Recommended articles of this week

Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.

This week, we would like to share several latest articles on neurodegenerative diseases.

Title: The role of meningeal populations of type II innate lymphoid cells in modulating neuroinflammation in neurodegenerative diseases
Authors: Sherry Sin-Hang Yeung, Yuen-Shan Ho, Raymond Chuen-Chung Chang
Type: Review Article of Experimental & Molecular Medicine
Abstract:
Recent research into meningeal lymphatics has revealed a never-before appreciated role of type II innate lymphoid cells (ILC2s) in modulating neuroinflammation in the central nervous system (CNS). To date, the role of ILC2-mediated inflammation in the periphery has been well studied. However, the exact distribution of ILC2s in the CNS and therefore their putative role in modulating neuroinflammation in neurodegenerative diseases such as Alzheimer’s disease (AD), multiple sclerosis (MS), Parkinson’s disease (PD), and major depressive disorder (MDD) remain highly elusive. Here, we review the current evidence of ILC2-mediated modulation of neuroinflammatory cues (i.e., IL-33, IL-25, IL-5, IL-13, IL-10, TNFα, and CXCL16-CXCR6) within the CNS, highlight the distribution of ILC2s in both the periphery and CNS, and discuss some challenges associated with cell type-specific targeting that are important for therapeutics. A comprehensive understanding of the roles of ILC2s in mediating and responding to inflammatory cues may provide valuable insight into potential therapeutic strategies for many dementia-related disorders.
Access this article: https://doi.org/10.1038/s12276-021-00660-5

Title: Multi-omics integration analysis identifies novel genes for alcoholism with potential overlap with neurodegenerative diseases
Authors: Manav Kapoor, Michael J. Chao, Emma C. Johnson, Gloriia Novikova, Dongbing Lai, Jacquelyn L. Meyers, Jessica Schulman, John I. Nurnberger Jr, Bernice Porjesz, Yunlong Liu, The Collaborative Study on the Genetics of Alcoholism (COGA), Tatiana Foroud, Howard J. Edenberg, Edoardo Marcora, Arpana Agrawal, Alison Goate
Type: Article of Nature Communications
Abstract:
Identification of causal variants and genes underlying genome-wide association study (GWAS) loci is essential to understand the biology of alcohol use disorder (AUD) and drinks per week (DPW). Multi-omics integration approaches have shown potential for fine mapping complex loci to obtain biological insights to disease mechanisms. In this study, we use multi-omics approaches, to fine-map AUD and DPW associations at single SNP resolution to demonstrate that rs56030824 on chromosome 11 significantly reduces SPI1 mRNA expression in myeloid cells and lowers risk for AUD and DPW. Our analysis also identifies MAPT as a candidate causal gene specifically associated with DPW. Genes prioritized in this study show overlap with causal genes associated with neurodegenerative disorders. Multi-omics integration analyses highlight, genetic similarities and differences between alcohol intake and disordered drinking, suggesting molecular heterogeneity that might inform future targeted functional and cross-species studies.
Access this article: https://doi.org/10.1038/s41467-021-25392-y

Title: Comparison of cognitive performance between patients with Parkinson’s disease and dystonia using an intraoperative recognition memory test
Authors: Lin Shi, Tianshuo Yuan, Shiying Fan, Jie Zheng, Yu Diao, Guofan Qin, Defeng Liu, Guanyu Zhu, Kai Qin, Huanguang Liu, Hua Zhang, Anchao Yang, Fangang Meng, Jianguo Zhang
Type: Article of Scientific Reports
Abstract:
Neuroscientific studies on the function of the basal ganglia often examine the behavioral performance of patients with movement disorders, such as Parkinson’s disease (PD) and dystonia (DT), while simultaneously examining the underlying electrophysiological activity during deep brain stimulation surgery. Nevertheless, to date, there have been no studies comparing the cognitive performance of PD and DT patients during surgery. In this study, we assessed the memory function of PD and DT patients with the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). We also tested their cognitive performance during the surgery using a continuous recognition memory test. The results of the MoCA and MMSE failed to reveal significant differences between the PD and DT patients. Additionally, no significant difference was detected by the intraoperative memory test between the PD and DT patients. The intraoperative memory test scores were highly correlated with the MMSE scores and MoCA scores. Our data suggest that DT patients perform similarly to PD patients in cognitive tests during surgery, and intraoperative memory tests can be used as a quick memory assessment tool during surgery.
Access this article: https://doi.org/10.1038/s41598-021-99317-6

Title: Exome-wide association study of levodopa-induced dyskinesia in Parkinson’s disease
Authors: Eva König, Alessandra Nicoletti, Cristian Pattaro, Grazia Annesi, Roberto Melotti, Alessandro Gialluisi, Christine Schwienbacher, Anne Picard, Hagen Blankenburg, Irene Pichler, Nicola Modugno, Marina Ciullo, Teresa Esposito, Francisco S. Domingues, Andrew A. Hicks, Mario Zappia, Peter P. Pramstaller
Type: Article of Scientific Reports
Abstract:
Levodopa is the standard long-term dopamine replacement therapy to treat Parkinson’s disease (PD) symptoms. With time, levodopa may induce debilitating dyskinesias (LID), the treatment of which represents a large clinically unmet need. However, time-to-LID onset varies between patients, reflecting a possible genetic component. We performed an hypothesis-free whole-exome sequencing (WES)-based screening of time-to-LID onset and attempted replication of previously published candidate gene studies. A WES association analysis was carried out in 134 PD patients in a meta-analytical framework. Replication was attempted in an independent study of 97 PD patients. Variants from previously reported candidate genes (OPRM1, COMT, BDNF) were also specifically examined. We significantly replicated, for the first time, an association of variant rs1799971 in the OPRM1 gene with time-to-LID onset. Furthermore, we identified two novel potentially functional variants, in the MAD2L2 (rs2233019) and MAP7 (rs35350783) genes, which were significantly associated at the discovery stage. In the replication study, the two variants showed direction-consistent effects but did not achieve the replication significance threshold. Our study provides the first WES results for time-to-LID onset, where we replicate association at OPRM1, and suggest new variants in MAD2L2 and MAP7 genes that are significant in discovery, but require larger datasets for replication. The results are being made publicly available to allow for independent external validation.
Access this article: https://doi.org/10.1038/s41598-021-99393-8

Title: Eight-hours conventional versus adaptive deep brain stimulation of the subthalamic nucleus in Parkinson’s disease
Authors: Tommaso Bocci, Marco Prenassi, Mattia Arlotti, Filippo Maria Cogiamanian, Linda Borrellini, Elena Moro, Andres M. Lozano, Jens Volkmann, Sergio Barbieri, Alberto Priori, Sara Marceglia
Type: Article of npj Parkinson’s Disease
Abstract:
This study compares the effects on motor symptoms between conventional deep brain stimulation (cDBS) and closed-loop adaptive deep brain stimulation (aDBS) in patients with Parkinson’s Disease. The aDBS stimulation is controlled by the power in the beta band (12–35 Hz) of local field potentials recorded directly by subthalamic nucleus electrodes. Eight subjects were assessed in two 8-h stimulation sessions (first day, cDBS; second day, aDBS) with regular levodopa intake and during normal daily activities. The Unified Parkinson’s Disease Rating Scale (UPDRS) part III scores, the Rush scale for dyskinesias, and the total electrical energy delivered to the tissues per second (TEEDs) were significantly lower in the aDBS session (relative UPDRS mean, cDBS: 0.46 ± 0.05, aDBS: 0.33 ± 0.04, p = 0.015; UPDRS part III rigidity subset mean, cDBS: 2.9143 ± 0.6551 and aDBS: 2.1429 ± 0.5010, p = 0.034; UPDRS part III standard deviation cDBS: 2.95, aDBS: 2.68; p = 0.047; Rush scale, cDBS 2.79 ± 0.39 versus aDBS 1.57 ± 0.23, p = 0.037; cDBS TEEDs mean: 28.75 ± 3.36 µj s⁻¹, aDBS TEEDs mean: 16.47 ± 3.33, p = 0.032 Wilcoxon’s sign rank test). This work further supports the safety and effectiveness of aDBS stimulation compared to cDBS in a daily session, both in terms of motor performance and TEED to the patient.
Access this article: https://doi.org/10.1038/s41531-021-00229-z

Title: Epigenetic inactivation of the autophagy–lysosomal system in appendix in Parkinson’s disease
Authors: Juozas Gordevicius, Peipei Li, Lee L. Marshall, Bryan A. Killinger, Sean Lang, Elizabeth Ensink, Nathan C. Kuhn, Wei Cui, Nazia Maroof, Roberta Lauria, Christina Rueb, Juliane Siebourg-Polster, Pierre Maliver, Jared Lamp, Irving Vega, Fredric P. Manfredsson, Markus Britschgi, Viviane Labrie
Type: Article of Nature Communications
Abstract:
The gastrointestinal tract may be a site of origin for α-synuclein pathology in idiopathic Parkinson’s disease (PD). Disruption of the autophagy-lysosome pathway (ALP) may contribute to α-synuclein aggregation. Here we examined epigenetic alterations in the ALP in the appendix by deep sequencing DNA methylation at 521 ALP genes. We identified aberrant methylation at 928 cytosines affecting 326 ALP genes in the appendix of individuals with PD and widespread hypermethylation that is also seen in the brain of individuals with PD. In mice, we find that DNA methylation changes at ALP genes induced by chronic gut inflammation are greatly exacerbated by α-synuclein pathology. DNA methylation changes at ALP genes induced by synucleinopathy are associated with the ALP abnormalities observed in the appendix of individuals with PD specifically involving lysosomal genes. Our work identifies epigenetic dysregulation of the ALP which may suggest a potential mechanism for accumulation of α-synuclein pathology in idiopathic PD.
Access this article: https://doi.org/10.1038/s41467-021-25474-x

Title: Dizziness in Parkinson’s disease patients is associated with vestibular function
Authors: Jeong-Ho Park, Suk Yun Kang
Type: Article of Scientific Reports
Abstract:
Dizziness is common in Parkinson’s disease (PD) patients. It is known that orthostatic hypotension (OH) is the main cause of such dizziness, but even without OH, quite a few PD patients complain of dizziness in the clinic. It can be regarded as non-specific because most of these patients have no neurological abnormalities. We hypothesized that this type of dizziness would be associated with vestibular function, although included patients did not have clinically confirmed vestibulopathy. We studied 84 patients without OH among 121 PD patients. Their clinical features and function were compared between patients with and without dizziness. Hoehn and Yahr stage (H&Y stage), the Unified Parkinson’s Disease Rating Scale (UPDRS) part III, the Korean version of the Mini-Mental State Examination (K-MMSE), education years, disease duration, total levodopa equivalent daily dose (LEDD), the presence of dizziness, the dizziness severity, and orthostatic hypotension were tested. Vestibular evoked myogenic potentials (VEMPs) were used to characterize vestibular function. Ocular (oVEMPs) and cervical (cVEMPs) were recorded. oVEMPs in the right side showed significantly reduced potentials (p = 0.016) in PD patients with dizziness, but cVEMPs did not (all ps > 0.2). Bilateral absent oVEMP responses were more common in PD patients with dizziness (p = 0.022), but the frequencies of bilateral absent cVEMP responses were not different between the dizzy and non-dizzy groups (p = 0.898). Dizziness in PD patients without orthostatic hypotension may be associated with vestibular hypofunction. Our results provide evidence that can aid clinicians when making a treatment plan for patients with dizziness. i.e., strategies to enhance reduced vestibular function may be helpful, but this suggestion remains to be evaluated.
Access this article: https://doi.org/10.1038/s41598-021-98540-5