Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies.

OBJECTIVE: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants. METHODS: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan-Meier survival analysis. RESULTS: A 5'-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5' risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3' of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3' variant rs356182) had an opposite direction of effect in iRBD compared to PD. INTERPRETATION: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3' of SNCA. Several 5' SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584-598.

Targeted Whole Exome Sequencing in Children With Early-Onset Epilepsy: Parent Experiences.

This study investigated the experiences of 25 caregivers of children with early-onset, treatment-resistant epilepsy who pursued whole exome sequencing to determine the impact of the test results on their child's treatment. Caregivers who consented to be recontacted were recruited from a previous study investigating the diagnostic yield of whole exome sequencing. A semistructured interview addressed questions based on one of 2 study phases. The first phase discussed the decision-making process for genetic testing (15 interviews), which revealed 4 major themes: (1) prognosis, (2) engagement, (3) concerns, and (4) autonomy. The second phase discussed the impact of genetic testing on treatment (10 interviews), which revealed 3 major themes: (1) testing features, (2) emotional impact, and (3) treatment outcomes. Overall, parents pursued genetic testing to obtain a clear prognosis, inform treatment decisions, engage with other families, and exercise autonomy. Caregivers felt that early testing is warranted to inform their child's diagnostic odyssey.

The impact of brain invasion criteria on the incidence and distribution of WHO grade 1, 2, and 3 meningiomas.

BACKGROUND: In 2016 brain invasion was added as a standalone diagnostic criterion for Grade 2 meningiomas in the WHO Classification of Brain Tumors. The aim of this study was to compare the incidence and distribution of meningiomas, and agreement, between the 2007 and 2016 WHO criteria. METHODS: All cases of intracranial meningiomas diagnosed between 2007 and 2020 at a tertiary care academic hospital were identified. The incidence of each meningioma grade in the WHO 2007 and WHO 2016 cohorts were compared. Additionally, each case in the 2007 cohort was re-graded according to the WHO 2016 criteria to determine the intra-class correlation (ICC) between criteria. RESULTS: Of 814 cases, 532 (65.4%) were in the 2007 WHO cohort and 282 (34.6%) were in the 2016 WHO cohort. There were no differences in the distribution of meningioma grades between cohorts (P = .11). Incidence rates were: 75.0% vs. 75.2% for Grade 1, 22.7% vs. 24.5% for Grade 2, and 2.3% vs. 0.4% for Grade 3, for the 2007 and 2016 cohorts, respectively. Upon re-grading, 21 cases (3.9%) were changed. ICC between original and revised grade was 0.92 (95% CI: 0.91-0.93). Amongst Grade 2 meningiomas with brain invasion, 75.8% had three or more atypical histologic features or an elevated mitotic index. CONCLUSIONS: Including brain invasion as a standalone diagnostic criterion for Grade 2 meningiomas had minimal impact on the incidence of specific meningioma grade tumors. There is strong agreement between the 2007 and 2016 WHO criteria, likely due to cosegregation of grade elevating features.

Survival and Recurrence Outcomes Following Adjuvant Radiotherapy for Grade 2 Intracranial Meningiomas: 13-Year Experience in a Tertiary-Care Center.

OBJECTIVE: We sought to evaluate overall survival (OS) and local recurrence (LR) in patients with grade 2 meningiomas treated with adjuvant radiotherapy compared to surgery alone at time of diagnosis. METHODS: All patients at the authors' institution between 2007 and 2020 were retrospectively reviewed. OS, LR, and treatment toxicities were assessed. Sensitivity analyses were performed for patients with initial gross total resection (GTR) and subtotal resection (STR). Kaplan-Meier analyses and log-rank test for significance were used to compare surgery alone and adjuvant radiotherapy groups. RESULTS: We included 189 patients with mean age 57.4 ± 14.6 years. Patients were 64% female, and median follow-up was 64 (interquartile range: 20-96) months. At initial treatment, 21 patients received adjuvant radiotherapy and 168 received surgery alone. There was no significant difference for OS (hazard ratio = 1.3 [95% confidence interval 0.4-4.5], P = 0.92) overall or when limited to GTR (P = 0.38) or STR (P = 0.85). There was no significant difference in LR overall (P = 0.75) or when restricted to GTR (P = 0.77) or STR (P = 0.20). No patient had radiotherapy stopped or altered because of side effects; however, 71.4% reported tolerable side effects during the treatment period and 14.3% reported chronic side effects persisting longer than 12 months post treatment. CONCLUSIONS: In a large retrospective cohort, we found no survival or local recurrence benefit to adjuvant radiotherapy in treatment of grade 2 meningiomas. Sensitivity analysis limited to initial GTR and STR also failed to demonstrate any OS or LR benefit with adjuvant radiotherapy. In our experience, there is limited utility to upfront adjuvant radiotherapy following initial surgical resection in the treatment of grade 2 meningiomas.

Using Peer Support to Strengthen Mental Health During the COVID-19 Pandemic: A Review.

Background: The coronavirus (COVID-19) pandemic has had a significant impact on society's overall mental health. Measures such as mandated lockdowns and physical distancing have contributed to higher levels of anxiety, depression, and other metrics indicating worsening mental health. Peer support, which is peer-to-peer provided social and emotional support, is an underutilized and effective mental health resource that can potentially be used to ameliorate mental health during these times. Objective: This review aims to summarize the toll that this pandemic has had on society's mental health as found in peer-reviewed literature from October 2019 to March 2021, as well as suggest the utility of peer support to address these needs. Methods: References for this review were chosen through searches of PubMed, Web of Science, and Google Scholar for articles published between October 2019 and March 2021 that used the terms: "coronavirus," "COVID-19," "mental health," "anxiety," "depression," "isolation," "mental health resources," "peer support," "online mental health resources," and "healthcare workers." Articles resulting from these searches and relevant references cited in those articles were reviewed. Articles published in English, French and Italian were included. Results: This pandemic has ubiquitously worsened the mental health of populations across the world. Peer support has been demonstrated to yield generally positive effects on the mental health of a wide variety of recipients, and it can be provided through numerous accessible mediums. Conclusions: Peer support can overall be beneficial for improving mental health during the COVID-19 pandemic and may be an effective tool should similar events arise in the future, although the presence of a few conflicting studies suggests the need for additional research.

Choice and Trade-offs: Parent Decision Making for Neurotechnologies for Pediatric Drug-Resistant Epilepsy.

This qualitative study investigated factors that guide caregiver decision making and ethical trade-offs for advanced neurotechnologies used to treat children with drug-resistant epilepsy. Caregivers with affected children were recruited to semi-structured focus groups or interviews at one of 4 major epilepsy centers in Eastern and Western Canada and the USA (n = 22). Discussions were transcribed and qualitative analytic methods applied to examine values and priorities (eg, risks, benefits, adherence, invasiveness, reversibility) of caregivers pertaining to novel technologies to treat drug-resistant epilepsy. Discussions revealed 3 major thematic branches for decision making: (1) features of the intervention-risks and benefits, with an emphasis on an aversion to perceived invasiveness; (2) decision drivers-trust in the clinical team, treatment costs; and (3) quality of available information about neurotechnological options. Overall, caregivers' definition of treatment success is more expansive than seizure freedom. The full involvement of their values and priorities must be considered in the decision-making process.

SMPD1 variants do not have a major role in rapid eye movement sleep behavior disorder.

Mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene were reported to be associated with Parkinson's disease and dementia with Lewy bodies. In the current study, we aimed to evaluate the role of SMPD1 variants in isolated rapid eye movement sleep behavior disorder (iRBD). SMPD1 and its untranslated regions were sequenced using targeted next-generation sequencing in 959 iRBD patients and 1287 controls from European descent. Our study reports no statistically significant association of SMPD1 variants and iRBD. It is hence unlikely that SMPD1 plays a major role in iRBD.

Carriers of both GBA and LRRK2 mutations, compared to carriers of either, in Parkinson's disease: Risk estimates and genotype-phenotype correlations.

INTRODUCTION: The clinical characteristics of Parkinson's disease (PD) associated with both the LRRK2 p.G2019S mutation and a GBA variant (LRRK2-GBA-PD) have not yet been determined. METHODS: In this retrospective observational study of Ashkenazi-Jewish (AJ) PD patients, we describe the clinical course and characteristics of LRRK2-GBA-PD and estimate the risk to develop PD for the double mutation carriers. Odds ratios (OR) were estimated using published data on frequencies of GBA and LRRK2 mutations. Demographic and clinical data was retrieved from medical records and from rating at last visit. RESULTS: Our analysis included 236 PD patients, divided into four groups: LRRK2-PD (n = 66), GBA-PD (n = 78), GBA-LRRK2-PD (n = 12) and mutation-negative PD (MNPD, n = 80 randomly selected). The estimated ORs in different models for GBA-LRRK2 PD were 15-28 (95% CI 6.7-72.0, p < 0.0001), compared to AJ controls. Using logistic regression (while controlling for sex, age at onset and PD duration), we found that probable REM-sleep behavior disorder (RBD) was significantly more common for GBA-PD than for LRRK2-PD, while none of the GBA-LRRK2-PD patients reported RBD. Dementia was significantly more common for GBA-PD than for the LRRK2-PD and MNPD. Psychosis was the most common for GBA-PD and least common for LRRK2-GBA-PD. CONCLUSIONS: While GBA-PD is characterized by higher rates of dementia, probable RBD and psychosis, it seems that compared to the other groups, these features are less common for LRRK2-GBA-PD. This may imply to a possible protective effect of LRRK2 p.G2019S mutation among GBA variant carriers.

Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson's disease.

BACKGROUND: Variants in GBA are the most common genetic risk factor for Parkinson's disease (PD), and are especially prevalent in the Ashkenazi Jewish (AJ) population. However, most studies on GBA in AJ genotype only seven selected Gaucher-associated pathogenic variants rather than sequencing the whole gene, which may leave carriers of PD-associated GBA variants undiscovered. METHODS: GBA was fully sequenced using molecular inversion probes (MIPs) and Sanger sequencing in 735 AJ PD patients and 662 AJ controls, from Israel and New York. Additional AJ control data (n = 3044) from the Inflammatory Bowel Disease Exome Portal was used. RESULTS: Full GBA sequencing increased the number of variants discovered by 17.4%, compared to targeted genotyping. An additional 17 PD patients were identified with GBA-associated PD. The p.E326K variant was found in 1.6% of AJ PD patients, making it the second most common PD-associated GBA variant in AJ. GBA variants were found in 18% of PD patients and 7.5% of controls (OR = 2.7, 95%CI = 1.9-3.8, p < 0.0001). CONCLUSION: Without full sequencing of GBA, or at minimum including p.E326K in the genotyping panel, a significant proportion of variant carriers go undiscovered and may be incorrectly assigned as non-carriers in studies or clinical trials.