Expanding the phenotypic and genotypic spectrum of DYT-TUBB4A with seven patients from India.

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.

Dysregulated Cerebrospinal Fluid Proteome of Spinocerebellar Ataxia Type 2 and its Clinical Implications.

BACKGROUND: Abnormalities in ataxin-2 associated with spinocerebellar ataxia type 2 (SCA2) may lead to widespread disruptions in the proteome. This study was performed to identify dysregulated proteome in SCA2 and to explore its clinical-radiological correlations. METHODS: Cerebrospinal fluid (CSF) samples from 21 genetically confirmed SCA2 were subjected to shotgun proteome analysis using mass spectrometry (MS) and tandem mass tag (TMT)-based multiplexing. Proteins with at least 1.5-fold change in abundance were identified. Their relative abundance was measured using parallel reaction monitoring (PRM) and correlated against disease-related factors. RESULTS: Eleven proteins were significantly upregulated in SCA2. They belonged to the family of cell adhesion molecules and granins. Their fold changes showed significant clinical, genetic, and radiological correlations. CONCLUSIONS: Significant dysregulation of CSF proteome is seen in SCA2. The dysregulated protein may have potential use in clinical evaluation of patients with SCA2. © 2024 International Parkinson and Movement Disorder Society.

HOMER1 Polymorphism and Parkinson's Disease-Psychosis: Is there an Association?

Objective: Homer1, a postsynaptic protein coded by the HOMER1 gene, presumably has a role in homeostatic plasticity that dampens neuronal responsiveness when the input activity is too high. HOMER1 polymorphism has been studied in major psychiatric disorders such as schizophrenia. The objective of this study is to investigate if polymorphisms of the HOMER1 gene are associated with psychosis in Parkinson's disease (PD-P). Methods: One hundred patients with Parkinson's disease (PD) and 100 healthy controls were enrolled consecutively in a PD-P biomarker study at the National Institute of Mental Health and Neurosciences, Bangalore, India. Of the 100 PD patients, 50 had psychosis (PD-P) and 50 did not have psychosis (PD-NP). Two single-nucleotide polymorphisms of HOMER1 (rs4704559 and rs4704560) were analyzed from the DNA isolated from peripheral blood. The allele and genotype frequencies in the PD-P and PD-NP groups were compared. Results: Analysis of HOMER1 rs4704560 revealed a significant difference in both genotype and allele levels between PD-P and PD-NP groups. There was an overrepresentation of T-allele (42% vs. 16%; P < 0.001) and TT genotype (24% vs. 6%; P < 0.001) in the PD-P group compared to PD-NP group. There was no significant difference between PD-P and PD-NP groups when various genotypes and allele frequencies related to HOMER1 rs4704559 were compared. Conclusion: PD-P is probably associated with overrepresentation of T-allele of HOMER1 rs4704560, and larger studies are warranted to confirm our results.

Impaired SHH responsiveness of induced pluripotent stem cell-derived floor plate cells carrying the LRRK2 I1371V mutation contributes to the ontogenic origin of lower dopaminergic-neuron yield.

Lower population of dopaminergic (DA)-neurons is known to increase susceptibility to PD, and our earlier study showed a lower yield of DA-neurons in LRRK2-I1371V mutation-carrying PD patient-iPSCs. While the role of SHH in DA-neurogenesis of Floor-Plate Cells (FPCs) is known, effect of LRRK2 mutations on SHH-responsiveness of FPCs impacting DA-neuronal yield has not been studied. We investigated SHH-responsiveness of FPCs derived from LRRK2-I1371V PD patient-derived iPSCs with regard to the expression of SHH receptors Patched1 (Ptch1) and Smoothened (Smo), in conjunction with nuclear Gli1 expression, intracellular Ca2+ rise, and cytosolic cAMP levels upon SHH induction. Additionally, we examined the mechanistic link with LRRK2-I1371V gain-of-function by assessing membrane-fluidity and Rab8A & Rab10 phosphorylation in SH-SY5Y cells and healthy control (HC)-FPCs overexpressing LRRK2-I1371V as well as FPCs. While total expression of Ptch1 and Smo was comparable, receptor expression on cell-surface was significantly lower in LRRK2-I1371V FPCs than in HC, with distinctly lower nuclear-expression of the downstream transcription factor Gli1. HC-FPCs transfected with LRRK2 I1371V exhibited a similarly reduced cell-surface expression of Ptch1 and Smo. Intracellular Ca2+ response was significantly lower with corresponding elevated cAMP levels in LRRK2-I1371V FPCs compared to HC upon SHH-stimulation. Both LRRK2-I1371V mutant FPCs and LRRK2-I1371V transfected SH-SY5Y and HC-FPCs further exhibited higher autophosphorylation of phospho LRRK2 (pLRRK2) serine1292 and serine935, as well as substrate phosphorylation of Rab8A & Rab10. Concurrent increase in membrane fluidity, accompanied by a decrease in membrane cholesterol, and lower expression of lipid raft marker Caveolin1 were also observed in them. These findings suggest that impaired SHH-responsiveness of LRRK2-I1371V PD FPCs indeed leads to lower yield of DA-neurons during ontogeny. Reduced cell-surface expression of SHH receptors is influenced by alteration in membrane fluidity owing to the increased substrate phosphorylation of Rab8A and reduced membrane protein trafficking due to pRab10, both results of the LRRK2-I1371V mutation.

Definition, diagnosis and classification of infection-related movement disorders: Consensus proposal.

BACKGROUND: Infection-related movement disorders (IRMD) present a complex diagnostic challenge due to the broad phenotypic spectrum, the variety of possible infectious aetiologies, and the complicated underlying mechanisms. Yet, a comprehensive framework for classifying IRMD is lacking. METHODS: An international consensus panel under the directives of the Movement Disorders Society Infection-Related Movement Disorders Study Group developed a comprehensive definition and a consensus classification system. Case scenarios were used for validation. RESULTS: A definition for IRMD and a two-axis-based classification system consisting of six descriptors are proposed, intended as tools for researchers and clinicians. Collected information on clinical characteristics, investigational findings, the infectious organism and presumed pathogenesis facilitate the evaluation of diagnostic certainty. CONCLUSION: The proposed framework will serve for optimised diagnostic algorithms, systematic aggregation of informative datasets across studies, and ultimately improved care and outcome of patients with IRMDs.

Generation of induced pluripotent stem cells (NIMHi015-A) from a Parkinson's Disease patient harbouring a homozygous Exon 3 deletion in the PRKN gene.

The Parkin (PRKN) gene mutation is prevalent in young-onset Parkinson's disease (PD), typically emerging before age 30, accompanied by early motor symptoms. Induced pluripotent stem cells (iPSCs) were derived from peripheral blood mononuclear cells of a PD patient with an exon 3 deletion in PRKN using Sendai-virus reprogramming. PD diagnosis was confirmed via the Unified Parkinson's Disease Rating Scale (UPDRS). Characterization of the iPSC line ensured self-renewal and pluripotency. This resource serves as a valuable platform for drug screening and elucidating the pathophysiology of this mutation, facilitating advancements in PD research.

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.

Differential patterns of functional connectivity in tremor dominant Parkinson's disease and essential tremor plus.

Tremor dominant Parkinson's disease (TDPD) and essential tremor plus (ETP) syndrome are commonly encountered tremor dominant neurological disorders. Although the basal ganglia thalamocortical (BGTC) and cerebello thalamocortical (CTC) networks are implicated in tremorogenesis, the extent of functional connectivity alterations across disorders is uncertain. This study aims to evaluate functional connectivity of the BGTC and CTC in TDPD and ETP. Resting state functional MRI was acquired for 25 patients with TDPD, ETP and 22 healthy controls (HC). Following pre-processing and denoising, seed-to-voxel based connectivity was carried out at FDR < 0.05 using ROIs belonging to the BGTC and CTC. Fahn-Tolosa-Marin tremor rating scale (FTMRS) was correlated with the average connectivity values at FDR < 0.05. Compared to HC, TDPD showed decreased connectivity between cerebellum and pre, post central gyrus. While, ETP showed decreased connectivity between pallidum and occipital cortex, precuneus, cuneus compared to HC. In comparison to ETP, TDPD showed increased connectivity between precentral gyrus, pallidum, SNc with the default mode network (DMN), and decreased connectivity between cerebellum with superior, middle frontal gyrus was observed. Tremor severity positively correlated with connectivity between SNc and DMN in TDPD, and negatively correlated with pallidal connectivity in ETP. Pattern of BGTC, CTC involvement is differential i.e., higher connectivity of the BGTC nodes in TDPD, and higher connectivity of cerebellar nodes in ETP. The interesting observation of pallidal involvement in ETP suggests the role of BGTC in the pathogenesis of ETP, and indicated similarities in concepts of tremor genesis in TDPD and ETP.

Clinical and Imaging Profile of Patients with Cerebrotendinous Xanthomatosis - a Video Case Series from India.

Background: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by bi-allelic pathogenic variants in CYP27A1 gene that results in the deposition of cholestanol in the eyes, tendons, soft tissues and nervous system leading to cataracts, xanthomas, and various neuropsychiatric manifestations. The aim of our study is to describe the clinical, radiological and genetic profile of patients with CTX. Methods: This is a retrospective chart review of patients with CTX diagnosed based on classical clinical and radiological findings. The available clinical details, and investigations, including imaging, electrophysiological, pathological and genetic data, were documented. Results: Five patients (4 males) were recruited in the study. The median age at presentation was 32 years (range: 21-66 years). Walking difficulty was the most common symptom at presentation. All patients had cataracts, tendon xanthomas, eye movement abnormalities, dysarthria, pyramidal signs, ataxia and gait abnormality. Dystonia was noted in three patients. Palatal tremor and parkinsonism were noted in one patient each. In MRI brain, dentate, and corticospinal tract involvement were the most frequent imaging findings. Bilateral hypertrophic olivary degeneration was noted in one patient and hot cross bun sign in two. Three patients underwent genetic testing and all had pathogenic variants confirming the diagnosis. Discussion: CTX is a rare treatable disorder. Apart from the usual neurological presentation with spastic-ataxia, it can present at a later age with parkinsonism. Typical patterns of imaging findings are helpful in early diagnosis which aids in the treatment to prevent the neurological sequelae of the disease.

Yoga as an Add-on Therapy in Parkinson's Disease: A Single Group Open-label Trial.

OBJECTIVE: We aimed to evaluate the effect of yoga on motor and non-motor symptoms and cortical excitability in patients with Parkinson's disease (PD). METHODS: We prospectively evaluated 17 patients with PD at baseline, after one month of conventional care, and after one month of supervised yoga sessions. The motor and non-motor symptoms were evaluated using the Unified Parkinson's disease Rating Scale (motor part III), Hoehn and Yahr stage, Montreal Cognitive Assessment, Hamilton depression rating scale, Hamilton anxiety rating scale, non-motor symptoms questionnaire and World Health Organization quality of life questionnaire. Transcranial magnetic stimulation was used to record resting motor threshold, central motor conduction time, ipsilateral silent period (iSP), contralateral silent period (cSP), short interval intracortical inhibition (SICI), and intracortical facilitation. RESULTS: The mean age of the patients was 55.5 ± 10.8 years, with a mean duration of illness of 4.0 ± 2.5 years. The postural stability of the patients significantly improved following yoga (0.59 ± 0.5 to 0.18 ± 0.4, p = 0.039). There was a significant reduction in the cSP from baseline (138.07 ± 27.5 ms) to 4 weeks of yoga therapy (116.94 ± 18.2 ms, p = 0.004). In addition, a significant reduction in SICI was observed after four weeks of yoga therapy (0.22 ± 0.10) to (0.46 ± 0.23), p = 0.004). CONCLUSION: Yoga intervention can significantly improve postural stability in patients with PD. A significant reduction of cSP and SICI suggests a reduction in GABAergic neurotransmission following yoga therapy that may underlie the improvement observed in postural stability. CLINICALTRIALSGOV IDENTIFIER: CTRI/2019/02/017564.

Global Perceptions and Utilization of Clinical Neurophysiology in Movement Disorders.

BACKGROUND: Clinical neurophysiology (CNP) involves the use of neurophysiological techniques to make an accurate clinical diagnosis, to quantify the severity, and to measure the treatment response. Despite several studies showing CNP to be a useful diagnostic tool in Movement Disorders (MD), its more widespread utilization in clinical practice has been limited. OBJECTIVES: To better understand the current availability, global perceptions, and challenges for implementation of diagnostic CNP in the clinical practice of MD. METHODS: The International Parkinson and Movement Disorders Society (IPMDS) formed a Task Force on CNP. The Task Force distributed an online survey via email to all the members of the IPMDS between August 5 and 30, 2021. Descriptive statistics were used for analysis of the survey results. Some results are presented by IPMDS geographical sections namely PanAmerican (PAS), European (ES), African (AFR), Asian and Oceanian (AOS). RESULTS: Four hundred and ninety-one IPMDS members (52% males), from 196 countries, responded. The majority of responders from the AFR (65%) and PAS (63%) sections had no formal training in diagnostic CNP (40% for AOS and 37% for ES). The most commonly used techniques are electroencephalography (EEG) (72%) followed by surface EMG (71%). The majority of responders think that CNP is somewhat valuable or very valuable in the assessment of MD. All the sections identified "lack of training" as one of the biggest challenges for diagnostic CNP studies in MD. CONCLUSIONS: CNP is perceived to be a useful diagnostic tool in MD. Several challenges were identified that prevent widespread utilization of CNP in MD.

Overview of management of infection-related movement disorders with focus on specific-infections.

Infections are important treatable causes of secondary movement disorders (MD) that can have heterogeneous presentations. According to various studies, infection-related movement disorders (IRMD) account for around 10-20% of secondary MD. Certain infections have a predilection for causing various MD, and some MD phenomenologies, such as acute cerebellar ataxia and opsoclonus-myoclonus-ataxia syndromes (OMAS), suggest a strong possibility of an underlying infectious cause. The underlying pathophysiology is multifaceted, including direct neuronal damage due to neurotropism, granulomas, abscesses causing structural damage, and inflammatory and autoimmune responses triggered by infections. Understanding the prevalence, spectrum, and pattern of these IRMD and common infections that are responsible helps in early diagnosis, and instituting appropriate, timely treatment, thereby improving the overall prognosis and avoiding unnecessary investigations. In this review, we aim to provide a brief overview of common infections associated with MD, common clinical presentations of IRMD, their underlying pathophysiology, and overall approach to their treatment, with a focus on specific treatments of prevalent and treatable IRMD.

Tardive dyskinesia in Asia- current clinical practice and the role of neurologists in the care pathway.

Tardive dyskinesia (TD) is a movement disorder that can arise as a side effect of treatment with dopamine receptor-blocking agents (DRBAs), including antipsychotic drugs (APDs) used to manage psychotic illnesses. Second-generation APDs (SGAs) are often preferred to first-generation drugs due to their lower propensity to cause TD, however many SGAs-treated patients still develop the condition. Although TD is a global health concern, evidence regarding the occurrence of TD and how it is managed in Asian countries is currently limited. This article reports the results of a systematic review of the published literature on TD focusing on its prevalence, types of patients, knowledge of the condition, causative factors, and usual treatment pathways in clinical practice in Asian countries. Epidemiological data suggest that the prevalence of TD is increasing globally due to an overall rise in APD use, contributing factors being polypharmacy with multiple APDs, the use of higher than necessary doses, and off-label use for non-psychotic indications. Although exact prevalence figures for TD in Asian countries are difficult to define, there is a similar pattern of rising APD use which will result in increasing numbers of TD patients in this region. These issues need to be addressed and strategies developed to minimize TD risk and manage this disabling condition which impacts patients' quality of life and daily functioning. To date, both research into TD has been predominantly psychiatry focused and the perspectives from neurologists regarding the clinical management of this challenging condition are scarce. However, neurologists have an essential role in managing the movement disorders manifestations that characterize TD. Optimum management of TD, therefore, should ideally involve collaboration between psychiatrists and neurologists in joint care pathways, wherever practical. Collaborative pathways are proposed in this article, and the challenges that will need to be addressed in Asian countries to improve the care of people with TD are highlighted, with a focus on the neurologist's viewpoint and the implications for the management of TD globally.

Free water imaging in Parkinson's disease and atypical parkinsonian disorders.

BACKGROUND: Free water (FW)-corrected diffusion measures are more precise compared to standard diffusion measures. This study comprehensively evaluates FW and corrected diffusion metrics for whole brain white and deep gray matter (WM, GM) structures in patients with Parkinson's disease (PD), progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) and attempts to ascertain the probable patterns of WM abnormalities. METHOD: Diffusion MRI was acquired for subjects with PD (n = 133), MSA (n = 25), PSP (n = 30) and matched healthy controls (HC) (n = 99, n = 24, n = 12). Diffusion metrics of FA, MD, AD, RD were generated and FW, corrected FA maps were calculated using a bi-tensor model. TBSS was carried out at 5000 permutations with significance at p < 0.05. For GM, diffusivity maps were extracted from the basal ganglia, and analyzed at an FDR with p < 0.05. RESULTS: Compared to HC, PD showed focal changes in FW. MSA showed changes in the cerebellum and brainstem, and PSP showed increase in FW involving supratentorial WM and midbrain. All three showed increased substantia nigra FW. MSA, PSP demonstrated increased FW in bilateral putamen. PD showed increased FW in left GP externa, and bilateral thalamus. Compared to HC, MSA had increased FW in bilateral GP interna, and left thalamic. PSP had an additional increase in FW of the right GP externa, right GP interna, and bilateral thalamus. CONCLUSION: The present study demonstrated definitive differences in the patterns of FW alterations between PD and atypical parkinsonian disorders suggesting the possibility of whole brain FW maps being used as markers for diagnosis of these disorders.