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.

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.

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.

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.

Mitochondrial Calcium Uptake 1 (MICU1) Gene-Related Myopathy with Extrapyramidal Signs: A Clinico-Radiological Case Report from India.

Myopathy with extrapyramidal signs (MPXPS) is a rarely reported entity worldwide, manifesting as a muscular dystrophy with movement disorders. It results from mutations in the mitochondrial calcium uptake 1 (MICU1) gene. We hereby describe a 17-year-old boy who presented with proximal myopathy, calf muscle hypertrophy, and skeletal deformities along with choreiform movements of his upper extremities. Muscle MRI revealed a distinctively early involvement of adductors with sparing of antero-lateral compartment of thigh. This report expands the clinico-radiological presentation and to the best of our knowledge, is the first report of MICU-related MPXPS from India.

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.

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.

Quality of life and Concerns of Parkinson's Disease Patients and their Caregivers during COVID-19 Pandemic: An Indian Study.

Objectives: Parkinson's disease (PD) patients have suffered during the coronavirus disease 2019 pandemic, with worsening of both motor and nonmotor symptoms. We conducted this study to evaluate the quality of life (QoL) and concerns of PD patients and their caregivers. Methods: The study was conducted in mixed method, where the baseline data was taken by face-to-face interview during the unlock phase of December 2020 to March 2021, when there was no lockdown. This included demography, Hoehn and Yahr (HY) stage, Parkinson's Disease Questionnaire-8 (PDQ-8), and Parkinson's Disease Questionnaire for Carer (PDQ-Carer). During the second wave of COVID-19 (April-June 2021), telephonic interview was conducted using Depression, Anxiety Stress Scale- 21 Items (DASS-21), PDQ-8, PDQ-Carer, and open-ended questions regarding their concerns. Results: Compared with the baseline data, PDQ-8 and PDQ-Carer scores showed significant worsening during the second wave. DASS-21 scores had significant correlation with PDQ-Carer and PDQ-8 scores. Female patients reported poorer QoL. Caregivers of non-vaccinated patients had worse PDQ-Carer Strain scores. There was no significant association between worsening of motor symptoms and PDQ-8 and PDQ-Carer scores. More than 80% patients and 70% caregivers reported anxiety and depression. Their concerns were regarding difficulties due to social isolation, restriction of activity, and financial constraints. Additionally, there were worries about patient care, vaccination, and recurrence of the wave. Conclusions: The QoL of both patients and their caregivers were affected by the pandemic. A significant proportion had anxiety and depression, and this correlated with QoL. There were some important concerns on various aspects of the pandemic.

Health status of persons with dementia and caregivers' burden during the second wave of COVID-19 pandemic: an Indian study / Estado de saúde de pessoas com demência e sobrecarga dos cuidadores durante a 2ª onda da pandemia de covid-19: um estudo indiano

ABSTRACT. Due to the disruption of normal flow of treatment during the restrictions related to the coronavirus disease 2019 (COVID-19) pandemic, the health status of persons with dementia (PwD) and their caregivers' burden might worsen. Objective: The article aims to find out the health status of PwD and caregivers' burden during the peak of second wave of COVID-19 and make a comparison with the preceding trough phase. Methods: The study was conducted with 53 PwD and their caregivers in two phases. On their visit to the hospital during the unlock phase (phase 1), data were collected for CDR from PwD, and NPI-Q and ZBI from their caregivers. During the peak of second wave (phase 2), data were collected for NPI-Q, ZBI, and DASS-21 through telephonic communication, and statistical analyses were performed on the collected data. Results: Significantly higher caregiver burden (p=0.001) and neuropsychiatric symptoms (NPSs) [both in severity (p=0.019) and distress (p=0.013)] were observed among the respondents during the peak of second wave of the pandemic as compared to the preceding trough phase. Positive correlations were observed between the caregiver burden and depression, anxiety, and stress of the caregivers (p<0.001) and between the severity of dementia in PwD and caregiver burden (p<0.001) for both the first and second phases. Positive correlation was also observed between the severity of dementia in PwD and depression (p=0.042) and stress (p=0.023) of caregivers. Conclusions: Significant increase in the burden and distress was observed among caregivers due to increased NPSs of PwD during the second wave of COVID-19 pandemic.

RESUMO. Devido à interrupção do fluxo normal de tratamento durante as restrições relacionadas à pandemia de COVID-19, o estado de saúde das pessoas com demência (PcD) e a sobrecarga de seus cuidadores podem piorar. Objetivo: O artigo teve como objetivo conhecer o estado de saúde da PcD e a sobrecarga dos cuidadores durante o pico da 2ª onda de COVID-19 e fazer uma comparação com a fase anterior. Métodos: O estudo foi realizado com 53 PcD e seus cuidadores em duas fases. Em sua visita ao hospital durante a fase de desbloqueio (Fase 1), CDR, NPI-Q e ZBI foram administrados às PcD e seus cuidadores. Durante o pico da segunda onda (Fase 2), NPI-Q, ZBI e DASS-21 foram administrados por telefone e foram realizadas análises estatísticas dos dados coletados. Resultados: Foram observados sobrecarga do cuidador significativamente maior (p=0,001) e sintomas neuropsiquiátricos [tanto em gravidade (p=0,019) quanto angústia (p=0,013)] entre os entrevistados durante o pico da 2ª onda da pandemia em comparação com a fase anterior de passagem. Foram observadas correlações positivas entre sobrecarga do cuidador e depressão, ansiedade e estresse dos cuidadores (p<0,001) e entre gravidade da demência em PcD e sobrecarga do cuidador (p<0,001) tanto para a 1ª quanto para a 2ª fase. Também foi observada correlação positiva entre a gravidade da demência em PcD e depressão (p=0,042) e estresse (p=0,023) dos cuidadores. Conclusões: Foi observado um aumento significativo na sobrecarga e angústia entre os cuidadores devido ao aumento dos sintomas neuropsiquiátricos de PcD durante a 2ª onda da pandemia de COVID-19.

Gait Apraxia with Exaggerated Upper Limb Movements as Presentation of AARS2 Related Leukoencephalopathy.

A 55-year-old male presented with apraxia of gait with exaggerated upper limb movement with relative preservation of cognition and mild spasticity of limbs. His investigations reveal posterior-predominant leukodystrophy in brain magnetic resonance imaging (MRI) and compound heterozygous mutations in mitochondrial alanyl-transfer RNA synthetase 2 (AARS2) by next generation sequencing. His asymptomatic brother also has MRI changes with subtle mild pyramidal signs. AARS2 mutation is a rare cause of mitochondrial encephalopathy which may give rise to leukodystrophy with premature ovarian failure, infantile cardiomyopathy, lung hypoplasia and myopathy. Gait apraxia as primary presenting feature of this rare variant of mitochondrial encephalomyopathy is hitherto un-reported.

Adaptation and Validation of Addenbrooke's Cognitive Examination-III in Bengali for Screening MCI and Dementia.

OBJECTIVE: Bengali, the 6th most spoken language globally with 268 million speakers, demands a culturally appropriate tool for screening any cognitive compromise in this population. Addenbrooke Cognitive Examination-III (ACE-III) is a standardized tool used for screening and/or diagnostic purpose worldwide. The aim of the present study was to adapt and validate ACE-III into Bengali language. METHODS: The ACE-III UK Version A (2012) was adapted with linguistically and culturally appropriate items and validated on Bengali speakers. The participants consisted of 40 dementia and 22 Mild Cognitive Impairment (MCI) patients and 120 healthy-controls. Reliability and validity were examined. Discriminant function analysis was done. Sensitivity and specificity were evaluated and optimum cut-offs were established for MCI and dementia. RESULTS: Both sensitivity and specificity of ACE-III-Bengali of identifying dementia was 1; sensitivity for MCI ranged from 0.83 to 1, specificity from 0.76 to 1. Discriminant function analysis showed a significant difference in all domains of ACE-III-Bengali between healthy individuals and persons with neurocognitive impairment. Separate optimum ACE-III-Bengali cut-off scores were established according to level of education. For low education (