SERUM IGF-1& URIC ACID IN PATIENTS WITH PARKINSONS DISEASE AND PARKINSON PLUS SYNDROME.

Missamma Mulagala 1 , Ritu Shree 2 , Gunjan Goyal 3 , Manoj K Goyal 2 , Sahil Mehta 2 , Manish Modi 2 , B R Mittal 4 and Bikash Medhi 1 . 1. MD, Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh, India. 2. DM, Department of Neurology, Post Graduate Institute of Medical Education and Research, Chandigarh, India. 3. M Phil, Department of Medical Parasitology, Post Graduate Institute of Medical Education and Research, Chandigarh, India. 4. MD, DNB, Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India. ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History Received: 14 December 2018 Final Accepted: 16 January 2019 Published: February 2019

IGF-1 is a potential biomarker for PD which plays a vital role in cell differentiation and survival of neurons in nervous system. It is found in high concentrations in substantia nigra and is known to increase survival of dopaminergic neurons as well as protect them from dopamine induced oxidative damage in vitro. [12] However, though serum levels of IGF-1 were found to be elevated compared to controls in some studies, other studies have not reported such an association. [13][14] In addition, relationship of levels of serum IGF-1 with duration and severity of PD and its role in differentiation of PD from Parkinson plus syndrome is still to be elucidated.
Uric acid is a major antioxidant and various studies have demonstrated that low levels of serum uric acid confer increased risk of developing PD in later part of life. Uric acid has free radical scavenging properties (scavenger of peroxyl and hydroxyl radicals) and has the ability of metal complexing capabilities, all together uric acid bind with iron and copper and reduce their ability to produce reactive oxygen species (ROS). [15][16] Various studies have concluded that low serum uric acid has increased risk of developing PD in elderly and uric acid can serve as a prognostic biomarker in identifying PD disease progression. [17] Thus, we conducted this study to evaluate the role of serum IGF-1 and uric acid in differentiating PD from healthy controls and other Parkinson plus syndromes. We also aimed to observe the relationship of levels of serum IGF-1 and uric acid with duration and severity of PD. Parkinsonism. The study group consisted of 99 patients, 68 age and sex matched healthy volunteers as controls. After enrolment into the study, all patients underwent detailed history, clinical examination, neurological examination, MMSE, and investigations as per predesigned proforma. Further division of Parkinsonism patients into Parkinson's disease (PD), progressive supranuclear palsy (PSP), multisystem atrophy (MSA) and corticobasal ganglionic degeneration (CBGD) was made as per standard criteria. [18][19][20][21] All the patients underwent UPDRS (Unified Parkinson Disease Rating Scale). [22] MRI brain was done in all the patients. All patients received treatment as per the standard treatment guidelines. They were followed up regularly in movement disorder clinic of our institute. Hoehn and Yahr (H & Y) staging [23] was used to assess the severity of disease. Patients with PD were further divided into young onset PD (YOPD) (n=10) if disease onset was below 40 years of age. The inclusion and exclusion criteria for the study group are given below.

Statistical Analysis:-
Data was analysed using IBM-SPSS version 22. Data was expressed as mean and standard deviation. One way Anova with Bonferroni correction was used to compare continuous variables between multiple groups. The correlation of serum IGF-1 and uric acid levels with various clinical parameters were assessed using Pearson's correlation coefficient. Discrete variables were compared using Chi square test. Two tailed p value <0.05 was considered statistically significant.

Results:-Demographic profile:
Present study included 99 patients with Parkinsonism. The results were compared with 68 age and sex matched healthy volunteers as controls. The demographic profile of the study group is provided in table 1.

Serum levels of IGF-1 between various groups:
The mean (±SD) serum levels of IGF-1 among various groups were given in table 2. On analysis, serum levels of IGF-1 were found to be significantly elevated (p< 0.001) in PD patients compared to controls. The difference in levels of serum IGF-1 between various Parkinsonism groups (PD, YOPD, PSP, MSA, CBGD) was not significant (p=0.622). Similarly, there was no significant difference in levels of serum IGF-1 when patients with different Parkinson plus syndromes were compared with controls.

Serum uric acid between various groups:
The mean (±SD) serum uric acid among various groups were given in table 2. On analysis, serum uric acid was significantly decreased (p< 0.001) in PD patients compared to controls. The difference in serum uric acid between various Parkinsonism groups (PD, YOPD, PSP, MSA, CBGD) was not significant (p=0.173). Similarly, there was no significant difference in serum uric acid between Parkinson Plus Syndrome and controls.
Comparison of Serum IGF-1 and Uric acid between total patients versus controls and PD versus PPS given in table 3.

Correlation between levels of serum IGF-1; uric acid and other disease related parameters in PD patients:
In current study, we tried to determine if various disease related factors (age of patient, age at onset of disease, duration of illness, total and motor UPDRS score) can correlate with serum IGF-1 and uric acid levels or not . On analysis, no significant correlation was observed between any of the above mentioned factors and levels of serum IGF-1 as indicated by Spearman rho and Pearson correlation. Significant inverse correlation of age of onset with serum uric acid levels (r = -0.206, p=0.04) was observed whereas no significant correlation of serum uric acid was observed with age of patient, duration of illness, total and motor UPDRS score as indicated by Spearman rho and Pearson correlation (Table 4).
We further correlated levels of serum IGF-1 with severity of PD as determined by Hoehn and Yahr staging. Levels of serum IGF-1 were higher in patients with stage 5 disease (504 ng/ml) and stage 3 disease (442.6 ± 80.45 ng/ml) compared to stage 2 (357.43 ± 130.53 ng/ml) and stage 1 (338.64 ± 58.95 ng/ml) disease. Serum IGF-1 Levels in stage 4 disease were 235.5 ± 24.1ng/ml. However, on analysis, the difference among various groups was statistically insignificant.

Sensitivity and specificity of serum IGF-1 and uric acid levels for diagnosis of PD or Parkinson plus syndromes compared to controls:
To achieve above mentioned motif, we calculated area under the ROC. On analysis, it was found that serum IGF-1 levels of 300 ng/ml were 68% sensitive and 67% specific for differentiating PD or Parkinson plus syndrome from healthy controls. Similarly, serum IGF-1 levels of 300 ng/ml were 69% sensitive and 64% specific for differentiating PD patients from healthy controls. Serum uric acid levels of 5.98 were 66% sensitive and 65% specific in diagnosis of PD and for differentiation of PD from controls.

Discussion:-
Current study included 99 patients with PD (n=77) and Parkinson plus syndromes (n=22). The demographic profile of patients was in accordance with previous studies and in general agreement with reported frequencies of PD and various Parkinson plus syndromes. In current study, levels of serum IGF-1 were found to be significantly highly elevated in patients with PD compared to healthy controls. These observations are in agreement with previous studies. Numao et al [9] conducted a case controlled study on 79 patients of early PD and 52 controls. They demonstrated high levels of serum IGF-1 in PD patients compared with controls. A meta-analysis by Li et al [24](166 PD patients and 323 healthy controls) demonstrated high levels of serum IGF-1 in PD patients compared with controls. Godau et al [7] conducted a study on 139 healthy controls and 15 PD patients found significant high serum IGF-1 in PD (P =0.004). This study observed inverse correlation of levels of serum IGF-1 with UPDRS motor score. The current study had demonstrated low serum uric acid levels in patients with PD compared with healthy controls. These observations will strengthen the results of previous studies, where in patients with decreased serum uric acid levels has high propensity of developing PD in later part of life. [15][16][17] These studies plus results of our study suggest that levels of serum IGF-1 and uric acid may serve as diagnostic biomarkers for PD. Our study did not find any correlation of disease severity with levels of serum IGF-1 as measured by UPDRS motor score and Hoehn and Yahr staging. Levels of serum IGF-1 were higher in patients with higher stage of PD as determined by Hoehn and Yahr stage, though the difference was not significant. This may be related to relatively small number of PD patients in stage 1, 4 and 5. Our study did not find any correlation of serum uric acid levels with UPDRS motor score and Hoehn and Yahr staging. No correlation of levels of serum IGF-1 with duration of illness and age at onset was observed in current study. Significant inverse correlation of age of onset with serum uric acid levels (r = -0.206, p=0.04) was observed whereas no significant correlation of serum uric acid was observed with age of patient, duration of illness, total and motor UPDRS score. This may be related to the fact that duration of illness was roughly similar in most of the patients in current study.

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We observed no significant difference of serum IGF-1 levels between PD and PPS groups. Thus, though serum IGF-1 levels may help in differentiating PD patients from controls, they are of limited utility in differentiating PD patients from patients with Parkinson plus syndrome. However, these results need to be replicated in studies with much higher sample size as numbers of patients with various Parkinson plus syndromes were relatively small in current cohort.
To conclude results of our study confirm that serum IGF-1 levels are indeed elevated in PD patients compared to healthy controls. Further studies employing higher sample size and based on measurement of serum IGF-1 levels will further help in delineating its role as as a biomarker in PD.