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Owing to the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signaling pathways. It also has several pathological mutant-variants, and their incidences show ethnicity biases and drug-response differences with expression in dopaminergic-neurons and astrocytes. Here, we aimed to assess the cell-intrinsic effect of the LRRK2-I1371V mutant variant, prevalent in East Asian populations, on astrocyte yield and biology, involving Nrf2-mediated glutathione machinery, glutamate uptake and metabolism, and ATP generation in astrocytes derived from LRRK2-I1371V PD patient iPSCs and independently confirmed in LRRK2-I1371V-overexpressed U87 cells. Astrocyte yield (GFAP-immunopositive) was comparable between LRRK2-I1371V and healthy control (HC) populations; however, the astrocytic capability to mitigate oxidative stress in terms of glutathione content was significantly reduced in the mutant astrocytes, along with a reduction in the gene expression of the enzymes involved in glutathione machinery and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Simultaneously, a significant decrease in glutamate uptake was observed in LRRK2-I1371V astrocytes, with lower gene expression of glutamate transporters SLC1A2 and SLC1A3. The reduction in the protein expression of SLC1A2 was also directly confirmed. Enzymes catalyzing the generation of γ glutamyl cysteine (precursor of glutathione) from glutamate and the metabolism of glutamate to enter the Krebs cycle (α-ketoglutaric acid) were impaired, with significantly lower ATP generation in LRRK2-I1371V astrocytes. De novo glutamine synthesis via the conversion of glutamate to glutamine was also affected, indicating glutamate metabolism disorder. Our data demonstrate for the first time that the mutation in the LRRK2-I1371V allele causes significant astrocytic dysfunction with respect to Nrf2-mediated antioxidant machinery, AT -generation, and glutamate metabolism, even with comparable astrocyte yields.

Progressive supranuclear palsy (PSP) is the second most common Parkinsonian disorder with complex etiology. The underlying molecular mechanism of PSP pathogenesis remains unclear. The present study aims to find the feasibility of using plasma miRNAs as novel biomarkers. Plasma-focused qPCR panels were used for microRNA profiling and identified differentially expressed microRNAs in PSP compared to controls. The DIANA-miRPath v3.0 was used to perform KEGG pathway analysis. We then confirmed the expression of selected candidates by RT-qPCR and their clinical utility was assessed by ROC analysis. Profiling data revealed 28 differentially expressed microRNAs in PSP. Five overexpressed miRNAs were selected for further analysis. The KEGG pathway analysis revealed 48 high-risk pathways. The study revealed that as a single marker—miR-19b-3p, miR-33a-5p, miR-130b-3p, miR-136-3p, and miR-210-3p had a specificity of 64.71%, 82.35%, 68.75%, 82.35%, and 70.59% at sensitivity 77.78%, 77.78%, 66.67%, 73.33%, and 66.67%, respectively. The result suggests that circulating plasma miRNAs were altered in PSP compared to control. The findings of this study may provide potential biomarkers and pathways associated with PSP. Further large-scale validation studies are required to confirm the same.

Objectives: Frontotemporal dementia (FTD) syndromes are a complex group of disorders characterised by profound changes in behaviour and cognition. Many of the observed behavioural abnormalities are now recognised to be due to impaired social cognition. While deficits in emotion recognition and empathy are well-recognised in behavioural-variant (Bv)FTD, limited information exists about the nature of social cognitive impairment in the language variant primary progressive aphasia (PPA) that includes progressive non-fluent aphasia (PNFA) and semantic dementia (SD), and in the motor variants FTD amyotrophic lateral sclerosis (FTD-ALS) and FTD progressive supranuclear palsy (FTD-PSP). This prospective study sought to explore the nature and profile of social cognition deficits across the spectrum of FTD. Methods: Sixty patients on the FTD spectrum, i.e., classical (16 with BvFTD and 20 with PPA) and overlap FTD syndromes (13 with FTD-ALS and 11 with FTD-PSP) were evaluated by means of the social cognition tasks, the Interpersonal Reactivity Index (IRI) for empathy, and pictures of facial affect (POFA) for emotion recognition. General cognition and behaviour were also assessed. Results: A significant impairment in emotion recognition and empathy was detected in both the classical and overlap FTD syndromes. The recognition of positive emotions was relatively preserved compared to that of negative emotions. Among the FTD subtypes, maximal impairment of empathy was demonstrated in FTD-PSP. Conclusion: Social cognition impairment is pervasive across the spectrum of FTD disorders, and tests of emotion recognition and empathy are clinically useful to identify the nature of behavioural problems in both classical and overlap FTD. Our findings also have implications for understanding the neural basis of social cognition in FTD.

Functional movement disorders (FMD) are a diagnostic and therapeutic challenge, both to the neurologist and psychiatrists. The phenomenology is varied and can present as tremors, dystonia, jerks/myoclonus, gait disorder, other abnormal movements or a combination. There has been an increase in the use of electrophysiological studies that are an important tool in the evaluation of FMDs. We searched the database platforms of MEDLINE, Google scholar, Web of Sciences, Scopus using the Medical Subject Heading terms (MeSH) for all the articles from 1st January 1970 till November 2022. A total of 658 articles were obtained by the search mechanism. A total of 79 relevant articles were reviewed thoroughly, of which 26 articles that had electrophysiological data were included in the present review. Variability, distractibility and entertainability can be demonstrated in functional tremors by using multichannel surface electromyography. Voluntary ballistic movements tend to decrease the tremor, while loading the tremulous limb with weight causes the tremor amplitude to increase in functional tremor. Presence of Bereitschaftspotential demonstrates the functional nature of palatal tremor and myoclonus. Co-contraction testing may be helpful in differentiating functional from organic dystonia. The R2 blink reflex recovery cycle has been found to be abnormally enhanced in organic blepharospasm, whereas it is normal in presumed functional blepharospasm. Plasticity is found to be abnormally high in organic dystonia and normal in functional dystonia, in addition to enhanced facilitation in patients with organic dystonia. Electrophysiological tests supplement clinical examination and helps in differentiating FMD from organic movement disorders.

Atypical Parkinsonian Syndromes (APS) form the third largest group of neurodegenerative disorders including Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA), and Corticobasal Syndrome (CBS). These conditions are characterized by rapid progression, poor prognosis, low survival rates, and limited treatment options. Few studies have suggested that genetic, environmental factors and inflammation contribute to the pathobiology of these complex disorders, however, the etiology of disease and progression remains unclear. A multicenter prospective longitudinal (3-time point) study will be conducted with a total sample size of 400 across all the groups (PSP, MSA, CBS). Patients with APS will be recruited after a detailed evaluation by movement disorder specialists and obtaining valid informed consent. The socio-demographic data and whole exome sequencing will be performed only at the baseline. Non-invasive procedures such as neurological and cognitive assessments, sleep quality assessments including polysomnography, brain imaging, and retinal imaging will be conducted at each time point. In addition, gene expressions, methylation patterns, inflammatory cytokines, disease-associated pathological proteins (Tau, pTau-181, α-synuclein and β-amyloid), non-targeted proteomics, skin biopsy, and iPSC will be performed at each time point eventually. The statistical analysis will be performed, followed by the developing of machine learning (ML) models. This unique native dataset in APS will enhance our understanding of the molecular mechanisms driving pathological protein aggregation and disease progression. Furthermore, the longitudinal design of the study enables a detailed examination of symptom development, progression, and management. The ML models combined with advanced imaging techniques will aid in early diagnosis, differentiation among APS types, and the development of future clinical trials and treatment strategies.

Atypical Parkinsonian Syndromes (APS) form the third largest group of neurodegenerative disorders including Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA), and Corticobasal Syndrome (CBS). These conditions are characterized by rapid progression, poor prognosis, low survival rates, and limited treatment options. Few studies have suggested that genetic, environmental factors and inflammation contribute to the pathobiology of these complex disorders, however, the etiology of disease and progression remains unclear. A multicenter prospective longitudinal (3-time point) study will be conducted with a total sample size of 400 across all the groups (PSP, MSA, CBS). Patients with APS will be recruited after a detailed evaluation by movement disorder specialists and obtaining valid informed consent. The socio-demographic data and whole exome sequencing will be performed only at the baseline. Non-invasive procedures such as neurological and cognitive assessments, sleep quality assessments including polysomnography, brain imaging, and retinal imaging will be conducted at each time point. In addition, gene expressions, methylation patterns, inflammatory cytokines, disease-associated pathological proteins (Tau, pTau-181, [alpha]-synuclein and [beta]-amyloid), non-targeted proteomics, skin biopsy, and iPSC will be performed at each time point eventually. The statistical analysis will be performed, followed by the developing of machine learning (ML) models.

Introduction Essential tremor (ET) is the most common movement disorder among adults. Although ET has been recognized as a mono-symptomatic benign illness, reports of non-motor symptoms and non-tremor motor symptoms have increased its clinical heterogeneity. The neural correlates of ET are not clearly understood. The aim of this study was to understand the neurobiology of ET using resting state fMRI. Methods Resting state functional MR images of 30 patients with ET and 30 age- and gender-matched healthy controls were obtained. The functional connectivity of the two groups was compared using whole-brain seed-to-voxel-based analysis. Results The ET group had decreased connectivity of several cortical regions especially of the primary motor cortex and the primary somatosensory cortex with several right cerebellar lobules compared to the controls. The thalamus on both hemispheres had increased connectivity with multiple posterior cerebellar lobules and vermis. Connectivity of several right cerebellar seeds with the cortical and thalamic seeds had significant correlation with an overall score of Fahn-Tolosa-Marin tremor rating scale (FTM-TRS) as well as the subscores for head tremor and limb tremor. Conclusion Seed-to-voxel resting state connectivity analysis revealed significant alterations in the cerebello-thalamo-cortical network in patients with ET. These alterations correlated with the overall FTM scores as well as the subscores for limb tremor and head tremor in patients with ET. These results further support the previous evidence of cerebellar pathology in ET.

Spinocerebellar ataxia, autosomal recessive-17 (SCAR17) is a rare hereditary ataxia characterized by ataxic gait, cerebellar signs and occasionally accompanied by intellectual disability and seizures. Pathogenic mutations in the CWF19L1 gene that code for CWF19 like cell cycle control factor 1 cause SCAR17. We report here two unrelated families with the clinical characteristics of global developmental delay, cerebellar ataxia, pyramidal signs, and seizures. Cerebellar atrophy, and T2/FLAIR hypointense transverse pontine stripes were observed in brain imaging. Exome sequencing identified novel homozygous mutations including a splice acceptor site variant c.1375-2 A > G on intron 12 in a male patient and a single nucleotide variant c.452 T > G on exon 5 resulting in a missense variant p.Ile151Ser in the female patient from two unrelated families, respectively. Sanger sequencing confirmed the segregation of these variants in the family members with autosomal recessive inheritance. Transcript analysis of the splice site variant revealed activation of a novel cryptic splice acceptor site on exon 13 resulting in an alternative transcription with a loss of nine nucleotides on exon 13. Translation of this transcript predicted an in-frame deletion of three amino acids p.(459_461del). We also observed a novel exon 13 skipping which results in premature termination of the protein product. Our study expands the phenotype, radiological features, and genotypes known in SCAR17.

Background A key factor in the propagation of α-synuclein pathology is the compromised protein quality control system. Variations in membrane association and astrocytic uptake between different α-synuclein forms suggest differences in exocytosis or membrane cleavage, potentially impacting the secretome's influence on dopaminergic neurons. We aimed to understand differences in protein degradation mechanisms of astrocytes for both wild-type (WT) and mutant forms of α-synuclein, specifically during periods of reduced degradation efficiency. We also investigated α-synuclein release into the secretome and its effects on healthy dopaminergic neurons. Methods Cellular models used were rat primary astrocytes alongside hiPSC-derived astrocytes, whose impact on rat primary dopaminergic neurons and the human SH-SY5Y cell line was investigated. We examined the release and accumulation of α-synuclein resulting from impaired degradatory pathways, including matrix metalloprotease-MMP9, the ubiquitin proteasomal pathway-UPS, and the autophagy-lysosomal pathway-ALP, using immunocytochemical analysis and flow cytometry. Additionally, we explored the effect of astrocytic secretome on dopaminergic-neuronal survival, neurite collapse and function. Results At early stages, astrocytes were able to deal efficiently with monomeric α-synuclein (via UPS), and larger aggregates (through MMP9 and autophagy), clearing extracellular α-synuclein and maintaining neuronal health. However, extended exposure to extracellular monomeric and aggregated α-synuclein compromised their proteasomal activity, inhibiting MMP9 and destabilizing autophagy, transforming astrocytes from protectors to promoters of neurodegeneration. This study is the first to elucidate the astrocytes' preferred degradation pathways for both monomeric and aggregated forms of α-synuclein, along with the subsequent effects of these payloads on the cellular degradation machinery. The astrocytic transformation is characterized by α-synuclein expulsion, increased release of inflammatory cytokines, and diminished secretion of growth factors leading to dopaminergic neuronal apoptosis and dysfunction, particularly neurite collapse, intracellular Ca 2+ response and vesicular dopamine release. The presence of phosphorylated and nitrated α-synuclein species in astrocytes also suggests their potential involvement in modifying both forms of the protein. Conclusion The initial protective action of astrocytes in clearing and degrading extracellular α-synuclein is severely compromised at latter stages, leading to astrocytic dysfunction and impairing neuron-glia cross-talk. This study underscores the criticality of integrating astrocytes into treatment paradigms in synucleinopathies.

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements, postures, or both. Dystonic movements are typically patterned, associated with twisting of body parts, and may have tremulousness. Dystonia is usually initiated or worsened by voluntary action and associated with overflow muscle activation. Cervical dystonia (CD) is the most prevalent form of dystonia. CD is a condition characterized by cranial muscle overactivity leading to abnormal intermittent or continuous posturing of the head. Non-motor symptoms are comorbidity of dystonia, which significantly hampers the quality of life among these patients. The symptoms can be as a result of the dystonia itself. However, studies have highlighted the involvement of cortical-striatal-thalamocortical circuits in primary dystonia that could be the pathophysiological basis for the non-motor symptoms. The non-motor symptoms that are commonly associated with dystonia are anxiety, depression, restless leg syndrome, excessive daytime sleepiness, cognitive disturbances, and poor sleep. This review attempts to summarize the literature on non-motor symptoms in patients with CD.