An Effort to Identify Genetic Determinants in Siblings With Wilson Disease Manifesting Striking Clinical Heterogeneity: An Exome Profiling Study of Two Indian Families.

BACKGROUND: Wilson disease (WD) is a rare autosomal recessive disorder of copper metabolism caused due to mutations in the copper transporter ATP7B. There is often a striking variability of clinical manifestations among patients with ATP7B mutations, including in siblings. This phenomenon may be caused by individual differences in copper accumulation in hepatocytes and intolerance to copper toxicity as governed by genetic variations in copper metabolism genes acting as modifier loci to the disease. OBJECTIVE: To elucidate the genetic basis of striking clinical heterogeneity among two siblings of two families with WD. METHODS: The disease diagnosis and subsequent clinical examinations were performed by expert clinicians. The younger siblings in both families presented with early neurological manifestations at a younger age than their older siblings. Interestingly, only the younger siblings were reported to have had hepatic manifestations. Exome sequencing of all the four individuals was performed to understand their heterogeneous phenotypic outcomes. RESULTS: Genetic screening revealed no difference in the ATP7B variant spectrum between the siblings of each family. However, the siblings of both the families were found to harbor mutually exclusive pathogenic variants in suspected modifier genes implicated in copper metabolism and/or other neurological and hepatic disorders having overlapping symptoms with WD, viz., CFTR, PPARG, ABCB11, ATP7A, CYP2D6, mTOR, TOR1A, and CP, which can potentially explain their differential clinical phenotypes. CONCLUSION: Clinical heterogeneity between siblings with WD with the same ATP7B mutation profile may be attributed to the presence of different pathogenic variants in potential modifier genes.

NMR Analyses and Statistical Modeling of Biobased Polymer Microstructures-A Selected Review.

NMR analysis combined with statistical modeling offers a useful approach to investigate the microstructures of polymers. This article provides a selective review of the developments in both the NMR analysis of biobased polymers and the statistical models that can be used to characterize these materials. The information obtained from NMR and statistical models can provide insights into the microstructure and stereochemistry of appropriate biobased polymers and establish a systematic approach to their analysis. In suitable cases, the analysis can help optimize the synthetic procedures and facilitate the development of new or modified polymeric materials for various applications. Examples are given of the studies of poly(hydroxyalkanoates), poly(lactic acid), and selected polysaccharides, e.g., alginate, pectin, and chitosan. This article may serve as both a reference and a guide for future workers interested in the NMR sequence analysis of biobased materials.

Illiterate Addenbrooke's Cognitive Examination-III in Three Indian Languages: An Adaptation and Validation Study.

BACKGROUND: Literacy is an important factor that predicts cognitive performance. Existing cognitive screening tools are validated only in educated populations and are not appropriate for older adults with little or no education leading to poor performance on these tests and eventually leading to misdiagnosis. This challenge for clinicians necessitates a screening tool suitable for illiterate or low-literate older individuals. OBJECTIVES: The objective was to adapt and validate Addenbrooke's Cognitive Examination-III (ACE-III) for screening general cognitive functions in illiterate and low-literate older populations in the Indian context in three languages. METHOD: The Indian illiterate ACE-III was systematically adapted by modifying the original items of the Indian literate ACE-III to assess the cognitive functions of illiterates and low-literates with the consensus of an expert panel of professionals working in the area of dementia and related disorders. A total of 180 illiterate or low-literate participants (84 healthy-controls, 50 with dementia, and 46 with mild cognitive impairment [MCI]) were recruited from three different centers speaking Bengali, Hindi, and Kannada to validate the adapted version. RESULTS: The optimal cut-off score for illiterate ACE-III to distinguish controls from dementia in all 3 languages was 75. The optimal cut-off scores in distinguishing between controls and MCI ranged from 79 to 82, with a sensitivity ranging from 93% to 99% and a specificity ranging from 72% to 99%. CONCLUSION: The test is found to have good psychometric properties and is a reliable cognitive screening tool for identifying dementia and MCI in older adults with low educational backgrounds in the Indian context.

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.

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.

Analysis of Semiology, Lesion Topography and Treatment Outcomes: A Prospective Study on Post Thalamic Stroke Holmes Tremor.

OBJECTIVE: Holmes tremor (HT) comprises rest, postural and intention tremor subtypes, usually involving both proximal and distal musculature. Perturbations of nigro-striatal pathways might be fundamental in the pathogenesis of HT along with cerebello-thalamic connections. METHODS: Nine patients with an HT phenotype secondary to thalamic stroke were included. Epidemiological and clinical records were obtained. Structural and functional brain imaging were performed with magnetic resonance imaging (MRI) or computed tomography (CT) and positron emission tomography (PET), respectively. Levodopa was administered in sequentially increasing dosage, with various other drugs in case of inadequate response. Longitudinal follow-up was performed for at least three months. The essential tremor rating assessment scale (TETRAS) was used for assessment. RESULTS: The mean latency from stroke to tremor onset was 50.4 ± 30.60 days (range 21-90 days). Dystonia was the most frequently associated hyperkinetic movement (88.8%). Tremor was bilateral in 22.2% of participants. Clinical response was judged based on a reduction in the TETRAS score by a prefixed value (≥ 30%), pertaining to which 55.5% (n = 5) of subjects were classified as responders and the rest as non-responders. The responders showed improvement with significantly lower doses of levodopa than the remaining nonresponders (240 ± 54.7 mg vs. 400 ± 40.8 mg; p = 0.012). CONCLUSION: Although levodopa is useful in HT, augmenting the dosage of levodopa beyond a certain point might not benefit patients clinically. Topography of vascular lesions within the thalamus might additionally influence the phenomenology of HT.

Genetic Variations and Altered Blood mRNA Level of Circadian Genes and BDNF as Risk Factors of Post-Stroke Cognitive Impairment Among Eastern Indians.

Post-stroke cognitive impairment (PSCI) is a clinical outcome in around 30% of post-stroke survivors. BDNF is a major gene in this regard. It is regulated by circadian rhythm. The circadian genes are correlated with stroke timings at molecular level. However, studies suggesting the role of these on susceptibility to PSCI are limited. We aim here to determine: (a) genetic risk variants in circadian clock genes, BDNF and (b) dysregulation in expression level of CLOCK, BMAL1, and BDNF that may be associated with PSCI. BDNF (rs6265G/A, rs56164415C/T), CLOCK (rs1801260T/C, rs4580704G/C), and CRY2 (rs2292912C/G) genes variants were genotyped among 119 post-stroke survivors and 292 controls from Eastern part of India. In addition, we analyzed their gene expression in Peripheral blood Mononuclear cells (PBMC) from 15 PSCI cases and 12 controls. The mRNA data for BDNF was further validated by its plasma level through ELISA (n = 38). Among the studied variants, only rs4580704/CLOCK showed an overall association with PSCI (P = 0.001) and lower Bengali Mini-Mental State Examination (BMSE) score. Its 'C' allele showed a correlation with attention deficiency. The language and memory impairments showed association with rs6265/BDNF, while the 'CC' genotype of rs2292912/CRY2 negatively influenced language and executive function. A significant decrease in gene expression for CLOCK and BDNF in PBMC (influenced by specific genotypes) of PSCI patients was observed than controls. Unlike Pro-BDNF, plasma-level mBDNF was also lower in them. Our results suggest the genetic variants in CLOCK, CRY2, and BDNF as risk factors for PSCI among eastern Indians. At the same time, a lowering expression of CLOCK and BDNF genes in PSCI patients than controls describes their transcriptional dysregulation as underlying mechanism for post-stroke cognitive decline.

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.

Sample sizes required to estimate the protective efficacy of a vaccine when there is an unequal allocation of individuals across the vaccine and placebo groups.

The effectiveness of a vaccine is measured by means of protective vaccine efficacy, defined by VE=1-ARVARU, where ARV and ARU are, respectively, the disease attack rates in the vaccinated and the unvaccinated population. For each of the cohoret and case-control designs, methods have been presented in the literature for calculating the required sample size when the desired width of the confidence interval and the probability of coverage are pre-specified, where an equal number of individuals were assumed to be allocated to the vaccine and placebo group. In this article, we present a method for calculating the required sample size with a specified degree of precision when there is an unequal allocation of individuals across the two groups. The sample size required to achieve a desired power for the relevant level α test has also been explored, keeping the unequal allocation proportion in mind. The fraction of individuals allocated to the placebo group (ρ) can be so chosen that the total sample size or the expected number of people developing the disease or some other criteria of interest is minimized.

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.

Gastrointestinal, Respiratory, and Olfactory Neurotropism of Sars-Cov2 as a Possible Trigger of Parkinson's Disease: Is a Multi-Hit Multi-Step Process on the Cards.

Since the first emergence of COVID-19 on the global stage, there has been a wealth of evidence to suggest that SARS-Cov2 is not merely a pulmonary pathogen. This virus is unique in its ability to disrupt cellular pathways related to protein homeostasis, mitochondrial function, stress response, and aging. Such effects raise concerns about the long-term fate of survivors of COVID-19 infection, particularly regarding neurodegenerative diseases. The concept of interaction between environmental factors and alpha-synuclein formation in the olfactory bulb and vagal autonomic terminals with subsequent caudo-cranial migration has received much attention in the context of PD pathogenesis. Anosmia and gastrointestinal symptoms are two well-known symptoms of COVID-19, with evidence of an olfactory bulb and vagal infiltration by SARS-CoV2. This raises the possibility of the spread of the viral particles to the brain along multiple cranial nerve routes. Neurotropism, coupled with the ability of the SARS-Cov2 virion to induce abnormal protein folding and stress responses in the central nervous system, in presence of an inflammatory milieu, reinforced by hypoxia, coagulopathy, and endothelial dysfunction, reverberates the intriguing possibility of activation of a neurodegenerative cascade leading to the development of pathological alpha-synuclein aggregates and thus, triggering the development of PD in survivors of COVID19. This review attempts to summarize and critically appraise existing evidence from basic science research and clinical reports of links between COVID-19 and PD and explores the prospect of a multi-hit pathophysiological process, induced by SARS-Cov2 infection, ultimately converging on perturbed cellular protein homeostasis, which although is intriguing, presently lacks robust evidence for confirmation.

Limb to Cranial Overflow Dystonia in a Patient After Stroke.

This case report describes noncontiguous overflow dystonia in a patient with diabetes, hypertension, and a history of left putaminal hemorrhage and right hemiparesis.

Bilayer Films of Poly(lactic acid) and Cottonseed Protein for Packaging Applications.

Poly(lactic acid) (PLA) is a common biobased film-former made from renewable biomass, such as polysaccharides from sugarcane, corn, or cassava. It has good physical properties but is relatively expensive when compared to the plastics used for food packaging. In this work, bilayer films were designed, incorporating a PLA layer and a layer of washed cottonseed meal (CSM), an inexpensive agro-based raw material from cotton manufacturing, where the main component is cottonseed protein. These bilayer films were made through the solvent casting method. The combined thickness of the PLA/CSM bilayer film was between 47 and 83 µm. The thickness of the PLA layer in this film was 10%, 30%, or 50% of the total bilayer film's thickness. Mechanical properties of the films, opacity, water vapor permeation, and thermal properties were evaluated. Since PLA and CSM are both agro-based, sustainable, and biodegradable, the bilayer film may be used as an eco-friendlier food packaging material, which helps reduce the environmental problems of plastic waste and microplastics. Moreover, the utilization of cottonseed meal may add value to this cotton byproduct and provide a potential economic benefit to cotton farmers.

Multi-arm covariate adjusted response adaptive designs for ordinal outcome clinical trials.

Covariate adjusted response adaptive designs are developed with ordinal categorical responses for phase III clinical trial involving multiple treatments. Stochastic ordering principle is used to order the treatments according to effectiveness and consequently allocation functions are developed by combining the cumulative odds ratios suitably. The performance of the proposed designs is investigated through relevant exact as well as large sample measures. To investigate the performance in a real situation, a real clinical trial involving lung cancer patients is further redesigned using the proposed allocation design.

Behavioral variations among vascular cognitive impairment subtypes - A comparative study.

Dementia of vascular origin is a distinct variety with a heterogeneous neuropsychological profile. Very few studies have compared the behavioral dysfunction in the large vessel and small vessel vascular dementia (VaD) and studied the association between executive dysfunction and behavioral dysfunction documented in these patients, between the white matter load in small vessel disease (SVD) and the behavioral dysfunction. 76 patients having a modified Hachinski Ischemic Scale score of ≥ 4 were recruited and categorized into a small vessel and large vessel VaD. The Neuropsychiatric Inventory (NPI) score ≥ 4 per domain for defining clinically relevant symptoms and the Clinical Dementia Rating Scale (CDR) for evaluating the severity of dementia were used. Behavioral and Psychological Symptoms of Dementia (BPSD) were present in 66.67% of patients with SVD and 53.57% of those having large vessel disease. Apathy, euphoria, and disinhibition were more common in SVD, while appetite alterations were more common in large vessel disease. Behavioral dysfunction was also associated with executive dysfunction in both the VaD subtypes and with white matter loads in SVD. We conclude that different VaD subtypes have different behavioral profiles. This might help in understanding the underlying pathophysiology, diagnosis and thus better management of this disorder.

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.