorp RG: Insulin-like growth factor-1 and risk of late-onset Alzheimer’s disease: findings from a family study. Neurobiol Aging 2014;35:725.e7–10. Mustafa A, Lannfelt L, Lilius L, Islam A, Winblad B, Adem A: Decreased plasma insulin-like growth factor-I level in familial Alzheimer’s disease patients carrying the Swedish APP 670/671 mutation. Dement Geriatr Cogn Disord 1999;10:446–451. Park IS, Oh YS, Lee KS, Yang DW, Song IU, Park JW, Kim JS: Subtype of mild cognitive impairment in elderly patients with essential tremor. Alzheimer Dis Assoc Disord 2014, Epub ahead of print. Pan JJ, Lee M, Honig LS, Vonsattel JP, Faust PL, Louis ED: Alzheimer’s-related changes in non-demented essential tremor patients vs. controls: links between tau and tremor? Parkinsonism Relat Disord 2014; 20: 655–658. Bermejo-Pareja F, Puertas-Martín V: Cognitive features of essential tremor: a review of the clinical aspects and possible mechanistic underpinnings. Tremor Other Hyperkinet Mov 2012; 2:http://tremorjournal.org/ article/view/74.
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1
© 2015 S. Karger AG, Basel 1420–8008/15/0396–0251$39.50/0 www.karger.com/dem
Original Research Article
Plasma Insulin-Like Growth Factor 1 Is Associated with Cognitive Impairment in Parkinson’s Disease Jianfang Ma Qianwen Jiang Jing Xu Qian Sun Yuan Qiao Wei Chen Yiwen Wu Ying Wang Qin Xiao Jun Liu Huidong Tang Shengdi Chen Department of Neurology and Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
Key Words Insulin-like growth factor 1 · Cognitive function · Parkinson’s disease · Essential tremor Abstract Objective: The aim of this study was to test plasma insulin-like growth factor 1 (IGF-1) change in Parkinson’s disease (PD) and essential tremor (ET), and assess the association of plasma IGF1 level with motor and nonmotor symptoms in PD and ET. Methods: Plasma IGF-1 was measured in 100 PD patients, 40 ET patients, and 76 healthy controls. Motor and nonmotor symptoms were assessed by different scales. Spearman correlation test and linear logistic model were used to analyze the correlation of plasma IGF-1 with motor and nonmotor symptoms of PD and ET. Results: The plasma IGF-1 level was significantly increased in PD compared to healthy controls and ET patients. In addition, low plasma IGF-1 was correlated with low MiniMental State Examination (MMSE) scores in PD patients. However, no correlation was found between plasma IGF-1 and MMSE scores in ET patients. Conclusion: Plasma IGF-1 increased significantly in PD but remained unchanged in ET. A low plasma IGF-1 level was associated © 2015 S. Karger AG, Basel with poor cognitive performance in PD but not in ET patients.
Introduction
Shengdi Chen Department of Neurology and Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine Shanghai 200025 (PR China) E-Mail chen_sd @ medmail.com.cn
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Insulin-like growth factor 1 (IGF-1) is a neurotrophic factor exerting a protective role in neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) [1–3]. The elevation of plasma IGF-1 in neurodegenerative diseases was considered a compensation mechanism to protect neurons from degeneration [2]. In addition, IGF-1 was also
252
Dement Geriatr Cogn Disord 2015;39:251–256 DOI: 10.1159/000371510
© 2015 S. Karger AG, Basel
Ma et al.: Plasma Insulin-Like Growth Factor 1 Is Associated with Cognitive Impairment in Parkinson’s Disease
found associated with the risk of cognitive decline in PD and Huntington’s disease (HD) [4, 5]. These data demonstrated an important role of IGF-1 in the pathogenesis of PD and related cognitive dysfunctions. Apart from the association of cognitive dysfunction, however, the relationship of plasma IGF-1 with other nonmotor symptoms of PD has never been examined. The mechanism of nonmotor symptoms in PD remained largely unknown, involving different neurotransmitter dysfunctions and more diffuse neurodegeneration. Therefore, it will be helpful to examine the change of IGF-1 in other nonmotor symptoms to further reveal the function of IGF-1 in PD. Essential tremor (ET) is a neurological disease characterized by bilateral postural tremor, which shares some similarity with PD symptoms. Recently, some studies demonstrated that cognitive impairment was not uncommon in ET patients, indicating that ET may be a slowly progressive neurodegenerative disease [6–8]. IGF-1 was increased in several neurodegenerative diseases, such as PD, AD, and HD. However, the relationship of plasma IGF-1 and ET has never been examined. In addition, it is not known whether IGF-1 is also associated with cognitive dysfunction in ET. Answering these two questions will further contribute to our understanding of the role of IGF-1 in neurodegenerative disorders. In the present study, we investigated plasma IGF-1 in PD, ET, and healthy people to study (1) the change of plasma IGF-1 in PD and ET, and (2) whether IGF-1 is associated with motor and nonmotor symptoms of PD and ET. Materials and Methods Study Population Our study population was recruited from two samples: (1) outpatient clinics of the Neurology Department of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine (from January 28, 2013 to September 30, 2013), and (2) an epidemiological study targeted on people ≥50 years old in the Malu suburb of Shanghai, China (from October 9, 2012 to October 18, 2013). All PD patients from the outpatient clinic and epidemiological samples, and all ET patients from the epidemiological study were recruited if they met the enrollment criteria and were willing to participate in our study. Healthy controls who were willing to participate in our study were randomly selected from the epidemiological sample. PD and ET patients were diagnosed by movement disorder specialists from the Neurology Department of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine. Diagnosis of PD was based on United Kingdom PD Society Brain Bank Diagnostic Criteria, excluding secondary causes or other parkinsonism-related diseases. Diagnosis of ET was based on the consensus statement of the Movement Disorder Society on Tremor, excluding other causes of tremor. Demographic information, PD and ET features (age of onset, duration, motor and nonmotor function), concurrent diseases, and medications were recorded. The total equivalent levodopa dosage was calculated for each patient with PD medications. After considering the confounding factors for IGF-1 (body mass index >30, diabetes, cancer, thyroid and pituitary diseases, medications including β-blocker, corticosteroid, neuroleptic drugs, hormone replacement), 13 idiopathic PD patients were excluded from our study. Finally, 100 idiopathic PD patients, 40 ET patients, and 76 healthy controls were enrolled in our study. All recruited people were informed of our study and asked to sign the consent forms. Approval for this study was obtained from the Ethics Committee of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine.
Assessment of Motor and Nonmotor Function of PD and ET Patients All PD patients were assessed in their ‘on’ state by the Unified Parkinson’s Disease Rating Scale part III (UPDRS-III) and Hoehn-Yahr Staging Scale (H-Y) for motor function. Nonmotor symptoms of all PD and ET
Downloaded by: University Toronto Libr. 198.143.60.33 - 8/3/2015 3:48:21 AM
Plasma Sampling and Measurement Overnight fasting blood samples were collected from all participants, immediately centrifuged, and stored at –70 ° C until analysis. The plasma IGF-1 levels were quantified by an IGF-1 enzyme-linked immunosorbent assay kit (BE504112, RB Corporation).
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Dement Geriatr Cogn Disord 2015;39:251–256 DOI: 10.1159/000371510
© 2015 S. Karger AG, Basel
Ma et al.: Plasma Insulin-Like Growth Factor 1 Is Associated with Cognitive Impairment in Parkinson’s Disease
Table 1. Demographic features and plasma IGF-1 of PD and ET patients and healthy controls
PD Patients Age, years Sex Male Female IGF-1, ng/l 1
100 67.84 ± 9.89 67 (67.0) 33 (33.0) 183.50 ± 38.611, 3
ET
Healthy controls
40 70.85 ± 11.39
76 67.75 ± 8.55
24 (60.0) 16 (40.0) 158.38 ± 32.472, 3
45 (59.2) 31 (40.8) 154.91 ± 36.09
p value 0.203a 0.520b 0.000a
Values are given as mean ± SD or n (%). a ANOVA test; b χ2 test; multiple comparison (Bonferroni). p = 0.000 between PD and controls; 2 p = 1.000 between ET and controls; 3 p = 0.001 between ET and PD.
patients were assessed by the Non-Motor Symptoms Questionnaire (NMSQ), Mini-Mental State Examination (MMSE), Scales for Outcomes in Parkinson’s Disease – Autonomic (SCOPA-AUT), Hamilton Depression Rating Scale, and Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire (RBDSQ). All scales used in this study had been validated in Chinese PD patients [9, 10]. Statistical Analysis Statistical analysis was performed using SPSS 19.0. Demographic data were compared among the three groups by the ANOVA and χ2 tests. Plasma IGF-1 was compared among the three groups by the ANOVA test, and multiple comparison analysis was performed by the Bonferroni test. The Spearman correlation test and linear logistic regression model were used to analyze the correlation between plasma IGF-1 level and disease duration, motor and nonmotor variables, educational background, and equivalent levodopa dosage in PD and ET patients. All tests were 2-tailed, and the results were considered statistically significant at p < 0.05.
Demographic features were comparable among PD, ET, and healthy control groups (table 1). Plasma IGF-1 was significantly increased in PD patients (183.50 ± 38.61 ng/l) compared to healthy controls (154.91 ± 36.09 ng/l, p = 0.000) and ET patients (158.38 ± 32.47 ng/l, p = 0.001) (table 1; fig. 1). However, no difference of plasma IGF-1 level was found between ET and controls (p = 1.000). Among the PD group, 23 patients were drug naïve and 77 were on antiparkinson medications. PD medications included levodopa/benseraside or carbidopa, dopamine agonists, amantadine, and trihexyphenidyl. There was no difference between drug-naïve and medication-treated PD patients in terms of demographic features and plasma IGF-1 level (table 2). Further Spearman correlation analysis did not found any association between plasma IGF-1 level and duration [Spearman’s rank correlation coefficient (r) = 0.075, p = 0.460], or levodopa equivalent dosage (r = –0.045, p = 0.658). In PD patients, plasma IGF-1 was positively correlated with MMSE scores (r = 0.222, p = 0.026). Further linear logistic regression also showed that plasma IGF-1 was correlated with MMSE scores (p = 0.001; fig. 1). However, no correlation was found between plasma IGF-1 and UPDRS-III scores (r = 0.094, p = 0.354), H-Y stage (r = 0.067, p = 0.510), SCOPA-AUT (r = 0.129, p = 0.201), Hamilton depression scores (r = 0.144, p = 0.153), NMSQ scores (r = 0.112, p = 0.266), and RBDSQ scores (r = 0.063, p = 0.535). In ET patients, no correlation was found between plasma IGF-1 and MMSE scores (r = 0.264, p = 0.145), SCOPA-AUT (r = –0.036, p = 0.847), Hamilton depression scores (r = –0.009, p = 0.959), NMSQ scores (r = –0.209, p = 0.196), RBDSQ scores (r = –0.077, p = 0.675), and disease duration (r = 0.231, p = 0.195).
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Results
254
Dement Geriatr Cogn Disord 2015;39:251–256 © 2015 S. Karger AG, Basel
DOI: 10.1159/000371510
Ma et al.: Plasma Insulin-Like Growth Factor 1 Is Associated with Cognitive Impairment in Parkinson’s Disease
200
*
IGF-1 (ng/l)
150 100 50 0 Control
a
PD Group
ET
400
IGF-1 (ng/l)
300 200 100
Table 2. Demographic features and plasma IGF-1 of drug-naïve and medication-treated PD patients
0
b
40
30
20 MMSE score
Drug naïve Patients Age, years Sex Male Female Age of onset, years LED, mg Duration, years UPDRS-III H-Y MMSE NMSQ SCOPA-AUT Hamilton RBDSQ IGF-1, ng/l
10
Medication treated
23 67.84 ± 9.89
77 70.85 ± 11.39
23 (56.5) 10 (43.5) 66.87 ± 11.12 – 2.34 ± 1.75 13.30 ± 8.97 1.30 ± 0.45 26.00 ± 5.31 4.22 ± 2.59 7.70 ± 4.41 4.61 ± 2.82 2.00 ± 2.17 185.64 ± 11.58
54 (70.1) 23 (29.9) 62.39 ± 9.06 274.76 ± 253.44 5.04 ± 4.21 20.47 ± 12.15 1.78 ± 0.76 25.75 ± 5.21 7.54 ± 5.05 11.01 ± 7.40 5.77 ± 4.29 3.10 ± 2.73 182.86 ± 37.90
0
p value 0.449a 0.312b
0.764a
Values are given as mean ± SD or n (%). LED = Levodopa dosage. a ANOVA test; b χ2 test.
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Fig. 1. a Plasma IGF-1 change among the 3 groups. b Correlation of plasma IGF-1 with MMSE scores in PD.
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Dement Geriatr Cogn Disord 2015;39:251–256 DOI: 10.1159/000371510
© 2015 S. Karger AG, Basel
Ma et al.: Plasma Insulin-Like Growth Factor 1 Is Associated with Cognitive Impairment in Parkinson’s Disease
Several studies have already reported that plasma IGF-1 was increased in PD [1, 4]. Our study confirmed the elevation of plasma IGF-1 in Chinese PD patients. Most studies suggested that IGF-1 increases as a compensation to protect neurodegeneration of dopaminergic neurons. This hypothesis was supported by animal model studies which showed that IGF-1 supplement prevented the loss of dopaminergic neurons [11]. In an AD model, IGF-1 also showed a protective effect on hippocampus degeneration [12], further supporting the protective role of IGF-1 in neurodegenerative diseases. However, we did not find any change of plasma IGF-1 in ET patients in our study. Although ET presents some similar clinical features to PD, these results indicated a probably different pathogenesis involved in ET, such as Purkinje neuron dysfunction [13, 14]. Moreover, we found that plasma IGF-1 was significantly increased in PD but did not change in ET patients. As we know, a differential diagnosis of tremulous PD and ET could be very difficult in certain circumstances because both diseases may share some similarity with regard to clinical features. Also, tremulous PD usually has a poor response to levodopa treatment and a favorable prognosis, making a differential diagnosis even more difficult. So it will be interesting to further investigate whether plasma IGF-1 could be used as a potential biomarker to differentiate PD from ET. However, we did not directly compare tremulous PD with ET, and the disease duration of ET in our study was about 15 years, which was quite longer than the PD duration of 4 years. We do not know how plasma IGF-1 changed during the entire course of PD or ET. Therefore, further well-designed studies are needed to answer this question. Our retrospective study also showed that plasma IGF-1 was associated with cognitive dysfunction in PD defined by MMSE scores. The association of plasma IGF-1 with cognitive impairment had already been reported in AD, PD, and HD [3–5]. However, the results were contradictory in some studies [3, 15, 16]. Our results supported the notion that low plasma IGF-1 was associated with poor cognitive performance, which is in agreement with the finding of the study by Pellecchia et al. [4]. As mentioned above, IGF-1 was protective for hippocampus and dopaminergic neuronal degeneration. A low level of plasma IGF-1 might be less protective than a high level, thus being associated with poor cognitive impairment in PD. Although the mechanism of cognitive impairment in PD is not the same as in AD, our results, together with those of other studies, suggested that both diseases might share some common pathway, such as the IGF-1 pathway. However, no association of plasma IGF-1 with cognitive impairment was found in ET patients, further indicating that the pathogenesis involved in cognitive dysfunction in ET is different from that in PD and AD, for example cerebellar dysfunction or tauopathy [17–19]. We also did not find any association between plasma IGF-1 with other nonmotor symptoms, including autonomic dysfunction and depression, which probably again suggested a different mechanism of neurodegeneration for these nonmotor symptoms in PD. There are some limitations of our study: (1) we did consecutive but not random sampling, so our sample might not be representative; (2) most of our study samples are from Shanghai (a certain area of China), so our results cannot be generalized to the whole country; (3) disease duration of PD was different between the drug-naïve and medication groups, and the sample of drug-naïve PD patients was small. So it is not sure whether disease course and medication have any effect on the change of IGF-1 in PD patients. Further studies with larger samples in different cities of China will overcome these drawbacks. In conclusion, our study found that plasma IGF-1 increased significantly in PD but remained unchanged in ET. Furthermore, low plasma IGF-1 was associated with cognitive impairment in PD but not in ET.
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Discussion
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Dement Geriatr Cogn Disord 2015;39:251–256 DOI: 10.1159/000371510
© 2015 S. Karger AG, Basel
Ma et al.: Plasma Insulin-Like Growth Factor 1 Is Associated with Cognitive Impairment in Parkinson’s Disease
Acknowledgements This study was supported by grants from the National Program of Basic Research (2010CB945200, 2011CB504104) of China, National Natural Science Fund (81371407), and National Nature Science for Youth (81200979). We thank Dr. Lifang Zhu and the other doctors from Malu Medical Center for their support of our epidemiology study.
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