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 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 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

A 12-month prospective real-life study of opicapone efficacy and tolerability in Emirati and non-White subjects with Parkinson's disease based in United Arab Emirates

Parkinson's disease (PD) is the second most common neurodegenerative disorder, and the condition is complicated by the emergence of wearing off/motor fluctuations with levodopa treatment after a variable period. COMT inhibitors when used as adjunct therapy to levodopa tend to smoothen out these wearing off fluctuations by enhancing delivery of levodopa and increasing its bioavailability to the brain. The study was conducted to investigate the motor and nonmotor effect, safety and tolerability of the third generation once-daily COMT inhibitor (opicapone), as add-on, adjuvant therapy to levodopa and at 6 and 12 months follow-up in a real-life cohort of consecutive Emirati and non-White PD patients. A real-life observational analysis using tolerability parameters as used previously by Rizos et al. and Shulman et al. based on clinical database of cases rat Kings College Hospital Dubai Parkinson care database. This was a prospective, single-arm follow-up clinical evaluation study that evaluated the effectiveness of opicapone 50 mg once-daily regime in 50 patients diagnosed with idiopathic neurodegenerative disorder. All patients were assessed with scales used in clinical pathway and include motor Unified Parkinson's Disease Rating Scale (UPDRS), nonmotor symptom scale (NMSS), quality of life (PDQ8) Parkinson's fatigue scale (PFS16) and King's Parkinson's Pain Scale (KIPS). Out of 50 patients treated with opicapone (72% male, mean age 66.9 years (SD 9.9, range 41-82 years) and mean duration of disease 5.7 years (SD 2.5 range (2-11), there was significant statistical improvements shown in motor function-UPDRS part 3: baseline 40.64 ± 2.7, at 6 months 32.12 ± 3.14 and after 12 months 33.72 ± 3.76. Nonmotor burden NMSS: 107.00 ± 21.86, at 6 months 100.78 ± 17.28 and 12 months 96.88 ± 16.11. Reduction in dyskinesias (UPDRS part 4): baseline 8.78 ± 1.07, at 6 months 7.4 ± 0.81 and 12 months 6.82 ± 0.75. Opicapone provides beneficial motor and nonmotor effects in Emirati and other non-White Parkinson's patients, resident in UAE, proving its efficacy across different racial groups as COMT activity may vary between races.S

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

Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

Extrahepatic portal vein obstruction with parkinsonism and symmetric hyperintense basal ganglia on T1 weighted MRI

Abnormal high signal in the globus pallidus on T1 weighted magnetic resonance imaging (MRI) of the brain has been well described in patients with chronic liver disease. It may be related to liver dysfunction or portal-systemic shunting. We report a case of extra hepatic portal vein obstruction with portal hypertension and esophageal varices that presented with extra pyramidal features. T1 weighted MRI brain scans showed increased symmetrical signal intensities in the basal ganglia. Normal hepatic function in this patient emphasizes the role of portal- systemic communications in the development of these hyperintensities, which may be due to deposition of paramagnetic substances like manganese in the basal ganglia