Association of brain-derived neurotrophic factor (Val66Met) polymorphism with the risk of Parkinson’s disease and influence on clinical outcome

192-201Parkinson’s disease (PD) is a common neurodegenerative disease. Motor symptoms of rigidity, tremor, and bradykinesia and non-motor symptoms like the cognitive deficit, autonomic dysfunction, dementia, anxiety and depression all contribute to morbidity. Emerging shreds of evidence suggest the role of BDNF (Val66Met) polymorphism in PD risk and associated cognitive deficit. Hence, the current study is aimed to investigate the role of BDNF Val66Met in the risk of PD development and associated cognitive abnormalities. A total of 269 PD cases and 271 healthy, age, ethnicity and gender matched controls were recruited in the study. Genomic DNA was isolated, amplified and SNP was identified using the RFLP method and validated by Sanger’s sequencing. There was a significant association of BDNF Val66Met with PD risk in both Dominant and recessive models (GG vs GA+AA: OR: 1.47, CI: 1.04-2.09, P =0.03, GG+GA vs AA: OR: 2.32, CI: 1.07-5.00, P =0.02). The main nonmotor symptom i.e. cognitive impairment was significantly associated with the variant genotype of BDNF Val66Met Polymorphism (GG vs GA+AA: OR: 1.47, CI: 1.04-2.09, P =0.03, GG+GA vs AA: OR: 2.32, CI: 1.07-5.00, P =0.02).We found a significant association of variant genotype with disease severity, the activity of daily living as assessed by S & E score as it was found to better with wild genotype and a significant decrease in quality of life with homozygous mutant genotype. We did not find significant differences in disease duration, absolute levodopa response among the genotypes. Our results implicate BDNF Val66Met polymorphism is associated with the risk of PD, cognitive impairment, poor quality of life and greater disease severity in PD

Association of 25-Hydroxyvitamin D Deficiency in Pediatric Epileptic Patients

How to Cite This Article: Chaudhuri IR, Mridula KR, Rathnakishore Ch, Balaraju B, Bandaru VCS. Association of 25-Hydroxyvitamin D Deficiency in Pediatric Epileptic Patients. Iran J Child Neurol. Spring 2017; 11(2):48-56. Abstract Objective Epilepsy is a chronic neurological disorder requiring long-term therapy using antiepileptic medications. Reports have incriminated long-term antiepileptic drugs use in deficiency of vitamin D and bone diseases in all age groups. We aimed to investigate the association between serum 25-hydroxyvitamin D levels and pediatric epilepsy in Indian patients. Materials & Methods We prospectively recruited 100 pediatric epilepsy patients, on monotherapy for minimum one-year duration, and 50 age and sex matched controls. This study was carried out at Yashoda Hospital, India from 2011-2014. All cases and controls underwent tests for serum 25-hydroxyvitamin D, alkaline phosphatase, serum calcium and phosphorus levels. Results Patients with 25-hydroxyvitamin D deficiency were significantly higher among cases (45%) than controls (24%). Mean alkaline phosphatase was significantly higher in cases and mean serum calcium was significantly lower (8.3±1.5) in cases. Amongst antiepileptic drugs, carbamazepine and sodium valproate were significantly associated with 25-hydroxyvitamin D deficiency. Risk of vitamin D deficiency was highest with sodium valproate usage (odds:4.0;95%CI 1.4-11.6) followed by carbamazepine use (odds: 2.7; 95%CI 1.0-6.8). After adjustment using multiple logistic regression, antiepileptic drugs showed independent association with 25-hydroxyvitamin D deficiency (odds:2.2;95%CI 0.9-4.5). Conclusion 25-hydroxyvitamin D deficiency was significantly associated with use of carbamazepine and sodium valproate in pediatric epilepsy.References 1. Santhosh NS, Sinha S, Satishchandra P. Epilepsy: Indian perspective. Ann Indian Acad Neurol2014;17(Suppl 1):S3-11. 2. Sridharan R, Murthy BN. Prevalence and pattern of epilepsy in India. Epilepsia 1999;40:631-66. 3. RainaSK,RazdanS,NandaR.Prevalence of neurological disorders in children less than 10 years of age in RS Pura town of Jammu and Kashmir. J Pediatr Neurosci 2011; 6:103-05. 4. Misra A, Aggarwal A, Singh O, Sharma S. Effect of carbamazepine therapy on vitamin D and parathormone in epileptic children. Pediatr Neurol 2010 Nov;43:320- 24. 5. Lazzari AA, Dussault PM, Thakore-James M, Gagnon D, Baker E, Davis SA et al.Prevention of bone loss and vertebral fractures in patients with chronic epilepsy-antiepileptic drug and osteoporosis prevention trial. Epilepsia 2013;54:1997-2004.6. Menon B, Harinarayan CV. The effect of anti epileptic drug therapy on serum 25-hydroxyvitamin D and parameters of calcium and bone metabolism a longitudinal study. Seizure 2010;19:153-58. 7. Chaudhuri JR, Mridula KR, Alladi S, Anamika A, Umamahesh U, Balaraju B et al. Serum 25-hydroxyvitamin D deficiency in ischemic stroke and subtypes in Indian patients. J Stroke 2014;16:44-50. 8. Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 2005;46:470-72. 9. Chaudhuri JR, Mridula KR, Anamika A, Boddu DB, Misra PK, Lingaiah A et al. Deficiency of 25-hydroxyvitamin d and dyslipidemia in Indian subjects. J Lipids 2013;2013:623420. 10. Gniatkowska-Nowakowska A. Fractures in epilepsy children. Seizure 2010;19:324-25. 11. Shellhaas RA, Barks AK, Joshi SM. Prevalence and risk factors for vitamin D insufficiency among children with epilepsy. Pediatr Neurol 2010;42:422-26. 12. Nettekoven S, Strohle A, Trunz B, Wolters M, Hoffmann S, Horn R, et al. Lichtinghagen R, Welkoborsky HJ, Tuxhorn I, Hahn A. Effects of antiepileptic drug therapy on vitamin D status and biochemical markers of bone turnover in children with epilepsy. Eur J Pediatr 2008;167:1369-77. 13. Rajantie J, Lamberg-Allardt C, Wilska M. Dose carbamazepine treatment lead to need of extera vitamin D in some mentally retarded children. Acta Pediatr Scand 1984;73:325-28. 14. Jekovec-Vrhovsek M, Kocijancic A, Prezelj J. Effect of vitamin D and calcium on bone mineral density in children with CP and epilepsy in full-term care. Dev Med Child Neurol 2000;42:403-05. 15. Pack AM. The Association between Antiepileptic Drugs and Bone Disease. Epilepsy Currents 2003; 3:91-95. 16. Babayigit A, Dirik E, Bober E, Cakmakci H. Adverse effects of antiepileptic drugs on bone mineral density. Pediatr Neurol 2006;35:177-81. 17. Pack AM. The impact of long-term antiepileptic drug use on bone health. Advanced Students 2005;5:S567-71.18. Voudris KA, Attilakos A, Katsarou E, Garoufi A, Dimou S, Skardoutsou A,et al. Early alteration in bone metabolism in epileptic children receiving carbamazepine monotherapy owing to the induction of hepatic drug-metabolizing enzymes. J Child Neurol 2005; 20: 513-16. 19. Malik R, Mohapatra JN, Kabi BC, Halder R. 5 Hydroxy Cholecalciferol Levels in Infants with Hypocalcemic Seizures J Nutr Food Sci 2014; 4:3 20. Razazizan N, Mirmoeini M, Daeichin S, Ghadiri K. Comparison of 25-hydroxy vitamin D, calcium and alkaline phosphatase levels in epileptic and non-epileptic children. Acta Neurol Taiwan 2013;22:112-16. 21. Krishnamoorthy G, Karande S, Ahire N, Mathew L, Kulkarni M. Bone Metabolism Alteration on Antiepileptic Drug Therapy. Indian J Pediatr 2009; 76 : 377-83. 22. Valsamis HA, Arora SK, Labban B, McFarlane SI.Antiepileptic drugs and bone metabolism. Nutr Metab (Lond) 2006;3:36 23. MintzerS, Boppana P, Toguri J, DeSantis A. Vitamin D levels and bone turnover in epilepsy patients taking carbamazepine or oxcarbamazepine. Epilepsia 2006;47:510-15. 24. Pack AM, Morrell MJ. Adverse effect of antiepileptic drug on bone structure: Epidemiology mechanisms and therapeutic indications.CNS Drugs 2001;15:633-42. 25. Yaghini O, Tonekaboni SH, Amir Shahkarami SM, Ahmad Abadi F, Shariat F, Abdollah Gorji F. Bone mineral density in ambulatory children with epilepsy. Indian J Pediatr 2015;82:225-29. 26. Verrotti A, Greco R, Morgese G, Chiarelli F. Increased bone turnover in epileptic patients treated with carbamazepine. Ann Neurol 2000;47: 385-88. 27. Ginige N,de Silva KSH, Wanigasinghe JK, Gunawardane NS, Munasinghe TMJ. Effects of long term anti epileptic drugs on serum vitamin D levels and bone profile in a cohort of Sri Lankan children. Int J Pediatr Endocrinol 2015,2015(Suppl 1):P66. 28. Hosseinpour F, Ellfolk M, Norlin M, Wikvall K. Phenobarbital suppresses vitamin D3 25-hydroxylase expression: a potential new mechanism for drug-induced osteomalacia. Biochem Biophys Res Commun 2007;357:603-07. 29. Heo K, Rhee Y, Lee HW, Lee SA, Shin DJ, Kim WJ, et al. The effect of topiramate monotherapy on bone mineral density and markers of bone and mineral metabolism in premenopausal women with epilepsy. Epilepsia 2011;52:1884-89. 30. Zhou C, Assem M, Tay JC, Watkins PB, Blumberg B, Schuetz EG, et al.Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia. J Clin Invest 2006;116:1703-12. 31. Pascussi JM, Robert A, Nguyen M, Walrant-Debray O, Garabedian M, Martin P, et al.. Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia. J Clin Invest 2005;115:177- 86. 32. Holick MF. Stay tuned to PXR: an orphan actor that may not be D-structive only to bone. J Clin Invest 2005;115:32- 4. 33. Perucca E. Clinical implications of hepatic microsomal enzyme induction by antiepileptic drugs. Pharmacol Ther 1987;33:139-44. 34. Koch HU, Kraft D, von Herrath D, Schaefer K. Influence of diphenylhydantoin and phenobarbital on intestinal calcium transport in the rat. Epilepsia 1972;13:829-41. 35. Weinstein RS, Bryce GF, Sappington LJ, King DW, Gallagher BB. Decreased serum ionized calcium and normal vitamin D metabolite levels with anticonvulsant drug treatment. J Clin Endocrinol Metab 1984;58:1003-09. 36. Onodera K, Takahashi A, Sakurada S, Okano Y. Effects of phenytoin and/or vitamin K2 (menatetrenone) on bone mineral density in the tibia of growing rats. Life Sci 2002; 70: 1533-42. 37. Vernillo AT, Rifkin BR, Hauschka PV. Phenytoin affects osteoblastic secretion from osteoblastic rat osteosarcoma 17/2.8 cells in culture. Bone 1990;11:309-12. 38. Guo C, Ronen GM, Atkinson SA. Long-term valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy. Epilepsia 2001; 42:1141-47. 39. Nakken KO, Tauboll E. Bone loss associated with use of antiepileptic drugs. Expert Opin Drug Saf 2010;9:561-71. 40. Lee RH,Lyles KW, Colon-Emeric C. A review of the effect of anticonvulsant medications on bone mineral density and fracture risk. Am J Geriatr Pharmacother 2010; 8:34-46. 41. Teagarden DL, Meador KJ, Loring DW. Low vitamin D levels are common in patients with epilepsy. Epilepsy Res 2014;108:1352-56. 42. Wu FJ, Sheu SY, Lin HC. Osteoporosis is associated with antiepileptic drugs: a population-based study. Epileptic Disord 2014;16:333-42. 43. Cansu A, Yesilkaya E, Serdaroglu A, Hirfanoglu TL, Camurdan O, Gulbahar O, et al. Evaluation of bone turnover in epileptic children using oxcarbazepine. Pediatr Neurol 2008;39:266-71. 44. Bergqvist AG, Schall JI, Stallings VA. Vitamin D status in children with intractable epilepsy, and impact of the ketogenic diet. Epilepsia 2007;48:66-71. 45. Nicolaidou P, Georgouli H, Kotsalis H, Matsinos Y, Papadopoulou A, Fretzayas A, et al.Effects of anticonvulsant therapy on vitamin D status in children: Prospective monitoring study. 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Association of brain-derived neurotrophic factor (Val66Met) polymorphism with the risk of Parkinson’s disease and influence on clinical outcome

Parkinson’s disease (PD) is a common neurodegenerative disease. Motor symptoms of rigidity, tremor, and bradykinesia and non-motor symptoms like the cognitive deficit, autonomic dysfunction, dementia, anxiety and depression all contribute to morbidity. Emerging shreds of evidence suggest the role of BDNF (Val66Met) polymorphism in PD risk and associated cognitive deficit. Hence, the current study is aimed to investigate the role of BDNF Val66Met in the risk of PD development and associated cognitive abnormalities. A total of 269 PD cases and 271 healthy, age, ethnicity and gender matched controls were recruited in the study. Genomic DNA was isolated, amplified and SNP was identified using the RFLP method and validated by Sanger’s sequencing. There was a significant association of BDNF Val66Met with PD risk in both Dominant and recessive models (GG vs GA+AA: OR: 1.47, CI: 1.04-2.09, P =0.03, GG+GA vs AA: OR: 2.32, CI: 1.07-5.00, P =0.02). The main nonmotor symptom i.e. cognitive impairment was significantly associated with the variant genotype of BDNF Val66Met Polymorphism (GG vs GA+AA: OR: 1.47, CI: 1.04-2.09, P =0.03, GG+GA vs AA: OR: 2.32, CI: 1.07-5.00, P =0.02).We found a significant association of variant genotype with disease severity, the activity of daily living as assessed by S & E score as it was found to better with wild genotype and a significant decrease in quality of life with homozygous mutant genotype. We did not find significant differences in disease duration, absolute levodopa response among the genotypes. Our results implicate BDNF Val66Met polymorphism is associated with the risk of PD, cognitive impairment, poor quality of life and greater disease severity in PD

Association of SLC6A3 gene polymorphisms with the pharmacokinetics of Levodopa and clinical outcome in patients with Parkinson’s disease

202-212Levodopa (LD) is the gold standard for the treatment of Parkinson’s disease (PD). Genetic polymorphisms in the SLC6A3 gene (Solute carrier family 6 member 3/DAT-Dopamine Transporter gene) are shown to have a functional impact on levodopa therapeutic response, motor complications of PD and adverse events. Hence the present study was carried out to investigate the association of SLC6A3 polymorphisms with the pharmacokinetics of levodopa and clinical response. A total of 150 PD patients were recruited in the study. Plasma levodopa was analysed by HPLC at 0, 1, 2, 3 and 4 h post levodopa administration and AUC was calculated. Genotyping of SLC6A3 40 bp VNTR and SLC6A3 rs393795 (G>T) polymorphisms was done by the PCR-RFLP method. The result shows that AUC of levodopa was significantly higher in patients carrying homozygous10/10 genotype (P =0008) compared to 9/9 genotype of SLC6A3 40 bp VNTR polymorphism. A similar difference was also observed in early-onset Parkinson’s disease (EOPD) and late-onset Parkinson’s disease (LOPD) groups. SLC6A310/10 genotype was found to be significantly associated with disease severity (P =0.05) compared with the 9/10 genotype in the EOPD group, however, there was no significant association with dyskinesia. To conclude, patients carrying SLC6A3 40VNTR 10/10 genotype were found to have higher levodopa exposure, disease severity and prone to further neurodegeneration

Association of SLC6A3 gene polymorphisms with the pharmacokinetics of Levodopa and clinical outcome in patients with Parkinson’s disease

Levodopa (LD) is the gold standard for the treatment of Parkinson’s disease (PD). Genetic polymorphisms in the SLC6A3 gene (Solute carrier family 6 member 3/DAT-Dopamine Transporter gene) are shown to have a functional impact on levodopa therapeutic response, motor complications of PD and adverse events. Hence the present study was carried out to investigate the association of SLC6A3 polymorphisms with the pharmacokinetics of levodopa and clinical response. A total of 150 PD patients were recruited in the study. Plasma levodopa was analysed by HPLC at 0, 1, 2, 3 and 4 h post levodopa administration and AUC was calculated. Genotyping of SLC6A3 40 bp VNTR and SLC6A3 rs393795 (G>T) polymorphisms was done by the PCR-RFLP method. The result shows that AUC of levodopa was significantly higher in patients carrying homozygous10/10 genotype (P =0008) compared to 9/9 genotype of SLC6A3 40 bp VNTR polymorphism. A similar difference was also observed in early-onset Parkinson’s disease (EOPD) and late-onset Parkinson’s disease (LOPD) groups. SLC6A310/10 genotype was found to be significantly associated with disease severity (P =0.05) compared with the 9/10 genotype in the EOPD group, however, there was no significant association with dyskinesia. To conclude, patients carrying SLC6A3 40VNTR 10/10 genotype were found to have higher levodopa exposure, disease severity and prone to further neurodegeneration

Dementia with Lewy bodies research consortia: A global perspective from the ISTAART Lewy Body Dementias Professional Interest Area working group

Dementia with Lewy bodies (DLB) research has seen a significant growth in international collaboration over the last three decades. However, researchers face a challenge in identifying large and diverse samples capable of powering longitudinal studies and clinical trials. The DLB research community has begun to focus efforts on supporting the development and harmonization of consortia, while also continuing to forge networks within which data and findings can be shared. This article describes the current state of DLB research collaborations on each continent. We discuss several established DLB cohorts, many of whom have adopted a common framework, and identify emerging collaborative initiatives that hold the potential to expand DLB networks and diversify research cohorts. Our findings identify geographical areas into which the global DLB networks should seek to expand, and we propose strategies, such as the creation of data-sharing platforms and the harmonization of protocols, which may further potentiate international collaboration.publishedVersio

Chaudhuri’s Dashboard of Vitals in Parkinson’s syndrome: an unmet need underpinned by real life clinical tests

We have recently published the notion of the “vitals” of Parkinson’s, a conglomeration of signs and symptoms, largely nonmotor, that must not be missed and yet often not considered in neurological consultations, with considerable societal and personal detrimental consequences. This “dashboard,” termed the Chaudhuri’s vitals of Parkinson’s, are summarized as 5 key vital symptoms or signs and comprise of (a) motor, (b) nonmotor, (c) visual, gut, and oral health, (d) bone health and falls, and finally (e) comorbidities, comedication, and dopamine agonist side effects, such as impulse control disorders. Additionally, not addressing the vitals also may reflect inadequate management strategies, leading to worsening quality of life and diminished wellness, a new concept for people with Parkinson’s. In this paper, we discuss possible, simple to use, and clinically relevant tests that can be used to monitor the status of these vitals, so that these can be incorporated into clinical practice. We also use the term Parkinson’s syndrome to describe Parkinson’s disease, as the term “disease” is now abandoned in many countries, such as the U.K., reflecting the heterogeneity of Parkinson’s, which is now considered by many as a syndrome

Nonmotor outcomes in Parkinson’s disease: is deep brain stimulation better than dopamine replacement therapy?

Nonmotor symptoms are an integral part of Parkinson’s disease and cause significant morbidity. Pharmacological therapy helps alleviate the disease but produces nonmotor manifestations. While deep brain stimulation (DBS) has emerged as the treatment of choice for motor dysfunction, the effect on nonmotor symptoms is not well known. Compared with pharmacological therapy, bilateral subthalamic nucleus (STN)-DBS or globus pallidum interna (GPi)-DBS has significant beneficial effects on pain, sleep, gastrointestinal and urological symptoms. STN-DBS is associated with a mild worsening in verbal fluency while GPi-DBS has no effect on cognition. STN-DBS may improve cardiovascular autonomic disturbances by reducing the dose of dopaminergic drugs. Because the motor effects of STN-DBS and GPi-DBS appear to be similar, nonmotor symptoms may determine the target choice in surgery of future patients

Effect of medication and deep brain stimulation on gait in Parkinson's disease and its quantitative analysis using Mobishoe – A comparative study

Background: Movement abnormalities pertaining to balance, posture, and gait are observed in Parkinson's disease patients. Gait characteristics vary widely and their analysis has been performed traditionally in gait labs. Freezing and festination usually occur at an advanced stage of the disease and are associated with reduced quality of life. Therapeutic strategies and surgical interventions are often modulated by the physician depending upon the clinical manifestations. Introduction of accelerometers and wireless data transmission systems made quantitative gait analysis possible and cost-effective. Objective: To assess spatiotemporal gait parameters (step height, length (spatial), and swing support time of each foot and double support time (temporal)) in subjects who underwent deep brain stimulation surgery using a purpose-built instrument—Mobishoe. Methods: A simple footwear-based gait sensing device—Mobishoe was built in-house. Thirty-six participants were included in the study after obtaining consent. Participants were made to wear Mobishoe and walk an empty corridor of 30m before Deep Brain Stimulation (DBS) in the drug on and off stated and post DBS in DBS stimulation on and medication off state (B1M0), DBS stimulation off—medication off state (B0M0), DBS stimulation off—medication on (B0M1), and DBS stimulation on and on medication (B1M1). Data was electronically captured and analyzed offline in MATrix LABoratory (MATLAB). Various gait parameters were extracted and analyzed. Results: Improvement in gait parameters was observed when the subject was on medication, on stimulation, or on both when compared to baseline. Improvement was similar with both medication and stimulation and was synergistic when both were used. Significant improvement was noted in spatial characteristics when the subjects were on both the treatments, which is the ideal treatment modality. Conclusion: Mobishoe is an affordable device which can measure spatiotemporal characteristics of gait. The best improvement was seen when the subjects were on both the treatment groups and the improvement can be justified as a synergistic effect of stimulation and medication