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LRRK2 G2019S variant is associated with transcriptional changes in Parkinson's disease human myeloid cells under proinflammatory environment

Navarro, Elisa; Efthymiou, Anastasia G; Parks, Madison; Riboldi, Giulietta M; Vialle, Ricardo A; Udine, Evan; Muller, Benjamin Z; Humphrey, Jack; Allan, Amanda; Argyrou, Charlie Charalambos; Lopes, Katia de Paiva; Münch, Alexandra; Raymond, Deborah; Sachdev, Rivka; Shanker, Vicki L; Miravite, Joan; Katsnelson, Viktoryia; Leaver, Katherine; Frucht, Steve; Bressman, Susan B; Marcora, Edoardo; Saunders-Pullman, Rachel; Goate, Alison; Raj, Towfique
The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is a major risk factor for the development of Parkinson's disease (PD). LRRK2, although ubiquitously expressed, is highly abundant in cells of the innate immune system. Given the importance of central and peripheral immune cells in the development of PD, we sought to investigate the consequences of the G2019S mutation on microglial and monocyte transcriptome and function. We have generated large-scale transcriptomic profiles of isogenic human induced microglial cells (iMGLs) and patient derived monocytes carrying the G2019S mutation under baseline culture conditions and following exposure to the proinflammatory factors IFNγ and LPS. We demonstrate that the G2019S mutation exerts a profound impact on the transcriptomic profile of these myeloid cells, and describe corresponding functional differences in iMGLs. The G2019S mutation led to an upregulation in lipid metabolism and phagolysosomal pathway genes in untreated and LPS/IFNγ stimulated iMGLs, which was accompanied by an increased phagocytic capacity of myelin debris. We also identified dysregulation of cell cycle genes, with a downregulation of the E2F4 regulon. Transcriptomic characterization of human-derived monocytes carrying the G2019S mutation confirmed alteration in lipid metabolism associated genes. Altogether, these findings reveal the influence of G2019S on the dysregulation of the myeloid cell transcriptome under proinflammatory conditions.
PMCID:11160623
PMID: 38854101
CID: 5668762

Myoclonus: an update

Thomas, Betsy; Frucht, Steven J
PURPOSE OF REVIEW/OBJECTIVE:Myoclonus, a common hyperkinetic movement disorder, can be disabling for patients. It is important to identify and classify myoclonus correctly to ensure appropriate workup and treatment. While the clinical history, examination, and process of classifying myoclonus remain largely unchanged, new causes and triggers for myoclonus are being elucidated, and new genetic causes have been found. Treatment can be challenging, though preliminary data about new options has been promising. RECENT FINDINGS/RESULTS:In this article, we will briefly outline the process of classifying and treating myoclonus. We will then discuss three specific scenarios where myoclonus has been identified: myoclonus associated with SARS-CoV-2 infections, spinal myoclonus following surgery or anesthesia of the spine, and auricular myoclonus. We will also discuss new genetic findings associated with myoclonus-dystonia, and promising results regarding the use of perampanel in treating myoclonus. SUMMARY/CONCLUSIONS:The process of describing unique scenarios associated with myoclonus has helped us build our understanding of the causes, genetic background, expected prognosis, and effective treatment of specific types of myoclonus. We hope that further studies on this topic will help tailor treatment.
PMID: 38785158
ISSN: 1473-6551
CID: 5655072

Sodium Oxybate in Alcohol-Responsive Essential Tremor of Voice: An Open-Label Phase II Study

O'Flynn, Lena C; Frucht, Steven J; Simonyan, Kristina
BACKGROUND:Essential tremor of voice (ETv) is characterized by involuntary oscillations of laryngeal and upper airway muscles, causing rhythmic alterations in pitch and loudness during both passive breathing and active laryngeal tasks, such as speaking and singing. Treatment of ETv is challenging and typically less effective compared with treatment of ET affecting extremities. OBJECTIVE:We conducted a proof-of-concept, open-label phase II study to examine the efficacy and central effects of sodium oxybate in patients with alcohol-responsive ETv. METHODS:All subjects received 1.0 to 1.5 g of oral sodium oxybate and underwent brain functional magnetic resonance imaging. The primary endpoint was the number of patients (% from total) with reduced ETv symptoms by at least 10% at about 40 to 45 minutes after sodium oxybate intake based on the combined visual analog scale score of ETv symptom severity. The secondary endpoint included changes in brain activity after sodium oxybate intake compared to baseline. RESULTS:Sodium oxybate reduced ETv symptoms on average by 40.8% in 92.9% of patients. Drug effects were observed about 40 to 45 minutes after intake, lasting about 3.5 hours, and gradually wearing off by the end of the fifth hour. The central effects of sodium oxybate were associated with normalized activity in the cerebellum, inferior/superior parietal lobules, inferior frontal gyrus, and insula and re-established functional relationships between these regions. CONCLUSIONS:Sodium oxybate showed high efficacy in ETv patients, with a likely central action on disorder pathophysiology. Sodium oxybate may be an effective novel oral drug for treatment of alcohol-responsive ETv patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
PMID: 37448353
ISSN: 1531-8257
CID: 5537832

Meropenem-Induced Facial Myoclonus [Case Report]

Millar Vernetti, Patricio; Dalamo, Kaia; Khan, Zenith; Gonzalez-Duarte, Alejandra; Frucht, Steven; Kaufmann, Horacio
PMCID:10448627
PMID: 37636233
ISSN: 2330-1619
CID: 5618502

Isolated and combined dystonias: Update

Bukhari-Parlakturk, Noreen; Frucht, Steven J
Dystonia is a hyperkinetic movement disorder with a unique motor phenomenology that can manifest as an isolated clinical syndrome or combined with other neurological features. This chapter reviews the characteristic features of dystonia phenomenology and the syndromic approach to evaluating the disorders that may allow us to differentiate the isolated and combined syndromes. We also present the most common types of isolated and combined dystonia syndromes. Since accelerated gene discoveries have increased our understanding of the molecular mechanisms of dystonia pathogenesis, we also present isolated and combined dystonia syndromes by shared biological pathways. Examples of these converging mechanisms of the isolated and combined dystonia syndromes include (1) disruption of the integrated response pathway through eukaryotic initiation factor 2 alpha signaling, (2) disease of dopaminergic signaling, (3) alterations in the cerebello-thalamic pathway, and (4) disease of protein mislocalization and stability. The discoveries that isolated and combined dystonia syndromes converge in shared biological pathways will aid in the development of clinical trials and therapeutic strategies targeting these convergent molecular pathways.
PMID: 37620082
ISSN: 0072-9752
CID: 5598862

Accuracy of clinical versus oculographic detection of pathological saccadic slowing

Grossman, Scott N; Calix, Rachel; Hudson, Todd; Rizzo, John Ross; Selesnick, Ivan; Frucht, Steven; Galetta, Steven L; Balcer, Laura J; Rucker, Janet C
Saccadic slowing as a component of supranuclear saccadic gaze palsy is an important diagnostic sign in multiple neurologic conditions, including degenerative, inflammatory, genetic, or ischemic lesions affecting brainstem structures responsible for saccadic generation. Little attention has been given to the accuracy with which clinicians correctly identify saccadic slowing. We compared clinician (n = 19) judgements of horizontal and vertical saccade speed on video recordings of saccades (from 9 patients with slow saccades, 3 healthy controls) to objective saccade peak velocity measurements from infrared oculographic recordings. Clinician groups included neurology residents, general neurologists, and fellowship-trained neuro-ophthalmologists. Saccades with normal peak velocities on infrared recordings were correctly identified as normal in 57% (91/171; 171 = 9 videos × 19 clinicians) of clinician decisions; saccades determined to be slow on infrared recordings were correctly identified as slow in 84% (224/266; 266 = 14 videos × 19 clinicians) of clinician decisions. Vertical saccades were correctly identified as slow more often than horizontal saccades (94% versus 74% of decisions). No significant differences were identified between clinician training levels. Reliable differentiation between normal and slow saccades is clinically challenging; clinical performance is most accurate for detection of vertical saccade slowing. Quantitative analysis of saccade peak velocities enhances accurate detection and is likely to be especially useful for detection of mild saccadic slowing.
PMID: 36183516
ISSN: 1878-5883
CID: 5359142

Comparison of Ultrasound and Electrical Stimulation Guidance for Onabotulinum Toxin-A Injections: A Randomized Crossover Study

Lungu, Codrin; Nmashie, Alexandra; George, Mary Catherine; Karp, Barbara I; Alter, Katharine; Shin, Susan; Tse, Winona; Frucht, Steven J; Wu, Tianxia; Koo, Vivian; Considine, Elaine; Norato, Gina; Hallett, Mark; Simpson, David M
BACKGROUND/UNASSIGNED:Botulinum neurotoxin (BoNT) injection is an established therapy for limb spasticity and focal limb dystonia. Comparative benefits of injection guidance procedures have not been rigorously studied. OBJECTIVES/UNASSIGNED:We compared 2 targeting techniques for onabotulinumtoxin-A (onabotA) injection for the treatment of focal hand dystonia and upper limb spasticity: electrophysiologic guidance using electrical stimulation (E-stim) and ultrasound (US). METHODS/UNASSIGNED:This was a 2-center, randomized, crossover, assessor-blinded trial. Participants with focal hand dystonia or upper limb spasticity, on stable onabotA therapy for at least 2 previous injection cycles, were randomly assigned to either E-stim or US with crossover at 3 months. The primary outcome was improvement in dystonia or spasticity severity on a visual analog scale (VAS; 0-100) measured 1 month after each injection. The secondary outcome was participant discomfort assessed on a VAS. Repeated-measures analysis of covariance was used with linear mixed-model covariate selection. RESULTS/UNASSIGNED:A total of 19 participants (13 men) completed the study, 10 with upper limb spasticity and 9 with dystonia. Benefit was equivalent between the 2 techniques (VAS least-square mean [LSmean] 51.5 mm with US and 53.1 with E-stim). E-stim was perceived as more uncomfortable by participants (VAS LSmean 34.5 vs. 19.9 for E-stim and US, respectively). Procedure duration was similar with the 2 procedures. There were no serious adverse events related to either approach. CONCLUSIONS/UNASSIGNED:US and E-Stim localization guidance techniques provide equivalent efficacy in onabotA injections for spasticity and dystonia. US guidance injections are more comfortable for participants. Both techniques are effective guidance methods, with US potentially preferable based on participant comfort.
PMCID:9631842
PMID: 36523503
ISSN: 2330-1619
CID: 5382442

Transcriptome deregulation of peripheral monocytes and whole blood in GBA-related Parkinson's disease

Riboldi, Giulietta Maria; Vialle, Ricardo A; Navarro, Elisa; Udine, Evan; de Paiva Lopes, Katia; Humphrey, Jack; Allan, Amanda; Parks, Madison; Henderson, Brooklyn; Astudillo, Kelly; Argyrou, Charalambos; Zhuang, Maojuan; Sikder, Tamjeed; Oriol Narcis, J; Kumar, Shilpa Dilip; Janssen, William; Sowa, Allison; Comi, Giacomo P; Di Fonzo, Alessio; Crary, John F; Frucht, Steven J; Raj, Towfique
BACKGROUND:Genetic mutations in beta-glucocerebrosidase (GBA) represent the major genetic risk factor for Parkinson's disease (PD). GBA participates in both the endo-lysosomal pathway and the immune response, two important mechanisms involved in the pathogenesis of PD. However, modifiers of GBA penetrance have not yet been fully elucidated. METHODS:We characterized the transcriptomic profiles of circulating monocytes in a population of patients with PD and healthy controls (CTRL) with and without GBA variants (n = 23 PD/GBA, 13 CTRL/GBA, 56 PD, 66 CTRL) and whole blood (n = 616 PD, 362 CTRL, 127 PD/GBA, 165 CTRL/GBA). Differential expression analysis, pathway enrichment analysis, and outlier detection were performed. Ultrastructural characterization of isolated CD14+ monocytes in the four groups was also performed through electron microscopy. RESULTS:We observed hundreds of differentially expressed genes and dysregulated pathways when comparing manifesting and non-manifesting GBA mutation carriers. Specifically, when compared to idiopathic PD, PD/GBA showed dysregulation in genes involved in alpha-synuclein degradation, aging and amyloid processing. Gene-based outlier analysis confirmed the involvement of lysosomal, membrane trafficking, and mitochondrial processing in manifesting compared to non-manifesting GBA-carriers, as also observed at the ultrastructural levels. Transcriptomic results were only partially replicated in an independent cohort of whole blood samples, suggesting cell-type specific changes. CONCLUSIONS:Overall, our transcriptomic analysis of primary monocytes identified gene targets and biological processes that can help in understanding the pathogenic mechanisms associated with GBA mutations in the context of PD.
PMCID:9386994
PMID: 35978378
ISSN: 1750-1326
CID: 5300042

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson's disease are associated with LRRC37A/2 expression in astrocytes

Bowles, Kathryn R; Pugh, Derian A; Liu, Yiyuan; Patel, Tulsi; Renton, Alan E; Bandres-Ciga, Sara; Gan-Or, Ziv; Heutink, Peter; Siitonen, Ari; Bertelsen, Sarah; Cherry, Jonathan D; Karch, Celeste M; Frucht, Steven J; Kopell, Brian H; Peter, Inga; Park, Y J; Charney, Alexander; Raj, Towfique; Crary, John F; Goate, A M
BACKGROUND:Parkinson's disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. METHODS:To better understand the genetic contribution of this region to PD and to identify novel mechanisms conferring risk for the disease, we fine-mapped the 17q21.31 locus by constructing discrete haplotype blocks from genetic data. We used digital PCR to assess copy number variation associated with PD-associated blocks, and used human brain postmortem RNA-seq data to identify candidate genes that were then further investigated using in vitro models and human brain tissue. RESULTS:We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble α-synuclein, and co-localized with Lewy bodies in PD brain tissue. CONCLUSION/CONCLUSIONS:These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with α-synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.
PMCID:9284779
PMID: 35841044
ISSN: 1750-1326
CID: 5269612

A Case of Opsoclonus-Myoclonus-Ataxia With Neuronal Intermediate Filament IgG Detected in Cerebrospinal Fluid [Case Report]

Merati, Melody; Rucker, Janet C; McKeon, Andrew; Frucht, Steven J; Hu, Jessica; Balcer, Laura J; Galetta, Steven L
ABSTRACT:A 62-year-old man presented with headache, fever, and malaise. He was diagnosed with Anaplasma phagocytophilum, confirmed by serum polymerase chain reaction, and started on oral doxycycline. After 5 days of treatment, the patient began to experience gait imbalance with frequent falls, as well as myoclonus, and confusion. Examination was notable for opsoclonus-myoclonus-ataxia (OMA) and hypometric saccades. Cerebrospinal fluid (CSF) autoimmune encephalitis panel demonstrated a markedly elevated neuronal intermediate filament (NIF) immunoglobulin G antibody titer of 1:16, with positive neurofilament light- and heavy-chain antibodies. These antibodies were suspected to have been triggered by the Anaplasma infection. Repeat CSF examination 8 days later still showed a positive immunofluorescence assay for NIF antibodies, but the CSF titer was now less than 1:2. Body computed tomography imaging was unrevealing for an underlying cancer. Our patient illustrates a postinfectious mechanism for OMA and saccadic hypometria after Anaplasma infection.
PMID: 35594157
ISSN: 1536-5166
CID: 5283712