New Insights into Freezing of Gait in Parkinson's Disease from Spectral Dynamic Causal Modeling.

BACKGROUND: Freezing of gait is one of the most disturbing motor symptoms of Parkinson's disease (PD). However, the effective connectivity between key brain hubs that are associated with the pathophysiological mechanism of freezing of gait remains elusive. OBJECTIVE: The aim of this study was to identify effective connectivity underlying freezing of gait. METHODS: This study applied spectral dynamic causal modeling (DCM) of resting-state functional magnetic resonance imaging in dedicated regions of interest determined using a data-driven approach. RESULTS: Abnormally increased functional connectivity between the bilateral dorsolateral prefrontal cortex (DLPFC) and the bilateral mesencephalic locomotor region (MLR) was identified in freezers compared with nonfreezers. Subsequently, spectral DCM analysis revealed that increased top-down excitatory effective connectivity from the left DLPFC to bilateral MLR and an independent self-inhibitory connectivity within the left DLPFC in freezers versus nonfreezers (>99% posterior probability) were inversely associated with the severity of freezing of gait. The lateralization of these effective connectivity patterns was not attributable to the initial dopaminergic deficit nor to structural changes in these regions. CONCLUSIONS: We have identified novel effective connectivity and an independent self-inhibitory connectivity underlying freezing of gait. Our findings imply that modulating the effective connectivity between the left DLPFC and MLR through neurostimulation or other interventions could be a target for reducing freezing of gait in PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The validation of a Japanese version of the New Freezing of Gait Questionnaire (NFOG-Q).

OBJECTIVE: This study aimed to develop a Japanese version of the New Freezing of Gait Questionnaire (NFOG-Q) and investigate its validity and reliability. METHODS: After translating the NFOG-Q according to a standardised protocol, 56 patients with Parkinson's disease (PD) were administered it. Additionally, the MDS-UPDRS parts II and III, Hoehn and Yahr (H&Y) stage, and number of falls over 1 month were evaluated. Spearman's correlation coefficients (rho) were used to determine construct validity, and Cronbach's alpha (α) was used to examine reliability. RESULTS: The interquartile range of the NFOG-Q scores was 10.0-25.3 (range 0-29). The NFOG-Q scores were strongly correlated with the MDS-UPDRS part II, items 2.12 (walking and balance), 2.13 (freezing), 3.11 (freezing of gait), and 3.12 (postural stability) and the postural instability and gait difficulty score (rho = 0.515-0.669), but only moderately related to the MDS-UPDRS item 3.10 (gait), number of falls, disease duration, H&Y stage, and time of the Timed Up-and-Go test (rho = 0.319-0.434). No significant correlations were observed between age and the time of the 10-m walk test. The internal consistency was excellent (α = 0.96). CONCLUSIONS: The Japanese version of the NFOG-Q is a valid and reliable tool for assessing the severity of freezing in patients with PD.

Extracellular transportation of α-synuclein by HLA class II molecules.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of α-synuclein aggregates in form of Lewy bodies. Genome-wide association studies have revealed that human leukocyte antigen (HLA) class II is a PD-associated gene, although the mechanisms linking HLA class II and PD remain elusive. Here, we identified a novel function of HLA class II in the transport of intracellular α-synuclein to the outside of cells. HLA class II molecules and α-synuclein formed complexes and moved to the cell surface at various degrees among HLA-DR alleles. HLA-DR with a DRB5∗01:01 allele, a putative PD-risk allele, substantially translocated normal and conformationally abnormal α-synuclein to the cell surface and extracellular vesicles. α-Synuclein/HLA class II complexes were found in A2058 melanoma cells, which express intrinsic α-synuclein and HLA-DR with DRB5∗01:01. Our findings will expand our knowledge of unconventional HLA class II function from autoimmune diseases to neurodegenerative disorders, shedding light on the association between the GWAS-prioritized PD-risk gene HLA-DR and α-synuclein.

Single-cell RNA-seq analysis identifies distinct myeloid cells in a case with encephalitis temporally associated with COVID-19 vaccination.

Recently accumulating evidence has highlighted the rare occurrence of COVID-19 vaccination-induced inflammation in the central nervous system. However, the precise information on immune dysregulation related to the COVID-19 vaccination-associated autoimmunity remains elusive. Here we report a case of encephalitis temporally associated with COVID-19 vaccination, where single-cell RNA sequencing (scRNA-seq) analysis was applied to elucidate the distinct immune signature in the peripheral immune system. Peripheral blood mononuclear cells (PBMCs) were analyzed using scRNA-seq to clarify the cellular components of the patients in the acute and remission phases of the disease. The data obtained were compared to those acquired from a healthy cohort. The scRNA-seq analysis identified a distinct myeloid cell population in PBMCs during the acute phase of encephalitis. This specific myeloid population was detected neither in the remission phase of the disease nor in the healthy cohort. Our findings illustrate induction of a unique myeloid subset in encephalitis temporally associated with COVID-19 vaccination. Further research into the dysregulated immune signature of COVID-19 vaccination-associated autoimmunity including the cerebrospinal fluid (CSF) cells of central nervous system (CNS) is warranted to clarify the pathogenic role of the myeloid subset observed in our study.

Ischemic Stroke Due to Heparin-induced Thrombocytopenia during Severe COVID-19 Infection.

A 53-year-old woman with severe coronavirus disease 2019 (COVID-19) pneumonia was admitted and treated with intravenous unfractionated heparin for thromboprophylaxis under general anesthesia with mechanical ventilation. She developed right hemiparesis after hospitalization due to a large hemorrhagic infarction. Her platelet count decreased from 243,000/µL at administration to 121,000/µL. Anti-platelet factor 4-heparin antibody testing was positive according to a latex immunoturbidimetric assay. She was therefore diagnosed with heparin-induced thrombocytopenia. We immediately stopped the heparin and started argatroban; the platelet count recovered, and thrombosis did not relapse. Physicians should consider heparin-induced thrombocytopenia as a cause of ischemic stroke in patients with COVID-19 infection.