The Genetic Drivers of Juvenile, Young, and Early-Onset Parkinson's Disease in India.

BACKGROUND: Recent studies have advanced our understanding of the genetic drivers of Parkinson's disease (PD). Rare variants in more than 20 genes are considered causal for PD, and the latest PD genome-wide association study (GWAS) identified 90 independent risk loci. However, there remains a gap in our understanding of PD genetics outside of the European populations in which the vast majority of these studies were focused. OBJECTIVE: The aim was to identify genetic risk factors for PD in a South Asian population. METHODS: A total of 674 PD subjects predominantly with age of onset (AoO) ≤50 years (encompassing juvenile, young, or early-onset PD) were recruited from 10 specialty movement disorder centers across India over a 2-year period; 1376 control subjects were selected from the reference population GenomeAsia, Phase 2. We performed various case-only and case-control genetic analyses for PD diagnosis and AoO. RESULTS: A genome-wide significant signal for PD diagnosis was identified in the SNCA region, strongly colocalizing with SNCA region signal from European PD GWAS. PD cases with pathogenic mutations in PD genes exhibited, on average, lower PD polygenic risk scores than PD cases lacking any PD gene mutations. Gene burden studies of rare, predicted deleterious variants identified BSN, encoding the presynaptic protein Bassoon that has been previously associated with neurodegenerative disease. CONCLUSIONS: This study constitutes the largest genetic investigation of PD in a South Asian population to date. Future work should seek to expand sample numbers in this population to enable improved statistical power to detect PD genes in this understudied group. © 2023 Denali Therapeutics and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Arg4810Lys mutation in RNF213 among Eastern Indian non-MMD ischemic stroke patients: a genotype-phenotype correlation.

INTRODUCTION: RNF213 mutations have been reported mostly in moyamoya disease (MMD) with varying frequencies across different ethnicities. However, its prevalence in non-MMD adult-onset ischemic stroke is still not well explored. AIMS AND OBJECTIVES: This present study thus aims to screen the most common RNF213 variant (Arg4810Lys, among East Asians) in the Eastern Indian non-MMD ischemic stroke patients and correlate it with long-term progression and prognosis of the patients. The subjects were analyzed for this variant using PCR-RFLP and confirmed using Sanger sequencing method. RESULT AND CONCLUSION: We have identified Arg4810Lys variant among eleven young-onset familial ischemic stroke patients in heterozygous manner. A positive correlation of the variant with positive family history (P = 0.001), earlier age at onset (P = 0.002), and history of recurrent stroke (P = 0.015) was observed. However, the carriers showed better cognitive performances in memory (P = 0.042) and executive function (P = 0.004). Therefore, we can conclude that Arg4810Lys/RNF213 - a pathogenic variant for young-onset familial ischemic stroke with higher incidence of recurrent events unlike in MMD cases, have no additional impact on cognition among Eastern Indians.

An Indian Young-onset Dementia With Parkinsonism With Double Heterozygous Mutations in ABCA7 and PRKN Identified Through Whole-exome Sequencing.

Alzheimer disease and Parkinson disease dementia are the 2 most common neurodegenerative diseases have substantial overlap in pathologic, genetic, and clinical manifestation and complex in nature. Here, for the first time, we report an Indian female young patient who presented with clinical manifestation of both Alzheimer disease and Parkinsonism, including dystonia with rapid disease progression. We identified a heterozygous mutation in the ATP-binding cassette transporter A7 gene and double heterozygous mutation in PRKN by whole-exome sequencing. This case is an example of complex etiology of neurodegenerative disorders and highlights the importance of genetic tests, including whole-exome sequencing in complex diseases.

Pragmatic deficits in patients with schizophrenia and right hemisphere damage: A pilot study.

BACKGROUND: While pragmatic deficits are well documented in patients with schizophrenia (SCZ) and right hemisphere damage (RHD), there is a paucity of research comparing the pragmatic deficits of these two groups. Do they experience similar cognitive dysfunction or is there a dissociation between the two patient groups? AIMS: To investigate the nature of pragmatic deficits in these two groups and to gain an understanding of the underlying cognitive mechanisms that might be associated with these deficits to further future investigations. METHODS & PROCEDURES: A total of 60 participants (15 patients with SCZ; 15 with RHD; 30 (15 + 15) healthy controls (HC) were administered the Bengali Audio-Visual Test-Battery for Assessment of Pragmatic Skills. OUTCOMES & RESULTS: Both SCZ and RHD patients were found to have significant pragmatic deficits compared with their matched controls. SCZ patients were found to score significantly better than the RHD group in six out of the 10 pragmatic skills when controlled for age and education. Discriminant function analysis was performed and 86.7% of the cases (HC = 100%, SCZ = 73.3% and RHD = 86.7%) were correctly reclassified into their original categories using the test scores. CONCLUSIONS & IMPLICATIONS: The study suggests that there is heterogeneity in the nature of the pragmatic breakdown within and across patient groups. Therefore, individualized restorative measures targeting the disrupted cognitive mechanism(s) might help elevate pragmatic competence and enhance the social functioning of patients with pragmatic deficits. WHAT THIS PAPER ADDS: What is already known on the subject Pragmatic deficits are common in adults with cognitive impairments of different etiologies. However, few studies have explored pragmatic deficits across clinical populations. Consequently, very little is known about the nature of pragmatic deficits in patients with schizophrenia and right hemisphere damage. What this paper adds to existing knowledge This work offers preliminary data on pragmatic difficulties in patients with schizophrenia and right hemisphere damage. This study overrides the boundaries of traditional classifications and evaluates pragmatic difficulties in these two clinical populations with reference to the underlying cognitive mechanisms, which might be disrupted. What are the potential or actual clinical implications of this work? The study adds a transdiagnostic perspective suggesting that there might be heterogeneity in pragmatic deficits, both within and across patient groups, and stresses the need for individualized therapy.

The scope of using pragmatic language tests for early detection of dementia: A systematic review of investigations using figurative language.

INTRODUCTION: Dementia cases are expected to rise to 81.1 million in 2040. Efforts are underway to develop diagnostic methods to facilitate early detection of the disease. Herein we review research findings focusing on pragmatic dysfunction in patients with dementia and evaluate the usefulness of assessing dementia and its progress with a battery of tests assessing figurative language skills. METHODS: A total of 74,778 article titles were identified from EMBASE, PubMed, and Google Scholar databases. After systematic screening, 51 journal articles were selected for the final review. RESULT: The review suggests that impaired figurative language might be a marker for early cognitive decline. Different forms of figurative language may be impaired at different stages of the disease and in different types of dementia involving different neuropathologies. CONCLUSION: The use of pragmatic tests in combination with the existing diagnostic protocols might increase the probability of early diagnosis. HIGHLIGHTS Pragmatic impairment could be a marker of early cognitive impairment. Figurative language-an important pragmatic aspect-is disrupted in mild cognitive impairment (MCI) and early Alzheimer's disease (AD). Figurative language impairment might precede literal language impairment. Pragmatic tests could be more sensitive than standard neuropsychological tests. Inclusion of pragmatic tests in diagnostic guidelines might bolster early detection.

Clinical Study of 668 Indian Subjects with Juvenile, Young, and Early Onset Parkinson's Disease.

OBJECTIVE: To determine the demographic pattern of juvenile-onset parkinsonism (JP, <20 years), young-onset (YOPD, 20-40 years), and early onset (EOPD, 40-50 years) Parkinson's disease (PD) in India. MATERIALS AND METHODS: We conducted a 2-year, pan-India, multicenter collaborative study to analyze clinical patterns of JP, YOPD, and EOPD. All patients under follow-up of movement disorders specialists and meeting United Kingdom (UK) Brain Bank criteria for PD were included. RESULTS: A total of 668 subjects (M:F 455:213) were recruited with a mean age at onset of 38.7 ± 8.1 years. The mean duration of symptoms at the time of study was 8 ± 6 years. Fifteen percent had a family history of PD and 13% had consanguinity. JP had the highest consanguinity rate (53%). YOPD and JP cases had a higher prevalence of consanguinity, dystonia, and gait and balance issues compared to those with EOPD. In relation to nonmotor symptoms, panic attacks and depression were more common in YOPD and sleep-related issues more common in EOPD subjects. Overall, dyskinesias were documented in 32.8%. YOPD subjects had a higher frequency of dyskinesia than EOPD subjects (39.9% vs. 25.5%), but they were first noted later in the disease course (5.7 vs. 4.4 years). CONCLUSION: This large cohort shows differing clinical patterns in JP, YOPD, and EOPD cases. We propose that cutoffs of <20, <40, and <50 years should preferably be used to define JP, YOPD, and EOPD.

Charcot-Marie-Tooth disease type 4J with spastic quadriplegia, epilepsy and global developmental delay: a tale of three siblings.

Charcot-Marie-Tooth (CMT) disease is mainly a disease of peripheral nervous system and patients typically present with features of demyelinating neuropathy or axonal neuropathy or both. Rarely patients present with features of central nervous system involvement. Parkinsonism, aphemia and familial epilepsy syndrome have previously come up as case reports in association with CMT type 4 J.We hereby describe a family with 3 siblings affected with CMT4J with homozygous FIG4 mutation who presented with global developmental delay, epilepsy and spastic quadriparesis.

Methods of Microencapsulation of Vegetable Oil: Principles, Stability and Applications - A Minireview.

In addition to being used in food, fuel and lubricants, vegetable oils are promising in many other applications such as food additives, nutritional supplements, cosmetics and biomedicine; however, their low oxidative stability can limit their use. Microencapsulation is a well-established method for the preservation of oil against degradation, controlled release of active ingredients, protection against external factors during storage, and enhanced durability. In this article, microencapsulation methods for vegetable oil are reviewed, including physical methods (spray-drying and freeze-drying), physicochemical methods (complex coacervation, ionic gelation and electrostatic layer-by-layer deposition), and chemical methods (interfacial/in situ polymerization). This article also provides information on the principles, parameters, advantages, disadvantages and applications of these methods.

Change-point analysis through integer-valued autoregressive process with application to some COVID-19 data.

In this article, we consider the problem of change-point analysis for the count time series data through an integer-valued autoregressive process of order 1 (INAR(1)) with time-varying covariates. These types of features we observe in many real-life scenarios especially in the COVID-19 data sets, where the number of active cases over time starts falling and then again increases. In order to capture those features, we use Poisson INAR(1) process with a time-varying smoothing covariate. By using such model, we can model both the components in the active cases at time-point t namely, (i) number of nonrecovery cases from the previous time-point and (ii) number of new cases at time-point t. We study some theoretical properties of the proposed model along with forecasting. Some simulation studies are performed to study the effectiveness of the proposed method. Finally, we analyze two COVID-19 data sets and compare our proposed model with another PINAR(1) process which has time-varying covariate but no change-point, to demonstrate the overall performance of our proposed model.

An optimal response adaptive design for multi-treatment clinical trials with ordinal categorical outcomes.

In clinical trials, fixed randomizations in a prefixed proportion (e.g. 1:1 or 2:1 for two treatment trials) may be adopted to allocate the entering patients among the competing treatments. However, such an allocation procedure ignores the knowledge obtained from the accrued information on the performance of the treatments until that point. However, while allocating, a fixed randomization may favor the most and the least effective treatments in a prefixed manner, and hence becomes instrumental to induce a conflict with the "individual ethics" requirement. Adaptive allocation designs are considered instead, for their ability to dynamically settle the issue of running randomization towards the treatment doing better - all using the available data but with a scope to compromise in statistical precision. Although most of the developments are pertinent to binary, continuous and survival responses, ordinal categorical responses are natural outcomes in many disciplines of clinical trials like Orthopedics and Ophthalmology. Therefore, to balance between ethics and precision in the context of a multi-treatment clinical trial producing ordinal categorical responses, an optimal response adaptive design is derived by minimizing a measure of "precision" subject to constrained number of "failures" ensuring higher number of assignments to the "best" treatment. Related design and inference-based characteristics are extensively studied - both theoretically and empirically. Further, the practical applicability of the developed design is envisaged through re-designing of a real clinical trial, where the responses are immediate and are measured in ordinal categorical scale.

Discussion on "Predictively consistent prior effective sample sizes," by Beat Neuenschwander, Sebastian Weber, Heinz Schmidli, and Anthony O'Hagan.

We extend the approach of finding effective sample size for a typical phase II clinical trial having efficacy and toxicity as two components of the response vector. The case of binary efficacy and binary toxicity is illustrated under Dirichlet and multivariate T priors.

Role of LRRK2 variant p.Gly2019Ser in patients with Parkinsonism.

Background & objectives: Parkinsonian disorder, including Parkinson's disease (PD), is an aetiologically complex neurodegenerative disorder. Mutations in leucine-rich repeat kinase 2 (LRRK2) gene have been implicated in an autosomal dominant form of PD with variable penetrance. The identification of a common LRRK2 variant (p.Gly2019Ser) in dementia with Lewy bodies indicated its potential role in Parkinsonian disorder. The current study was aimed to identify the p.Gly2019Ser variant in Indian patients with Parkinsonian disorder. Methods: The patient group consisting of 412 classical PD patients, 107 PD patients with cognitive impairment, 107 patients with Parkinson plus syndrome and 200 unrelated controls were recruited from eastern part of India. The allele representing p.Gly2019Ser variant was screened by polymerase chain reaction followed by restriction fragment length polymorphism analysis. Results: The p.Gly2019Ser variant was identified in an East Indian young-onset female PD patient in a heterozygous state having several motor and autonomic problems without disturbed cognition. Her younger brother, sister and elder son harbouring the same mutation were asymptomatic carriers for the variant. However, the influence of DNM3 on decreased disease onset in this family was not clear. Interpretation & conclusions: Identification of the p.Gly2019Ser variant in only one patient among a large number of Indian patients (n=626) with Parkinsonian disorder in our study suggests a limited role of the LRRK2 variant towards disease pathogenesis.

Circular-circular regression model with a spike at zero.

With reference to a real data on cataract surgery, we discuss the problem of zero-inflated circular-circular regression when both covariate and response are circular random variables and a large proportion of the responses are zeros. The regression model is proposed, and the estimation procedure for the parameters is discussed. Some relevant test procedures are also suggested. Simulation studies and real data analysis are performed to illustrate the applicability of the model.

A class of Covariate-Adjusted Response-Adaptive Allocation Designs for Multitreatment Binary Response Trials.

A class of covariate-adjusted response-adaptive randomization procedures is developed for binary treatment outcomes in a phase III clinical trial set up involving multiple treatments. The target allocation is developed by combining the ethical aspects with statistical precision under the existence of treatment covariate interaction. Relevant measures of the performance for the proposed allocation designs are studied and compared.

A response adaptive design for ordinal categorical responses.

A two treatment response adaptive design is developed for phase III clinical trials with ordinal categorical treatment outcome using Goodman-Kruskal measure of association. Properties of the proposed design are studied both empirically and theoretically and the acceptability is further illustrated using two real data-sets; one from a clinical trial with trauma patients and the other from a trial with patients having rheumatoid arthritis.

Epidemiology of dementia and its burden in the city of Kolkata, India.

OBJECTIVES: Increase in aging population is expected to lead to increasing prevalence of dementia in India. In this study, we aimed to determine prevalence, incidence, and mortality of dementia and its subtypes and assess dementia burden in terms of disability-adjusted life years (DALY). METHODS: A community study was conducted over 5 years (2003-2008) in Kolkata, India, on 100,802 (males 53,209) randomly selected subjects to assess prevalence and capture data on incident cases and deaths. Standard case definitions were used. The data were used to estimate years of life lost (YLL) due to premature mortality, years of life lived with disability (YLD), and DALY, based on Global Burden of Disease 2010 approach. RESULTS: During 2003-2004, there were 103 (men 55) cases of dementia. The prevalence was 1.53% (age adjusted 1.12%) at age ≥65 years. In those ≥55 years age, average annual incidence rate of dementia was 72.57 per 100,000. All-cause standardized mortality ratio in dementia cases was 4.74 (men 6.19, women 3.03). The burden of dementia in 2007-2008 revealed that overall YLL was 47.13 per 100,000 and YLD ranged from 1.87 to 16.95 per 100,000 depending on the clinical severity of dementia. The overall DALY lost per 100,000 due to dementia for the year 2007-2008 was 74.19. CONCLUSIONS: This community study revealed a low prevalence and incidence of dementia with consequent low DALY-derived burden of illness compared with many industrialized nations. YLL formed major component of DALY indicating premature mortality to be an outcome of dementia burden. Copyright © 2016 John Wiley & Sons, Ltd.

Development of Bengali Audio-Visual Test Battery for Assessment of Pragmatic Skills: Preliminary Normative Data Based on Educational Level.

Pragmatic competence may be disrupted due to psychological and neurological causes. For appropriate remedy and rehabilitation, a precise assessment of pragmatic skills is important. However, there is no test battery in the Bengali language, and consequently, there is no published data on pragmatic ability of Bengali speakers. Due to the vast diversity of the population, it becomes increasingly difficult to assess pragmatic ability of an individual without a proper knowledge of the normal variations. To address this problem we have developed a test battery in Bengali, and to begin with, we have administered it to one hundred and five (105) normal healthy persons having different levels of education. The four groups having 17 years and above, 15 to < 17 years, 12 to < 15 years and 10 to < 12 years of education yielded a normative score of 193, 189, 171 and 150, respectively. These normative scores will allow clinicians to make a proper assessment of patients suffering from pragmatic deficits and help avoid interpreting social differences as neurological deficits.

Electrochemical immunosensors for Salmonella detection in food.

Pathogen detection is a critical point for the identification and the prevention of problems related to food safety. Failures at detecting contaminations in food may cause outbreaks with drastic consequences to public health. In spite of the real need for obtaining analytical results in the shortest time possible, conventional methods may take several days to produce a diagnosis. Salmonella spp. is the major cause of foodborne diseases worldwide and its absence is a requirement of the health authorities. Biosensors are bioelectronic devices, comprising bioreceptor molecules and transducer elements, able to detect analytes (chemical and/or biological species) rapidly and quantitatively. Electrochemical immunosensors use antibody molecules as bioreceptors and an electrochemical transducer. These devices have been widely used for pathogen detection at low cost. There are four main techniques for electrochemical immunosensors: amperometric, impedimetric, conductometric, and potentiometric. Almost all types of immunosensors are applicable to Salmonella detection. This article reviews the developments and the applications of electrochemical immunosensors for Salmonella detection, particularly the advantages of each specific technique. Immunosensors serve as exciting alternatives to conventional methods, allowing "real-time" and multiple analyses that are essential characteristics for pathogen detection and much desired in health and safety control in the food industry.

Formulation and antitumorigenic activities of nanoencapsulated nifetepimine: A promising approach in treating triple negative breast carcinoma.

Triple negative breast cancer (TNBC) is one of the most common invasive malignancies among women, associated with poor prognosis. Standard chemotherapy targets all dividing cells, resulting in dose-limiting toxicities. In this study, we demonstrated a strategy of encapsulating a hydrophobic synthetic compound, nifetepimine, having anticancer properties, in poly (lactic-co-glycolic acid) nanoparticles to increase selectivity of drug to cancerous cells with minimum toxicity towards normal cells. Nanoencapsulated nifetepimine (30-100nm) having loading and encapsulation efficiency of 7.45% and 75% respectively, was successfully internalized inside TNBC cells upon sustained release resulting in apoptosis. An in vivo bio-distribution study indicated that nanonifetepimine selectively accumulated into breast tumor sites of mice, primarily due to prolonged blood circulation time and binding of nifetepimine to epidermal growth factor receptor that remains overexpressed in most of the TNBC tumors. Moreover, we observed significant reduction in breast tumor volume with improved survival implying high tumor targetability of nanonifetepimine.