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INTRODUCTION: Magnetic resonance imaging (MRI) based brain morphometric changes in unilateral 6-hydroxydopamine (6-OHDA) induced Parkinson's disease (PD) model can be elucidated using voxel-based morphometry (VBM), study of alterations in gray matter volume and Machine Learning (ML) based analyses. METHODS: We investigated gray matter atrophy in 6-OHDA induced PD model as compared to sham control using statistical and ML based analysis. VBM and atlas-based volumetric analysis was carried out at regional level. Support vector machine (SVM)-based algorithms wherein features (volume) extracted from (a) each of the 150 brain regions (b) statistically significant features (only) and (c) volumes of each cluster identified after application of VBM (VBM_Vol) were used for training the decision model. The lesion of the 6-OHDA model was validated by estimating the net contralateral rotational behaviour by the injection of apomorphine drug and motor impairment was assessed by rotarod and open field test. RESULTS AND DISCUSSION: In PD, gray matter volume (GMV) atrophy was noted in bilateral cortical and subcortical brain regions, especially in the internal capsule, substantia nigra, midbrain, primary motor cortex and basal ganglia-thalamocortical circuits in comparison with sham control. Behavioural results revealed an impairment in motor performance. SVM analysis showed 100% classification accuracy, sensitivity and specificity at both 3 and 7 weeks using VBM_Vol. CONCLUSION: Unilateral 6-OHDA induced GMV changes in both hemispheres at 7th week may be associated with progression of the disease in the PD model. SVM based approaches provide an increased classification accuracy to elucidate GMV atrophy.
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Atrofia , Sustancia Gris , Imagen por Resonancia Magnética , Oxidopamina , Sustancia Gris/patología , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/efectos de los fármacos , Atrofia/patología , Animales , Masculino , Modelos Animales de Enfermedad , Apomorfina/farmacología , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Máquina de Vectores de Soporte , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/diagnóstico por imagen , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/diagnóstico por imagenRESUMEN
BACKGROUND: Variants in the TUBB4A gene are associated with dystonia (DYT-TUBB4A), Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum (H-ABC) and spastic paraplegia. Phenotypes intermediate to these three broad phenotypes are also observed. These are rare disorders, and data from diverse populations remains limited. We report seven Indian cases with dystonia phenotype related to TUBB4A mutation. CASES: Among these seven patients, age at onset ranged from 5 to 48 years. Five patients had cranio-cervical onset of dystonia. One patient had prominent parkinsonism with dystonia. Patients responded well to botulinum toxin injected for laryngeal, cervical and jaw dystonia. The patient with parkinsonism responded well to levodopa, albeit with development of dyskinesias. Apart from the common p.Arg2Gly variant in three patients with DYT-TUBB4A, other variants included p.Arg262Pro, p.Arg39Cys and p.Asp245Asn. CONCLUSIONS: We report the first collection of cases with TUBB4A mutation from India. We expand the phenotype to include levodopa-responsive parkinsonism. Indian patients, consistent with global literature, harbor prominent adductor dysphonia, cervical and jaw dystonia, which responds well to botulinum treatment.
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Fenotipo , Tubulina (Proteína) , Humanos , India , Masculino , Femenino , Adulto , Persona de Mediana Edad , Tubulina (Proteína)/genética , Adulto Joven , Adolescente , Niño , Trastornos Distónicos/genética , Trastornos Distónicos/tratamiento farmacológico , Preescolar , Genotipo , Mutación , Distonía/genética , Distonía/tratamiento farmacológicoRESUMEN
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.
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Background: Minimum clinically important difference (MCID) is the smallest change in an outcome measure that is considered clinically meaningful. Using validated MCID thresholds for outcomes powers trials adequately to detect meaningful treatment effects, aids in their interpretation and guides development of new outcome measures. Objectives: To provide a comprehensive summary of MCID thresholds of various symptom severity scales reported in movement disorder. Methods: We conducted systematic review of the literature and included studies of one or more movement disorders, and reporting MCID scales. Results: 2763 reports were screened. Final review included 32 studies. Risk of bias (RoB) assessment showed most studies were of good quality. Most commonly evaluated scale was Unified Parkinson's Disease Rating Scale (UPDRS) (11 out of 32). Four studies assessing MDS-UPDRS had assessed its different sub-parts, reporting a change of 2.64,3.05,3.25 and 0.9 points to detect clinically meaningful improvement and 2.45,2.51,4.63 and 0.8 points to detect clinically meaningful worsening, for the Part I, II, III and IV, respectively. For Parts II + III, I + II + III and I + II + III + IV, MCID thresholds reported for clinically meaningful improvement were 5.73, 4.9, 6.7 and 7.1 points respectively; while those for clinically meaningful worsening were 4.7, 4.2, 5.2 and 6.3 points, respectively. MCID thresholds reported for other scales included Abnormal Involuntary Movement Scale (AIMS), Toronto Western Spasmodic Torticollis Rating Scale (TWSRS), and Burke-Fahn-Marsden Dystonia Scale (BFMD). Conclusion: This review summarizes all the MCID thresholds currently reported in Movement disorders research and provides a comprehensive resource for future trials, highlighting the need for standardized and validated MCID scales in movement disorder research.
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INTRODUCTION: Guidelines recommend screening older people (> 60-65 years) with type 2 diabetes (T2D) for cognitive impairment, as it has implications in the management of diabetes. The Montreal Cognitive Assessment (MoCA) is a sensitive test for the detection of mild cognitive impairment (MCI) in the general population, but its validity in T2D has not been established. METHODS: We administered MoCA to patients with T2D (age ≥ 60 years) and controls (no T2D), along with a culturally validated neuropsychological battery and functional activity questionnaire. MCI was defined as performance in one or more cognitive domains ≥ 1.0 SD below the control group (on two tests representing a cognitive domain), with preserved functional activities. The discriminant validity of MoCA for the diagnosis of MCI at different cut-offs was ascertained. RESULTS: We enrolled 267 patients with T2D and 120 controls; 39% of the participants with T2D met the diagnostic criteria for MCI on detailed neuropsychological testing. At the recommended cut-off on MoCA (< 26), the sensitivity (94.2%) was high, but the specificity was quite low (29.5%). The cut-off score of < 23 showed an optimal trade-off between sensitivity (69.2%), specificity (71.8%), and diagnostic accuracy (70.8%). The cut-off of < 21 exhibited the highest diagnostic accuracy (74.9%) with an excellent specificity (91.4%), a good positive and negative predictive value (78.5% and 73.7%, respectively). CONCLUSIONS: The recommended screening cut-off point on MoCA of < 26 has a suboptimal specificity and may increase the referral burden in memory clinics. A lower cut-off of < 21 on MoCA maximizes the diagnostic accuracy. Interactive Visual Abstract available for this article.
Type 2 diabetes (T2D) is a risk factor for cognitive dysfunction which potentially impacts diabetes self-management skills. Guidelines recommend screening older adults with diabetes for early detection of cognitive impairment. For screening cognitive impairment in busy endocrine clinics, we need a test that is easy and rapid to administer, sensitive enough to pick the cognitive deficits of T2D and at the same time gives less false-positive outcomes. The Montreal Cognitive Assessment (MoCA) scale is a widely available cognitive screening tool, but there are no studies evaluating its discriminant properties in people with diabetes. We evaluated the performance metrics of MoCA in this population. We found mild cognitive impairment in four out of ten participants with T2D at or above 60 years of age. At the recommended cut-off on MoCA (< 26), the sensitivity was high, but the specificity quite low. We found better diagnostic accuracy at lower cut-offs (20/21), with high specificity but a lower sensitivity. At this cut-off, approximately one out of five people screened using MoCA would require detailed neuropsychological testing, and four out of five who undergo detailed evaluation would have true cognitive impairment.
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BACKGROUND: The merits of classifying the heterogeneous group of essential tremors into essential tremor (ET) and essential tremor plus (ETP) are debated. OBJECTIVES: We studied the electrophysiological and spiral characteristics of tremor in ET and ETP. METHODS: We reviewed standardized videos from a tremor database and clinically classified patients into ET, ETP, or dystonic tremor (DT). The following variables were derived from combined tri-axial accelerometry-surface electromyography (EMG)-peak frequency, total power, peak power, full width half maximum, tremor stability index and EMG-coherence. We analyzed hand-drawn spirals to derive mean deviation, tremor variability, inter-, and intra-loop widths. We compared these variables among the groups. RESULTS: We recruited 72 participants (81.9% male) with mean age 47.7 ± 16.1 years and Fahn-Tolosa-Marin Tremor Rating Scale total score 31.1 ± 14.1. Patients with ET were younger (P = 0.014) and had less severe tremor (P = 0.020) compared to ETP and DT. In ETP group, 48.6% had subtle dystonia. Peak frequency was greater in ETP (7.3 ± 0.3 Hz) compared to DT (6.1 ± 0.4 Hz; P = 0.024). Peak power was greater in ETP and DT for postural tremor. Rest tremor was recordable on accelerometry in 26.7% of ET. Other variables were similar among the groups. CONCLUSION: Electrophysiological evaluation revealed postural tremor of frequency 6 to 7 Hz in ET, ETP, and DT with subtle differences more severe tremor in ETP and DT, and higher frequency in ETP compared to DT. Our findings suggest a similar tremor oscillator in these conditions, supporting the view that these entities are part of a spectrum of tremor disorders, rather than distinct etiological entities.
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Distonía , Trastornos Distónicos , Temblor Esencial , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Distonía/complicaciones , Trastornos Distónicos/complicaciones , Electromiografía , Temblor Esencial/diagnósticoRESUMEN
Primary CNS Vasculitis (PCNSV) is a rare, diverse, and polymorphic CNS blood vessel inflammatory condition. Due to its rarity, clinical variability, heterogeneous imaging results, and lack of definitive laboratory markers, PCNSV diagnosis is challenging. This retrospective cohort analysis identified patients with histological diagnosis of PCNSV. Demographic data, clinical presentation, neuroimaging studies, and histopathologic findings were recorded. We enrolled 56 patients with a positive biopsy of CNS vasculitis. Most patients had cerebral hemisphere or brainstem symptoms. Most brain MRI lesions were bilateral, diffuse discrete to confluent white matter lesions. Frontal lobe lesions predominated, followed by inferior cerebellar lesions. Susceptibility-weighted imaging (SWI) hemorrhages in 96.4% (54/56) of patients, either solitary microhemorrhages or a combination of micro and macrohemorrhages. Contrast-enhanced T1-WIs revealed parenchymal enhancement in 96.3% (52/54 patients). The most prevalent pattern of enhancement observed was dot-linear (87%), followed by nodular (61.1%), perivascular (25.9%), and patchy (16.7%). Venulitis was found in 19 of 20 individuals in cerebral DSA. Hemorrhages in SWI and dot-linear enhancement pattern should be incorporated as MINOR diagnostic criteria to diagnose PCNSV accurately within an appropriate clinical context. Microhemorrhages in SWI and venulitis in DSA, should be regarded as a potential marker for PCNSV.
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Imagen por Resonancia Magnética , Vasculitis del Sistema Nervioso Central , Humanos , Estudios Retrospectivos , Estudios de Cohortes , Vasculitis del Sistema Nervioso Central/diagnóstico por imagen , Vasculitis del Sistema Nervioso Central/patología , HemorragiaRESUMEN
Background: COVID-19 infection is associated with neurological manifestations, including various types of movement disorders (MD). A thorough review of individual patients with COVID-19-induced MD would help in better understanding the clinical profile and outcome of these patients and in prognostication. Objective: We conducted an individual patient-systematic review to study the clinical and imaging profile and outcomes of patients with COVID-19-associated MD. Methods: A systematic literature search of PubMed, EMBASE, and Cochrane databases was conducted by two independent reviewers. Individual patient data COVID from case reports and case series on COVID-19-associated MD, published between December 2019 and December 2022, were extracted and analyzed. Results: Data of 133 patients with COVID-19-associated MD from 82 studies were analyzed. Mean age was 55 ± 18 years and 77% were males. A mixed movement disorder was most commonly seen (41%); myoclonus-ataxia was the most frequent (44.4%). Myoclonus significantly correlated with age (odds ratio (OR) 1.02 P = 0.03, CI 1-1.04). Tremor had the longest latency to develop after SARS-CoV-2 infection [median (IQR) 21 (10-40) days, P = 0.009, CI 1.01-1.05]. At short-term follow-up, myoclonus improved (OR 14.35, P value = 0.01, CI 1.71-120.65), whereas parkinsonism (OR 0.09, P value = 0.002, CI 0.19-0.41) and tremor (OR 0.16, P value = 0.016, CI 0.04-0.71) persisted. Conclusion: Myoclonus-ataxia was the most common movement disorder after COVID-19 infection. Myoclonus was seen in older individuals and usually improved. Tremor and parkinsonism developed after a long latency and did not improve in the short-term.
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Background: Parkinson's disease (PD) is an increasingly common neurodegenerative condition, which causes movement dysfunction and a broad range of non-motor symptoms. There is no molecular or biochemical diagnosis test for PD. The miRNAs are a class of small non-coding RNAs and are extensively studied owing to their altered expression in pathological states and facile harvesting and analysis techniques. Methods: A total of 48 samples (16 each of PD, aged-matched, and young controls) were recruited. The small extracellular vesicles (sEVs) were isolated and validated using Western blot, transmission electron microscope, and nanoparticle tracking analysis. Small RNA isolation, library preparation, and small RNA sequencing followed by differential expression and targeted prediction of miRNA were performed. The real-time PCR was performed with the targeted miRNA on PD, age-matched, and young healthy control of plasma and plasma-derived sEVs to demonstrate their potential as a diagnostic biomarker. Results: In RNA sequencing, we identified 14.89% upregulated (fold change 1.11 to 11.04, p < 0.05) and 16.54% downregulated (fold change -1.04 to -7.28, p < 0.05) miRNAs in PD and controls. Four differentially expressed miRNAs (miR-23b-3p, miR-29a-3p, miR-19b-3p, and miR-150-3p) were selected. The expression of miR-23b-3p was "upregulated" (p = 0.002) in plasma, whereas "downregulated" (p = 0.0284) in plasma-derived sEVs in PD than age-matched controls. The ROC analysis of miR-23b-3p revealed better AUC values in plasma (AUC = 0.8086, p = 0.0029) and plasma-derived sEVs (AUC = 0.7278, p = 0.0483) of PD and age-matched controls. Conclusion: We observed an opposite expression profile of miR-23b-3p in PD and age-matched healthy control in plasma and plasma-derived sEV fractions, where the expression of miR-23b-3p is increased in PD plasma while decreased in plasma-derived sEV fractions. We further observed the different miR-23b-3p expression profiles in young and age-matched healthy control.
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Objective: To determine the feasibility, reliability, and acceptability of video teleconference (VTC)-based neuropsychological assessment using Addenbrooke's cognitive examination-III (ACE-III). Methods: This study was performed from January 2022 to April 2022, during the third wave of the COVID-19 pandemic in India. We administered ACE-III using video-teleconferencing and compared the scores to face-to-face (FTF) testing for the eligible participants. We also conducted a participant's satisfaction survey of VTC-administered ACE-III compared to FTF-administered ACE-III, using a 7-point Likert scale. Results: We screened 37 participants and 24 (64.9%) successfully underwent ACE-III testing through VTC. We included 20 patients (mean age: 62.7 ± 10 years, mean education: 12.0 ± 4.6 years, 85% men) for final analysis, (who completed both VTC and FTF-administered ACE-III). Nine patients had major neurocognitive disorder (dementia), eight had mild neurocognitive disorder (MCI), and three had subjective cognitive decline (SCD). The two tests were administered at a median gap of 36 (18,74.5) days. The Intraclass correlation coefficients (ICC) of ACE-3 total scores (0.97) and the subdomain scores was high (>0.8). There was "very low" to "no" bias on the Bland-Altman plots, across all domains. The mean overall satisfaction score was 4.1, indicating that VTC is "as good as" FTF. Conclusions: Results support the feasibility and acceptability of remote administration of ACE-III via VTC. There is a good agreement between the ACE-III scores across VTC and in-person conditions.