Association of dopamine receptor D3 polymorphism with Levodopa-induced Dyskinesia: A study on Parkinson's disease patients from India.

INTRODUCTION: Levodopa-induced dyskinesia (LID) is a debilitating motor feature in a subset of patients with Parkinson's disease (PD) after prolonged therapeutic administration of levodopa. Preliminary animal and human studies are suggestive of a key role of dopamine type 3 (D3) receptor polymorphism (Ser9Gly; rs6280) in LID. Its contribution to development of LID among Indian PD patients has remained relatively unexplored and merits further investigation. METHODS AND MATERIALS: 200 well-characterised PD patients (100 without LID and 100 with LID) and 100 age-matched healthy controls were recruited from the outpatient department of Institute of Neurosciences Kolkata. MDS-UPDRS (Unified Parkinson's Disease Rating Scale from International Movement Disorder Society) Part III and AIMS (abnormal involuntary movement scale) were performed for estimation of severity of motor features and LID respectively in the ON state of the disease. Participants were analysed for the presence of Ser9Gly single nucleotide variant (SNV) (rs6280) by polymerase chain reaction followed by restriction fragment length polymorphism techniques. RESULTS: The frequency of AA genotype (serine type) was more frequently present in PD patients with LID compared to PD patients without LID (50 % vs 28 %; P = 0.002; OR = 2.57, 95 % CI: 1.43 - 4.62). The abnormal involuntary movement scale score was significantly higher in PD patients with AA genotype compared to carriers of glycine allele (AG + GG) (4.08 ± 3.35; P = 0.002). CONCLUSION: We observed a significant association of serine type SNV (rs6280) in D3 receptor gene in a cohort of PD patients with LID from India. More severe motor severity was found in patients with glycine substitution of the same SNV. The current study emphasised the role of D3 receptor in the pathogenesis of LID.

Levodopa-induced Dyskinesia in Parkinson's Disease: Plausible Inflammatory and Oxidative Stress Biomarkers.

BACKGROUND: Pathophysiology of levodopa-induced dyskinesia (LID) remains obscure. Increased dopamine metabolism due to prolonged levodopa treatment can exacerbate oxidative damage and neuroinflammatory pathology in Parkinson's disease (PD). Association of novel peripheral markers with LID severity might provide insight into LID pathomechanisms. OBJECTIVE: We aimed to study specific peripheral blood inflammatory-oxidative markers in LID patients and investigate their association with clinical severity of LID. METHOD: Motor, non-motor and cognitive changes in PD with and without LID compared to healthy-matched controls were identified. Within the same cohort, inflammatory marker (sLAG3, TOLLIP, NLRP3 and IL-1ß) levels and antioxidant enzyme activities were determined by ELISA and spectrophotometric methods. RESULTS: LID patients showed distinctly upregulated TOLLIP, IL-1ß levels with significant diminution of antioxidant activity compared to controls. Significant negative association of cognitive markers with oxidative changes was also observed. CONCLUSION: To our understanding, this is the first study that indicates the involvement of toll-like receptor-mediated distinct and low-grade inflammatory activation in LID pathophysiology.

Vitamin D deficiency and genetic polymorphisms of vitamin D-associated genes in Parkinson's disease.

Parkinson's disease (PD) and vitamin D share a unique link as vitamin D deficiency (VDD) prevails in PD. Thus, an in-depth understanding of vitamin D biology in PD might be crucial for therapeutic strategies emphasising vitamin D. Specifically, explicating the effect of VDD and genetic polymorphisms of vitamin D-associated genes in PD, like VDR (vitamin D receptor) or GC (vitamin D binding protein) may aid the process along with polymorphisms of vitamin D metabolising genes (e.g., CYP2R1 and CYP27A1) in PD. Literature review of single nucleotide polymorphisms (SNPs) related to vitamin D levels [GC (GC1-rs7041 and GC2-rs4588), CYP2R1, CYP24A1 and CYP27B1] and vitamin D function [VDR (FokI - rs2228570 and rs10735810; ApaI - rs7976091, rs7975232BsmI and rs1544410; and TaqI - rs731236)] was conducted to explore their relationship with PD severity globally. VDR-FokI polymorphism was reported to be significantly associated with PD in Hungarian, Chinese and Japanese populations, whereas VDR-ApaI polymorphism was found to affect PD in the Iranian population. However, VDR-TaqI and BsmI polymorphisms had no significant association with PD severity. Conversely, GC1 polymorphisms reportedly affected vitamin D levels without influencing the disease severity. CYP2R1 (excluding rs1993116) was also reportedly linked to clinical manifestations of PD. Genetic polymorphisms might cause VDD despite enough sunlight exposure and vitamin D-rich food intake, enhancing inflammation, there by influencing PD pathophysiology. Knowledge of the polymorphisms associated with VDD appears promising for developing precision vitamin D-dosing therapeutic strategies against PD.

Characterizing gait and exploring neuro-morphometry in patients with PSP-Richardson's syndrome and vascular parkinsonism.

Gait differentiation in progressive supranuclear palsy (PSP) and vascular parkinsonism (VaP) is sometimes difficult to detect with the naked eye. Here, we compared specific gait parameters, neuro-morphometric indices, and their associations between patients with PSP Richardson's syndrome (PSP-RS) and VaP. A total of 18 PSP-RS and 13 VaP patients were recruited. Spatio-temporal gait parameters (GAITRite®) and neuroanatomical morphometry (FreeSurfer pipeline) were assessed. The groups were compared using unpaired t-tests involving 10000 random permutations after statistically controlling for total UPDRS-III and H&Y scores. Statistically significant differences between the groups were decided at < 5% Benjamini-Hochberg False Discovery Rate (FDR) for multiple-comparison related corrections. Spearman's correlations were performed to assess the significant associations (p < 0.05) between the gait parameters and morphometry indices. Among all the spatio-temporal gait parameters, PSP-RS patients displayed greater stride time, step time, swing time, and stance time variabilities compared to VaP. Morphometric analyses showed that thalamus, and caudate volumes were significantly lower, but cerebellar cortex, hippocampus, amygdala, accumbens, and putamen volumes were higher in PSP-RS than VaP. Moreover, the bilateral insula was significantly thinner in VaP than in PSP-RS. Correlation analyses support the involvement of limbic structures besides cerebellum in postural control during self-paced walking of PSP-RS patients. Our findings underline the importance of examining individual brain regions to understand the association of cortical and subcortical morphometric estimates and gait variability parameters in PSP-RS and VaP. This study suggests the involvement of the limbic system in addition to the classical neural structures for motor control and gait.

Dietary and Environmental Risk Factors in Parkinson's and Alzheimer's Disease: A Semi-Quantitative Pilot Study.

Objective: Environmental influence and dietary variations are well-known risk factors for various diseases including neurodegenerative disorders. Preliminary evidence suggests that diet in early-life and living environment might influence the incidence of Parkinson's disease (PD) in later phase of life. There have been limited epidemiologic studies on this aspect especially in India. In this hospital-based case-control study, we intended to identify dietary and environmental risk factors of PD. Methods: Patients with PD (n = 105), Alzheimer's disease (AD) (n = 53) and healthy individuals (n = 81) were recruited. Dietary intake and environmental exposures were assessed using a validated Food-Frequency and Environmental Hazard Questionnaire. Their demographic details and living environment were also recorded using the same questionnaire. Results: Pre-morbid consumption of carbohydrate and fat was significantly higher whereas dietary fiber and fruit content was significantly lesser in PD as compared to AD and healthy age-matched controls. Meat and milk intake was the highest among all the food groups in PD patients. Rural living and their habitation near water bodies were significantly more frequent in PD patients. Conclusion: We found that past intake of carbohydrate, fat, milk, and meat are associated with increased risk of PD. On the other hand, rural living and habitat near water bodies might be associated with incidence and severity of PD. Hence, preventive strategies related to dietary and environmental modulators in PD might be clinically useful in the future.

Short-Latency Afferent Inhibition Correlates with Stage of Disease in Parkinson's Patients.

BACKGROUND: Sensory-motor decoupling at the cortical level involving cholinergic circuitry has also been reported in Parkinson's Disease (PD). Short-latency afferent inhibition (SAI) is a transcranial magnetic stimulation (TMS) paradigm that has been used previously to probe cortical cholinergic circuits in well-characterised subgroups of patients with PD. In the current study, we compared SAI in a cohort of PD patients at various stages of disease and explored correlations between SAI and various clinical measures of disease severity. METHODS: The modified Hoehn and Yahr (H&Y) scale was used to stage disease in 22 patients with PD. Motor and cognitive function were assessed using the MDS-UPDRS (Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale) part III and MoCA (Montreal Cognitive Assessment) score, respectively. Objective gait assessment was performed using an electronic walkway (GAITRite®). SAI was measured as the average percentage inhibition of test motor-evoked potentials (MEPs) conditioned by electrical stimulation of the contralateral median nerve at the wrist. RESULTS: SAI was significantly reduced in patients with advanced PD (H&Y stage 3) compared to early PD patients (H&Y stage 1) on pairwise comparison. The visuospatial executive function and orientation domains of cognition demonstrated significant negative associations with SAI. CONCLUSION: Cortical sensory-motor integration is progressively diminished as disease progresses. The observation that a reduction in SAI is associated with a reduction in cognitive function possibly reflects the progressive involvement of cortical cholinergic circuits in PD with increasing motor stage. Future longitudinal studies are necessary to confirm this preliminary result.

Effects of non-invasive vagus nerve stimulation on clinical symptoms and molecular biomarkers in Parkinson's disease.

Non-invasive vagus nerve stimulation (nVNS) is an established neurostimulation therapy used in the treatment of epilepsy, migraine and cluster headache. In this randomized, double-blind, sham-controlled trial we explored the role of nVNS in the treatment of gait and other motor symptoms in Parkinson's disease (PD) patients. In a subgroup of patients, we measured selected neurotrophins, inflammatory markers and markers of oxidative stress in serum. Thirty-three PD patients with freezing of gait (FOG) were randomized to either active nVNS or sham nVNS. After baseline assessments, patients were instructed to deliver six 2 min stimulations (12 min/day) of the active nVNS/sham nVNS device for 1 month at home. Patients were then re-assessed. After a one-month washout period, they were allocated to the alternate treatment arm and the same process was followed. Significant improvements in key gait parameters (speed, stance time and step length) were observed with active nVNS. While serum tumor necrosis factor- α decreased, glutathione and brain-derived neurotrophic factor levels increased significantly (p < 0.05) after active nVNS treatment. Here we present the first evidence of the efficacy and safety of nVNS in the treatment of gait in PD patients, and propose that nVNS can be used as an adjunctive therapy in the management of PD patients, especially those suffering from FOG. Clinical trial registration: identifier ISRCTN14797144.

Novel inflammasome and oxidative modulators in Parkinson's disease: A prospective study.

INTRODUCTION: The etiopathogenesis of Parkinson's disease (PD) is not clear. Yet, it seems likely that inflammation as well as oxidative stress plays a major role in the disease pathogenesis. Based on our previous findings, we aimed to investigate prospective changes in peripheral inflammasome and oxidative modulators in relation to the progression of motor symptoms and severity of PD. METHODS: Levels of inflammatory and oxidative markers in the serum of PD patients and healthy controls were estimated by quantitative ELISA and spectrophotometric methods at the baseline and at the end of one year. RESULTS: In PD patients, serum NLRP3 inflammasome and IL-1ß levels increased significantly over a year, compared to the baseline. The average enzymatic activity of serum SOD1 was also augmented at one-year follow-up. Alongside these serummarker changes, the mean motorseverity of this patient cohort worsened over the time period. CONCLUSION: This pioneering study identified a novel association of peripheral inflammatory and oxidative markers with the progression of PD. Correlation of these serum proteins with the central pathological changes in PD and disease severity in a prospective manner might be useful not only for prognostication, but for understanding disease mechanisms and for planning future therapeutic strategies.

Is peripheral alpha synuclein a marker for gait velocity in Parkinson's disease?

BACKGROUND: The extent of gait abnormality is non-uniform across motor phenotypes of Parkinson's disease (PD). The biological basis of this heterogeneity remains intriguing. Moreover, the relationship of gait impairment with various neurodegenerative protein markers in PD is not well established. OBJECTIVES: Here, we aimed to explore the interplay between gait parameters and specific serum protein markers in PD. METHODS: A total of 62 PD patients were consecutively recruited. Blood samples and gait data were acquired from 37 and 34 patients respectively. Two-dimensional spatio-temporal gait parameters were estimated using an electronic walkway (GAITRite®, CIR Systems Inc., USA). Serum phosphorylated alpha synuclein (p-Ser129-a-syn) and total a-syn levels were measured using commercially available ELISA kit. Data was analyzed using SPSS Version 20 (IBM). RESULTS: We found that phosphorylated a-syn levels were significantly higher in PD patients with postural instability and gait difficulty compared to tremor dominant variant. Significant reduction in gait velocity was also observed with increasing levels of this pathological form of a-syn. Regression modelling showed that phosphorylated a-syn is an independent predictor of gait velocity. DISCUSSION: Our findings indicate that concentrations of peripheral p-Ser129-a-syn but not total a-syn could be a potential contributor of gait impairment in PD. Further investigation on the systemic role of phosphorylated a-syn on gait would bridge the gap between central and peripheral mechanisms underlying phenotypic variability in PD.

Nigrosome and Neuromelanin Imaging as Tools to Differentiate Parkinson's Disease and Parkinsonism.

Parkinson's disease (PD) lacks a definitive diagnosis due to a lack of pathological validation of patients at antemortem. The risk of misdiagnosis is high in the early stages of PD, often eluded by atypical parkinsonian symptoms. Neuroimaging and laboratory biomarkers are being sought to aid in the clinical diagnosis of PD. Nigrosome imaging and neuromelanin (NM)-sensitive magnetic resonance imaging (MRI) are the new emerging tools, both technically simple plus cost-effective for studying nigral pathology, and have shown potential for authenticating the clinical diagnosis of PD. Visual assessment of the nigrosome-1 appearance, at 3 or 7 Tesla, yields excellent diagnostic accuracy for differentiating idiopathic PD from healthy controls. Moreover, midbrain atrophy and putaminal hypointensity in nigrosome-1 imaging are valid pointers in distinguishing PD from allied parkinsonian disorders. The majority of studies employed T2 and susceptibility-weighted imaging MRI sequences to visualize nigrosome abnormalities, whereas T1-weighted fast-spin echo sequences were used for NM imaging. The diagnostic performance of NM-sensitive MRI in discriminating PD from normal HC can be improved further. Longitudinal studies with adequate sampling of varied uncertain PD cases should be designed to accurately evaluate the sensitivity and diagnostic potential of nigrosome and NM imaging techniques. Equal weightage is to be given to uniformity and standardization of protocols, data analysis, and interpretation of results. There is tremendous scope for identifying disease-specific structural changes in varied forms of parkinsonism with these low-cost imaging tools. Nigrosome-1 and midbrain NM imaging may not only provide an accurate diagnosis of PD but could mature into tools for personally tailored treatment and prognosis.

Comparing Stop Signal Reaction Times in Alzheimer's and Parkinson's Disease.

BACKGROUND: To investigate the relative contributions of cerebral cortex and basal ganglia to movement stopping, we tested the optimum combination Stop Signal Reaction Time (ocSSRT) and median visual reaction time (RT) in patients with Alzheimer's disease (AD) and Parkinson's disease (PD) and compared values with data from healthy controls. METHODS: Thirty-five PD patients, 22 AD patients, and 29 healthy controls were recruited to this study. RT and ocSSRT were measured using a hand-held battery-operated electronic box through a stop signal paradigm. RESULT: The mean ocSSRT was found to be 309 ms, 368 ms, and 265 ms in AD, PD, and healthy controls, respectively, and significantly prolonged in PD compared to healthy controls (p = 0.001). The ocSSRT but not RT could separate AD from PD patients (p = 0.022). CONCLUSION: Our data suggest that subcortical networks encompassing dopaminergic pathways in the basal ganglia play a more important role than cortical networks in movement-stopping. Combining ocSSRT with other putative indices or biomarkers of AD (and other dementias) could increase the accuracy of early diagnosis.

Clinical Significance of Applause Sign in Patients with Progressive Supranuclear Palsy.

Applause sign (AS) is a clinical phenomenon observed in several neurological disorders including progressive supranuclear palsy (PSP). We investigated the factors associated with AS in patients with PSP. PSP patients with AS showed greater motor impairment compared to those with negative AS. Global cognition including attention and memory were affected more in patients with positive AS. We also observed that gait variability, a known marker for unstable gait is pronounced in those who presented with positive AS. Hence, the clinician might expect a more severe disease and an unstable gait in a PSP patient presenting with AS.

Soluble LAG-3 and Toll-interacting protein: Novel upstream neuro-inflammatory markers in Parkinson's disease.

INTRODUCTION: There is some evidence regarding the role of LAG-3, TLR mediated neuroinflammation in PD. METHODS: sLAG-3, TOLLIP, NLRP3 levels were measured in PD and healthy controls. RESULTS: These markers were significantly higher in PD and were associated with progression. CONCLUSION: sLAG3 and TOLLIP are involved in the NLRP3 mediated inflammatory activation in PD.

Spectrum of hospitalized NeuroCOVID diagnoses from a tertiary care neurology centre in Eastern India.

PURPOSE: To describe the spectrum of hospitalized NeuroCOVID on admission in a tertiary neurology centre in Kolkata, the largest and most populated metropolitan city in Eastern India. METHOD: We retrospectively studied confirmed COVID-19 patients admitted with a neurological condition from 1st May 2020 to 30th January 2021. Neurological diagnoses and their temporal relationship to respiratory features along with clinicodemographic profile for such patients was ascertained. RESULT: 228 patients were diagnosed with NeuroCOVID at our centre. Of the 162 included population (median age was 59 (50-70) and 62.3% (101) were male) and 73.5% were diagnosed with NeuroCovid before any respiratory or febrile features. 46 patients (28.8%) had a pre/co-existing neurological illness, and 103 (63.6%) had systemic comorbidities. No significant difference was observed when comparing demographics and comorbidities of NeuroCOVID patients presenting with and without fever and respiratory features. Moreover, no individual NeuroCOVID diagnosis was more prone to present with respiratory or febrile features. Diabetes mellitus was the only comorbidity which was significantly higher in the ischemic stroke group, all other comorbidities and characteristics were evenly distributed between stroke and non-stroke NeuroCOVID patients and encephalopathy non encephalopathy NeuroCOVID patients. CONCLUSION: Stroke and encephalopathy are the most prevalent parainfectious neurological conditions occurring with COVID-19 in the Indian population. This study demonstrates seemingly low-risk individuals (i.e. people without pre-existing systemic and neurological comorbidities) may develop neurological conditions. Moreover, NeuroCOVID may manifest independent of respiratory features and fever.