Resequencing the complete SNCA locus in Indian patients with Parkinson's disease.

The genetic loci implicated in familial Parkinson's disease (PD) have limited generalizability to the Indian PD population. We tested mutations and the frequency of known mutations in the SNCA gene in a PD cohort from India. We selected 298 PD cases and 301 age-matched controls for targeted resequencing (before QC), along with 363 PD genomes of Indian ancestry and 1029 publicly available whole genomes from India as healthy controls (IndiGenomes), to determine the frequency of monogenic SNCA mutations. The raw sequence reads were analyzed using an in-house analysis pipeline, allowing the detection of small variants and structural variants using Manta. The in-depth analysis of the SNCA locus did not identify missense or structural variants, including previously identified SNCA mutations, in the Indian population. The familial forms of SNCA gene variants do not play a major role in the Indian PD population and this warrants further research in the under-represented population.

A Novel PINK1 p.F385S Loss-of-Function Mutation in an Indian Family with Parkinson's Disease.

BACKGROUND: Most Parkinson's disease (PD) loci have shown low prevalence in the Indian population, highlighting the need for further research. OBJECTIVE: The aim of this study was to characterize a novel phosphatase tensin homolog-induced serine/threonine kinase 1 (PINK1) mutation causing PD in an Indian family. METHODS: Exome sequencing of a well-characterized Indian family with PD. A novel PINK1 mutation was studied by in silico modeling using AlphaFold2, expression of mutant PINK1 in human cells depleted of functional endogenous PINK1, followed by quantitative image analysis and biochemical assessment. RESULTS: We identified a homozygous chr1:20648535-20648535 T>C on GRCh38 (p.F385S) mutation in exon 6 of PINK1, which was absent in 1029 genomes from India and in other known databases. PINK1 F385S lies within the highly conserved Deutsche Forschungsgemeinschaft (DFG) motif, destabilizes its active state, and impairs phosphorylation of ubiquitin at serine 65 and proper engagement of parkin upon mitochondrial depolarization. CONCLUSIONS: We characterized a novel nonconservative mutation in the DFG motif of PINK1, which causes loss of its ubiquitin kinase activity and inhibition of mitophagy. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Quantifying abnormal writing kinematics in writer's cramp using a novel software platform.

BACKGROUND: Writer's cramp is a task-specific focal hand dystonia, which is diagnosed clinically. Quantification of defect in WC is done using clinical scales, while digitized platforms are lacking. OBJECTIVE: To design and test a platform that can differentiate and quantify the abnormal kinematics of writing using a software interface and to validate it in adult-onset isolated writer's cramp (WC). METHODS: A native platform was designed using Java and Wacom Intuos pro tablet and the data analyzed using a MATLAB-based platform called Large Data-Based Evaluation of Kinematics in Handwriting (LEKH). We standardized this new platform by comparing the handwriting between patients with WC and age, and gender and education-matched healthy controls, using standard tasks to assess the kinematics. RESULTS: Comparison of the writing of right-handed WC patients (N = 21) and 39 healthy controls (N = 39) showed that patients differed from controls in the frequency of strokes (P < 0.001), number of inversions of velocity (P < 0.001), number of breaks (P = 0.02), air time and paper time (P < 0.001). CONCLUSIONS: Using the LEKH platform, the kinematic profile of patients with WC could be differentiated from healthy controls. Studies in larger samples will be needed to derive statistical models that can differentiate the flexion and extension types of WC which can help in muscle selection and to quantify the effects of treatment.

Deep Brain Stimulation for Parkinson's Disease-the Developing World's Perspective.

Background: Deep brain stimulation (DBS) is the most widely used device-assisted therapy in patients with moderately advanced stages of Parkinson's disease (PD) experiencing motor complications. Only a minority of eligible patients get the opportunity to undergo DBS in the developing world. Objectives: To examine the proportion and characteristics of patients with motor complications of PD who are willing for DBS and who undergo surgery. Methods: Patients with motor complications of PD eligible for DBS over a five-year study period (2016-2020) were included. The demographic, clinical and socio-economic characteristics and information on their status in 2021 were collected and analyzed. Results: Among 1017 patients, 223 had motor symptoms qualifying for DBS and follow-up information available. Only 78 (35%) opted for surgery. The willing patients had higher socioeconomic status, were older and had longer duration of PD and motor complications, more freezing of gait, cognitive symptoms, and neuropsychiatric disturbances. 37 of them were found unfit during pre-operative work-up; only 41 (18%) with motor complications were finally taken up for DBS. Age, duration or severity of motor symptoms did not differ between patients who were finally selected for surgery and those who were not. Conclusions: Less than one-fifth of our patients with motor complications of PD finally underwent DBS. The patients appeared to wait till the late stages of PD, before making a decision on availing surgical treatment. The delay resulted in nearly half of them being found unfit in pre-operative work-up. Our findings may enable clinicians to counsel eligible patients more efficiently.

Depotentiation of associative plasticity is intact in Parkinson's disease with mild dyskinesia.

OBJECTIVE: Depotentiation of homosynaptic plasticity of the primary motor cortex (M1) is impaired in patients with Parkinson's disease (PD) who have developed dyskinesias. In this exploratory study, we tested whether this holds true for heterosynaptic plasticity induced by paired associative stimulation (PAS). METHODS: Dyskinetic (n=11) and Non-dyskinetic (n=11), levodopa-treated PD patients were tested in M1 with PAS25ms alone, PAS25ms preceded by continuous theta-burst stimulation of the cerebellum (cTBSCB-PAS) as a method to evoke a larger plastic response in M1, and each of these two interventions followed by a depotentiation protocol (cTBS150pulses) to M1. RESULTS: PAS25ms and cTBSCB-PAS25ms induced long-term potentiation (LTP)-like responses in both groups of PD patients, with cTBSCB significantly boosting the plastic response. Both these LTP-like responses could be depotentiated by cTBS150, in both groups of patients. CONCLUSIONS: Cerebellar stimulation enhances heterosynaptic plasticity in PD irrespective of dyskinesias. Depotentiation mechanisms of heterosynaptic plasticity are preserved in PD patients, including those with dyskinesias. The lack of depotentiation of LTP-like plasticity as a hallmark of dyskinesia in PD patients is not absolute. The ability to depotentiate LTP-like plasticity may potentially depend on the type of plasticity induced (homosynaptic or heterosynaptic), the circuits involved in these responses and the adequacy of dopaminergic stimulation.

Plastic responsiveness of motor cortex to paired associative stimulation depends on cerebellar input.

OBJECTIVE: The extent of plastic responses of motor cortex (M1) to paired associative stimulation (PAS) varies among healthy subjects. Continuous theta-burst stimulation (cTBS) of cerebellum enhances the mean PAS-induced plasticity in groups of healthy subjects. We tested whether the initial status of Responder or Non -Responder to PAS, influenced the effect of cerebellar stimulation on PAS-induced plasticity. METHODS: We assessed in 19 young healthy volunteers (8 Responders, 11 Non-Responders to PAS), how cTBS and iTBS (intermittent TBS) applied to the cerebellum before a PAS protocol influenced the plastic responsiveness of M1 to PAS. We tested whether the PAS-induced plastic effects could be depotentiated by a short cTBS protocol applied to M1 shortly after PAS and whether cerebellar stimulation influenced GABA-ergic intracortical inhibition and M1 plasticity in parallel. RESULTS: Cerebellar cTBS restored the M1 response to PAS in Non-Responders while cerebellar iTBS turned the potentiating response to PAS to a depressive response in both groups. The depotentiation protocol abolished both responses. CONCLUSION: Non-Responder status to PAS is a state of M1 amenable to bidirectional plastic modulation when primed by a change in cerebello-thalamic drive. SIGNIFICANCE: The meaning of lack of responsiveness to certain protocols probing plasticity should be reconsidered.

Apraxia of Lid Opening in Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease-Frequency, Risk Factors and Response to Treatment.

BACKGROUND: New-onset apraxia of lid opening (ALO) is reported to occur in Parkinson's disease (PD) patients following Deep Brain Stimulation (DBS). There are only few systematic studies on this uncommon disorder of eyelid movements. OBJECTIVES: We aimed to examine the frequency, temporal evolution, predisposing factors and response to treatment, of new-onset ALO in PD patients who underwent bilateral subthalamic nucleus (STN) DBS. METHODS: We retrospectively reviewed the data of patients who underwent STN DBS at our centre between 1999 and 2017, with a minimum of 2 years of follow up after surgery. RESULTS: New-onset ALO was seen in 17 (9.1%) of the 187 patients after an average of 16.9 months (Range - 6-36 months). Comparison of the groups with and without ALO revealed that ALO occurred more often in older patients, both at the onset of PD symptoms and at surgery and in those with non-tremor dominant subtypes of PD and freezing of gait at baseline. The extent of levodopa dose reduction after surgery and the pre-operative severity of motor symptoms were not risk factors. Response to adjustments of dopaminergic medications and stimulation parameters was ill-sustained or nil. Botulinum toxin therapy resulted in satisfactory improvement in the majority. CONCLUSIONS: New-onset ALO is an uncommon phenomenon that manifests months after STN DBS. Development of ALO is likely to be due to the effects of chronic stimulation of basal ganglia-thalamo-cortical or brain stem circuits controlling lid movements in susceptible patients. Botulinum toxin therapy offers relatively better relief of symptoms than other strategies.

Dopamine Receptor D3 rs6280 is Associated with Aberrant Decision-Making in Parkinson's Disease.

BACKGROUND: The functional Ser9Gly single nucleotide polymorphism (SNP) in the dopamine D3 receptor gene is associated with impulse control disorders (ICD) in Parkinson's disease (PD) in Indian patients. Whether the same SNP modulates impulsivity in PD patients without active ICD is unknown. We aimed to compare decision-making under uncertainty in PD patients with DRD3 p.S9G (rs6280) variants CT/CC or TT. METHODS: We conducted a cross-sectional study including PD patients (n = 78) whose DRD3 p.S9G (rs6280) genotypic status was known (CC, CT, and TT). Decision-making was assessed using the Iowa Gambling Task (IGT). RESULTS: IGT total (p = 0.267) or block scores did not differ between the DRD3 rs6280 variant groups. Deck choice analysis revealed that the CT/CC group showed a skewed preference in deck choice (p = 0.002) due to significantly fewer draws from deck B, compared to all other decks (deck A, p < 0.001; deck C, p = 0.004; deck D, p = 0.002). CONCLUSIONS: The functional Ser9Gly DRD3 variant is associated with aberrant decision-making under uncertainty in PD patients without active ICD. This ability to modulate impulsivity may underlie its association with clinical ICD in PD.

Dopamine D3 receptor Ser9Gly variant is associated with impulse control disorders in Parkinson's disease patients.

INTRODUCTION: Impulse control disorders (ICD) are reported to occur at variable frequencies in different ethnic groups. Genetic vulnerability is suspected to underlie the individual risk for ICD. We investigated whether the allelic variants of dopamine (DRD3), glutamate (GRIN2B) and serotonin (HTR2A) receptors are linked to ICD in Indian Parkinson's disease (PD) patients. METHODS: We conducted a prospective, case-control study which included PD patients (70 with ICD, 100 without ICD categorized after direct psychiatric interview of patient and caregiver) and 285 healthy controls. Single nucleotide polymorphism (SNP) variants of DRD3 p.S9G (rs6280), GRIN2B c.2664C>T (rs1806201) and HTR2A c.102T>C (rs6313) were genotyped. RESULTS: Multivariate regression analysis revealed that DRD3 p.Ser9Gly (rs6280) heterozygous variant CT (OR = 2.22, 95% CI: 1.03-4.86, p = 0.041), higher daily Levodopa equivalent doses (LED) of drugs (for 100 mg LED, OR = 1.14, 95% CI: 1.01-1.29, p = 0.041), current dopamine agonist but not Levodopa use (OR = 2.16, 95% CI: 1.03-4.55, p = 0.042) and age of onset of motor symptoms under 50 years (OR 2.09, 95% CI: 1.05-4.18, p = 0.035) were independently associated with ICD. CONCLUSION: DRD3 p.Ser9Gly (rs6280) CT genotype is associated with ICD in Indian PD patients and this association is novel. Enhanced D3 receptor affinity due to gain-of-function conferred by the glycine residues could impair reward-risk assessment in the mesolimbic system and contribute to development of impulsive behaviour, in carriers of this genotype.

The decade after subthalamic stimulation in advanced Parkinson's disease: A balancing act.

AIM: The duration of improvement in quality of life after subthalamic nucleus deep brain stimulation (STN DBS) for Parkinson's disease (PD) and the presurgical identification of factors predicting sustained clinical benefits have implications in patient selection and timing of surgery. These aspects were assessed in patients who underwent yearly assessment for at least 7 years after surgery. MATERIALS AND METHODS: The quality of life, motor and cognitive outcomes of 25 patients who completed the 7-year assessment, and 12 patients who completed the 10-year assessment, were analyzed. RESULTS: The improvement in quality of life was sustained only for 5 years, while the severity of motor signs and motor fluctuations remained reduced at 7 and 10 years. Tremor and rigidity showed more enduring reduction than bradykinesia and axial signs. The dose reduction in medications could be maintained until 7 years, by which time, the axial scores were worse than that seen at the pre-DBS levels. At 10 years, a higher levodopa requirement and recurrence of dyskinesias were noted. Patients with greater pre-DBS levodopa-responsive motor signs had greater long-term motor improvement. CONCLUSIONS: STN DBS performed in patients with advanced motor fluctuations and severe dyskinesias provide only an average of 5 years of quality of life improvement. STN DBS in patients with motor signs that are less responsive to levodopa results in shorter duration of clinical benefits. The improvements in the severity of motor fluctuations, rigidity, and tremor are the most enduring benefits of STN DBS that last a decade . However, these are offset by worsening axial and cognitive functions, bradykinesia, a higher levodopa requirement, and recurrence of dyskinesias by the end of the decade.

Do nonmotor symptoms in Parkinson's disease differ from normal aging?

BACKGROUND: Nonmotor symptoms in Parkinson's disease are frequent and affect health-related quality of life of patients. The severity and domains of nonmotor symptoms involved in Parkinson's disease and normal aging have not been compared before. METHODS: We performed a prospective case-control study to assess the frequency and severity of nonmotor symptoms in patients with Parkinson's disease (n = 174) and age-matched normal controls (n = 128) using the Non-Motor Symptoms Scale. RESULTS: Nonmotor symptoms in Parkinson's disease were ubiquitous, more frequent, and more severe than in normal aging, particularly in women. Cardiovascular, mood/cognition, and perceptual problems/hallucinations domains were rarely involved in age-matched controls. Age had no effect and sex some influence on nonmotor symptoms in Parkinson's disease. In contrast, in controls, nonmotor symptoms increased with age, and sex had no effect. CONCLUSIONS: Nonmotor symptoms in Parkinson's disease differ from those in aging in frequency, severity, sex predilection, and domain involvement.

Long-term stability of effects of subthalamic stimulation in Parkinson's disease: Indian Experience.

Reports of long-term effects of subthalamic (STN) stimulation for Parkinson's disease (PD) are few, mostly open-label evaluations and from Western centers. We used single-blind and open-label motor, cognitive and quality of life (QOL) evaluations to study the effects of bilateral STN stimulation in 45 patients over 5 years. Our patients showed a stable and substantial reduction in the cardinal signs of PD, motor fluctuations, and dyskinesias but less so for axial signs. The reduction in medications and the intensity of electrical stimulation needed also remained stable during follow up. Although the total QOL and its parkinsonism and social components showed sustained benefits till 5 years, the gains in emotional and systemic subsets were short lasting. Global scores for mood and cognition did not show significant worsening. Benefits of STN stimulation on the cardinal signs, motor complications, and QOL of advanced PD were substantial and sustained till 5 years. The initial benefits in axial motor signs and emotional and psychological aspects of QOL did not show similar stability. In general, the procedure had insignificant impact on cognition and mood. This is the first report of STN stimulation in Asian patients with PD.