Unravelling the Parkinson's puzzle, from medications and surgery to stem cells and genes: a comprehensive review of current and future management strategies.

Parkinson's disease (PD) is a neurodegenerative disorder, prevalent in the elderly population. Neuropathological hallmarks of PD include loss of dopaminergic cells in the nigro-striatal pathway and deposition of alpha-synuclein protein in the neurons and synaptic terminals, which lead to a complex presentation of motor and non-motor symptoms. This review focuses on various aspects of PD, from clinical diagnosis to currently accepted treatment options, such as pharmacological management through dopamine replacement and surgical techniques such as deep brain stimulation (DBS). The review discusses in detail the potential of emerging stem cell-based therapies and gene therapies to be adopted as a cure, in contrast to the present symptomatic treatment in PD. The potential sources of stem cells for autologous and allogeneic stem cell therapy have been discussed, along with the progress evaluation of pre-clinical and clinical trials. Even though recent techniques hold great potential to improve the lives of PD patients, we present the importance of addressing the safety, efficacy, ethical, cost, and regulatory concerns before scaling them to clinical use.

Exosomal microRNAs in Parkinson's disease: insights into biomarker potential and disease pathology.

Parkinson's disease (PD) is a prevalent neurodegenerative condition primarily affecting the elderly population. Despite its high incidence in aged individuals, there are no reliable blood-based biomarkers for clinical diagnosis of PD and early screening of susceptible individuals. Recent studies have revealed the significance of exosomes in mediating cell-to-cell communications by transferring bioactive molecules, such as proteins, nucleic acids (including miRNAs), lipids, and metabolites, between cells. Due to their ability to carry diverse molecular cargo and their involvement in various physiological and pathological processes, exosomes have gained significant attention as potential disease biomarkers. Notably, exosomes have the ability to cross the blood-brain barrier, and as a result, they can be found in circulating body fluids, including cerebrospinal fluid (CSF), serum, and plasma. Therefore, the identification of PD-specific exosomes in blood samples could be a promising avenue with biomarker potential for advancing clinical diagnosis and planning therapeutic strategies. This review highlights the current understanding of exosomal miRNAs in PD pathology, emphasising their potential for clinical utility as biomarkers even though several challenges may have to be overcome to precisely utilize exosomal miRNAs as biomarkers specific to PD.

Understanding the role of genetic variability in LRRK2 in Indian population.

BACKGROUND: Genetic variability in LRRK2 has been unequivocally established as a major risk factor for familial and sporadic forms of PD in ethnically diverse populations. OBJECTIVES: To resolve the role of LRRK2 in the Indian population. METHODS: We performed targeted resequencing of the LRRK2 locus in 288 cases and 298 controls and resolved the haplotypic structure of LRRK2 in a combined cohort of 800 cases and 402 controls in the Indian population. We assessed the frequency of novel missense variants in the white and East Asian population by leveraging exome sequencing and densely genotype data, respectively. We did computational modeling and biochemical approach to infer the potential role of novel variants impacting the LRRK2 protein function. Finally, we assessed the phosphorylation activity of identified novel coding variants in the LRRK2 gene. RESULTS: We identified four novel missense variants with frequency ranging from 0.0008% to 0.002% specific for the Indian population, encompassing armadillo and kinase domains of the LRRK2 protein. A common genetic variability within LRRK2 may contribute to increased risk, but it was nonsignificant after correcting for multiple testing, because of small cohort size. The computational modeling showed destabilizing effect on the LRRK2 function. In comparison to the wild-type, the kinase domain variant showed 4-fold increase in the kinase activity. CONCLUSIONS: Our study, for the first time, identified novel missense variants for LRRK2, specific for the Indian population, and showed that a novel missense variant in the kinase domain modifies kinase activity in vitro. © 2018 International Parkinson and Movement Disorder Society.

Severity of Writer's Cramp is Related to Faulty Motor Preparation.

We characterized, in 37 writer's cramp (WC) patients and 14 healthy volunteers (HV), the buildup of motor representations contralateral ("intended") and ispsilateral ("unintended") to the movement to be produced and the excitability changes in left primary motor cortex during the early reaction time (RT) of a pre-cued reaching movement to pick up a pen with either hand to write. We also tested the excitability of interhemispheric pathways from right dorsal premotor and motor cortices to left motor cortex. During early RT (1) the motor cortex excitability of unintended muscle representations did not decrease in patients as in HV and (2) the connection from the contralateral dorsal premotor cortex to the "intended" motor representation did not function in patients. In HV, the efficiency of intracortical GABA-ergic circuits at rest predicted the degree of excitability changes in the intended motor representation in the early RT. This was not true in patients who had lower efficiency of GABA-ergic circuits. Interestingly, the more severe was the writing impairment, the higher was the level of excitability in the intended and unintended motor representations. It demonstrates, for the first time, that abnormal motor preparation influences the severity of the writing impairment in WC patients.

Environment-Modulated Crystallization of Cu2O and CuO Nanowires by Electrospinning and Their Charge Storage Properties.

This article reports the synthesis of cuprous oxide (Cu2O) and cupric oxide (CuO) nanowires by controlling the calcination environment of electrospun polymeric nanowires and their charge storage properties. The Cu2O nanowires showed higher surface area (86 m2 g-1) and pore size than the CuO nanowires (36 m2 g-1). Electrochemical analysis was carried out in 6 M KOH, and both the electrodes showed battery-type charge storage mechanism. The electrospun Cu2O electrodes delivered high discharge capacity (126 mA h g-1) than CuO (72 mA h g-1) at a current density of 2.4 mA cm-2. Electrochemical impedance spectroscopy measurements show almost similar charge-transfer resistance in Cu2O (1.2 Ω) and CuO (1.6 Ω); however, Cu2O showed an order of magnitude higher ion diffusion. The difference in charge storage between these electrodes is attributed to the difference in surface properties and charge kinetics at the electrode. The electrode also shows superior cyclic stability (98%) and Coulombic efficiency (98%) after 5000 cycles. Therefore, these materials could be acceptable choices as a battery-type or pseudocapacitive electrode in asymmetric supercapacitors.

Deep brain stimulation for movement disorders.

Deep Brain Stimulation (DBS) was introduced into clinical practice nearly four decades ago and is currently the standard of care for patients with Parkinson's disease experiencing motor complications. Apart from this, it has several other established and emerging applications in movement disorders. The exact mechanisms by which DBS provides relief in movement disorders are still unclear; disruption of pathological neuronal synchrony and abnormal information flow through the neuronal circuits involved, are the most likely underlying mechanisms. DBS has been established to be a relatively safe procedure if patients are carefully selected and followed up by experienced multidisciplinary teams. Alternatives to the traditional stereotactic frame based techniques of lead implantation are emerging, and these, along with the other recent technological advances, are likely to extend the availability of this therapy to an increasing number of patients in the future.

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.

Cerebellar sensory processing alterations impact motor cortical plasticity in Parkinson's disease: clues from dyskinetic patients.

The plasticity of primary motor cortex (M1) in patients with Parkinson's disease (PD) and levodopa-induced dyskinesias (LIDs) is severely impaired. We recently reported in young healthy subjects that inhibitory cerebellar stimulation enhanced the sensorimotor plasticity of M1 that was induced by paired associative stimulation (PAS). This study demonstrates that the deficient sensorimotor M1 plasticity in 16 patients with LIDs could be reinstated by a single session of real inhibitory cerebellar stimulation but not sham stimulation. This was evident only when a sensory component was involved in the induction of plasticity, indicating that cerebellar sensory processing function is involved in the resurgence of M1 plasticity. The benefit of inhibitory cerebellar stimulation on LIDs is known. To explore whether this benefit is linked to the restoration of sensorimotor plasticity of M1, we conducted an additional study looking at changes in LIDs and PAS-induced plasticity after 10 sessions of either bilateral, real inhibitory cerebellar stimulation or sham stimulation. Only real and not sham stimulation had an antidyskinetic effect and it was paralleled by a resurgence in the sensorimotor plasticity of M1. These results suggest that alterations in cerebellar sensory processing function, occurring secondary to abnormal basal ganglia signals reaching it, may be an important element contributing to the maladaptive sensorimotor plasticity of M1 and the emergence of abnormal involuntary movements.

Validity of Montreal Cognitive Assessment in non-english speaking patients with Parkinson's disease.

BACKGROUND: The Montreal Cognitive Assessment is a brief and easy screening tool for accurately testing cognitive dysfunction in Parkinson's disease. We tested its validity for use in non-English (Malayalam) speaking patients with Parkinson's disease. MATERIALS AND METHODS: We developed a Malayalam (a south-Indian language) version of Montreal Cognitive Assessment and applied to 70 patients with Parkinson's disease and 60 age- and education-matched healthy controls. Metric properties were assessed, and the scores were compared with the performance in validated Malayalam versions of Mini Mental Status Examination and Addenbrooke's Cognitive Examination. RESULTS: The Montreal Cognitive Assessment-Malayalam showed good internal consistency and test-retest reliability and its scores correlated with Mini Mental Status Examination (patients: R = 0.70; P < 0.001; healthy controls: R = 0.26; P = 0.04) and Addenbrooke's Cognitive Examination (patients: R = 0.8; P < 0.001; healthy controls: R = 0.52; P < 0.001) scores. CONCLUSION: This study establishes the reliability of cross-cultural adaptation of Montreal Cognitive Assessment for assessing cognition in Malayalam-speaking Parkinson's disease patients for early screening and potential future interventions for cognitive dysfunction.

Kenaf-based activated carbon: A sustainable solution for high-performance aqueous symmetric supercapacitors.

This study presents an innovative method for synthesizing activated carbon with an exceptionally high surface area (3359 m2 g-1) using kenaf fiber-based biochar through chemical activation. The achieved specific surface area surpasses activated carbon derived from other reported fiber-based precursors. The resulting activated carbon was investigated as electrodes for supercapacitors, revealing a remarkable maximum capacitance of 312 F g-1 at a current density of 0.5 A g-1. An aqueous symmetric supercapacitor employing these high-surface-area electrodes exhibited an outstanding energy density of 18.9 Wh kg-1 at a power density of 250 W kg-1. Notably, the supercapacitor retained exceptional capacitance, maintaining 93% of its initial capacitance even after 5000 charge-discharge cycles.

A Review on Implantable Neuroelectrodes.

The efficacy of every neuromodulation modality depends upon the characteristics of the electrodes used to stimulate the chosen target. The geometrical, chemical, mechanical and physical configuration of electrodes used in neurostimulation affects several performance attributes like stimulation efficiency, selectivity, tissue response, etc. The efficiency of stimulation in relation to electrode impedance is influenced by the electrode material and/or its geometry. The nature of the electrode material determines the charge transfer across the electrode-tissue interface, which also relates to neuronal tissue damage. Electrode morphology or configuration pattern can facilitate the modulation of extracellular electric field (field shaping). This enables selective activation of neurons and minimizes side effects. Biocompatibility and biostability of the electrode materials or electrode coating have a role in glial formation and tissue damage. Mechanical and electrochemical stability (corrosion resistance) determines the long-term efficacy of any neuromodulation technique. Here, a review of electrodes typically used for implantable neuromodulation is discussed. Factors affecting the performance of electrodes like stimulation efficiency, selectivity and tissue responses to the electrode-tissue interface are discussed. Technological advancements to improve electrode characteristics are also included.

Quantitative susceptibility mapping from basal ganglia and related structures: correlation with disease severity in progressive supranuclear palsy.

OBJECTIVE: We examined whether mean magnetic susceptibility values from deep gray matter structures in patients with progressive supranuclear palsy (PSP) differed from those in patients with Parkinson's disease (PD) and healthy volunteers, and correlated with the PSP rating scale. METHODS: Head of caudate nucleus, putamen, globus pallidus, substantia nigra and red nucleus were the regions of interest. Mean susceptibility values from these regions in PSP patients were estimated using quantitative susceptibility mapping. Correlations with clinical severity of disease as measured by the PSP rating scale were examined. The mean susceptibility values were also compared with those from healthy volunteers and age- and disease duration-matched patients with PD. RESULTS: Data from 26 healthy volunteers, 26 patients with PD and 27 patients with PSP, were analysed. Patients with PSP had higher mean susceptibility values from all regions of interest when compared to both the other groups. The PSP rating scale scores correlated strongly with mean susceptibility values from the red nucleus and moderately with those from the putamen and substantia nigra. The scores did not correlate with mean susceptibility values from the caudate nucleus or globus pallidus. In patients with PD, the motor deficits correlated moderately with mean susceptibility values from substantia nigra. CONCLUSIONS: In patients with PSP, mean susceptibility values indicating the severity of mineralization of basal ganglia and related structures correlate with disease severity, the correlation of red nucleus being the strongest. Further studies are warranted to explore whether mean susceptibility values could serve as biomarkers for PSP.

A data mining approach to analyze the role of biomacromolecules-based nanocomposites in sustainable packaging.

Recent decades have witnessed a surge in research interest in bio-nanocomposite-based packaging materials, but still, a lack of systematic analysis exists in this domain. Bio-based packaging materials pose a sustainable alternative to petroleum-based packaging materials. The current work employs bibliometric analysis to deliver a comprehensive outline on the role of bio nanocomposites in packaging. India, Iran, and China were revealed to be the top three nations actively engaged in this domain in total publications. Islamic Azad University in Iran and Universiti Putra Malaysia in Malaysia are among the world's best institutions in active research and publications in this field. The extensive collaboration between nations and institutions highlights the significance of a holistic approach towards bio-nanocomposite. The National Natural Science Foundation of China is the leading funding body in this field of research. Among authors, Jong whan Rhim secured the topmost citations (2234) in this domain (13 publications). Among journals, Carbohydrate Polymers secured the maximum citation count (4629) from 36 articles; the initial one was published in 2011. Bio nanocomposite is the most frequently used keyword. Researchers and policymakers focussing on sustainable packaging solutions will gain crucial insights on the current research status on packaging solutions using bio-nanocomposites from the conclusions.

Understanding the Solid-Electrolyte-Interface (SEI) Formation in Glyme Electrolyte Using Time-Of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS).

Lithium-ion batteries are commonly used for energy storage due to their long lifespan and high energy density, but the use of unsafe electrolytes poses significant health and safety concerns. An alternative source is necessary to maintain electrochemical efficacy. This research demonstrates new safe glyme-based electrolytes for silica/carbon (SiOx/C) nanocomposite derived from Australian rice husk (RH). The quality of SiOx/C was preserved by using deep eutectic solvent-based pre-treatment and single-step carbonization, which was confirmed through the X-ray analysis of the crystalline phase of silica. The electrochemical assessment of SiOx/C anode using various glyme-based electrolytes for LIBs was carried out. Among them, the resultant half cells based on diglyme electrolyte is superior to others with the first discharge capacity at 1274 mAh/g and a reversible discharge capacity of 759.7 mAh/g. Ex-situ SEM and Time-of-Flight Secondary Ion Mass Spectrometry (ToF- SIMS) analysis of the electrode indicated that diglyme not only improves the capacity but also sustains the electrode architecture for longer cycle life with more LiF-based components and also showed the absence of HF components. Importantly, the addition of fluoroethylene carbonate (FEC) additive enhanced the cycling stability. These results provide a new perspective on developing advanced SiOx/C anode using glyme electrolytes for Li-ion batteries.

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.

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.

Cerebellar and basal ganglia structural connections in humans: Effect of aging and relation with memory and learning.

Introduction: The cerebellum and basal ganglia were initially considered anatomically distinct regions, each connected via thalamic relays which project to the same cerebral cortical targets, such as the motor cortex. In the last two decades, transneuronal viral transport studies in non-human primates showed bidirectional connections between the cerebellum and basal ganglia at the subcortical level, without involving the cerebral cortical motor areas. These findings have significant implications for our understanding of neurodevelopmental and neurodegenerative diseases. While these subcortical connections were established in smaller studies on humans, their evolution with natural aging is less understood. Methods: In this study, we validated and expanded the previous findings of the structural connectivity within the cerebellum-basal ganglia subcortical network, in a larger dataset of 64 subjects, across different age ranges. Tractography and fixel-based analysis were performed on the 3 T diffusion-weighted dataset using Mrtrix3 software, considering fiber density and cross-section as indicators of axonal integrity. Tractography of the well-established cerebello-thalamo-cortical tract was conducted as a control. We tested the relationship between the structural white matter integrity of these connections with aging and with the performance in different domains of Addenbrooke's Cognitive Examination. Results: Tractography analysis isolated connections from the dentate nucleus to the contralateral putamen via the thalamus, and reciprocal tracts from the subthalamic nucleus to the contralateral cerebellar cortex via the pontine nuclei. Control tracts of cerebello-thalamo-cortical tracts were also isolated, including associative cerebello-prefrontal tracts. A negative linear relationship was found between the fiber density of both the ascending and descending cerebellum-basal ganglia tracts and age. Considering the cognitive assessments, the fiber density values of cerebello-thalamo-putaminal tracts correlated with the registration/learning domain scores. In addition, the fiber density values of cerebello-frontal and subthalamo-cerebellar (Crus II) tracts correlated with the cognitive assessment scores from the memory domain. Conclusion: We validated the structural connectivity within the cerebellum-basal ganglia reciprocal network, in a larger dataset of human subjects, across wider age range. The structural features of the subcortical cerebello-basal ganglia tracts in human subjects display age-related neurodegeneration. Individual morphological variability of cerebellar tracts to the striatum and prefrontal cortex was associated with different cognitive functions, suggesting a functional contribution of cerebellar tracts to cognitive decline with aging. This study offers new perspectives to consider the functional role of these pathways in motor learning and the pathophysiology of movement disorders involving the cerebellum and striatum.

Oromandibular Dystonia - A Systematic Review.

Oromandibular dystonia (OMD) is a clinical problem which is commonly encountered in the practice of movement disorders. OMD results from a variety of genetic and acquired etiologies and can occur as an isolated manifestation, or as part of an isolated generalized or a combined dystonia syndrome. There are only very few systematic reviews on this condition which often causes significant disability. We review here the etiology, clinical features, diagnostic approach and management of OMD.