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A pathogenic variant in RAB32 causes autosomal dominant Parkinson's disease and activates LRRK2 kinase.
BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder. Mendelian forms have revealed multiple genes, with a notable emphasis on membrane trafficking; RAB GTPases play an important role in PD as a subset are both regulators and substrates of LRRK2 protein kinase. To explore the role of RAB GTPases in PD, we undertook a comprehensive examination of their genetic variability in familial PD. METHODS: Affected probands from 130 multi-incident PD families underwent whole-exome sequencing and genotyping, Potential pathogenic variants in 61 RAB GTPases were genotyped in relatives to assess disease segregation. These variants were also genotyped in a larger case-control series, totaling 3,078 individuals (2,734 with PD). The single most significant finding was subsequently validated within genetic data (6,043 with PD). Clinical and pathologic findings were summarized for gene-identified patients, and haplotypes were constructed. In parallel, wild-type and mutant RAB GTPase structural variation, protein interactions, and resultant enzyme activities were assessed. FINDINGS: We found RAB32 c.213C>G (Ser71Arg) to co-segregate with autosomal dominant parkinsonism in three multi-incident families. RAB32 Ser71Arg was also significantly associated with PD in case-control samples: genotyping and database searches identified thirteen more patients with the same variant that was absent in unaffected controls. Notably, RAB32 Ser71Arg heterozygotes share a common haplotype. At autopsy, one patient had sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In transfected cells the RAB32 Arg71 was twice as potent as Ser71 wild type to activate LRRK2 kinase. INTERPRETATION: Our study provides unequivocal evidence to implicate RAB32 Ser71Arg in PD. Functional analysis demonstrates LRRK2 kinase activation. We provide a mechanistic explanation to expand and unify the etiopathogenesis of monogenic PD. FUNDING: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J. Fox Foundation for Parkinson's Research, and the UK Medical Research Council.
Fatigue predicts quality of life after leucine‐rich glioma‐inactivated 1‐antibody encephalitis
AbstractPatient‐reported quality‐of‐life (QoL) and carer impacts are not reported after leucine‐rich glioma‐inactivated 1‐antibody encephalitis (LGI1‐Ab‐E). From 60 patients, 85% (51 out of 60) showed one abnormal score across QoL assessments and 11 multimodal validated questionnaires. Compared to the premorbid state, QoL significantly deteriorated (p < 0.001) and, at a median of 41 months, fatigue was its most important predictor (p = 0.025). In total, 51% (26 out of 51) of carers reported significant burden. An abbreviated five‐item battery explained most variance in QoL. Wide‐ranging impacts post‐LGI1‐Ab‐E include decreased QoL and high caregiver strain. We identify a rapid method to capture QoL in routine clinic or clinical trial settings.
Common Data Elements for Disorders of Consciousness: Recommendations from the Working Group on Hospital Course, Confounders, and Medications.
The convergence of an interdisciplinary team of neurocritical care specialists to organize the Curing Coma Campaign is the first effort of its kind to coordinate national and international research efforts aimed at a deeper understanding of disorders of consciousness (DoC). This process of understanding includes translational research from bench to bedside, descriptions of systems of care delivery, diagnosis, treatment, rehabilitation, and ethical frameworks. The description and measurement of varying confounding factors related to hospital care was thought to be critical in furthering meaningful research in patients with DoC. Interdisciplinary hospital care is inherently varied across geographical areas as well as community and academic medical centers. Access to monitoring technologies, specialist consultation (medical, nursing, pharmacy, respiratory, and rehabilitation), staffing resources, specialty intensive and acute care units, specialty medications and specific surgical, diagnostic and interventional procedures, and imaging is variable, and the impact on patient outcome in terms of DoC is largely unknown. The heterogeneity of causes in DoC is the source of some expected variability in care and treatment of patients, which necessitated the development of a common nomenclature and set of data elements for meaningful measurement across studies. Guideline adherence in hemorrhagic stroke and severe traumatic brain injury may also be variable due to moderate or low levels of evidence for many recommendations. This article outlines the process of the development of common data elements for hospital course, confounders, and medications to streamline definitions and variables to collect for clinical studies of DoC.
Common Data Elements for Disorders of Consciousness: Recommendations from the Working Group on Neuroimaging.
BACKGROUND: Over the past 5 decades, advances in neuroimaging have yielded insights into the pathophysiologic mechanisms that cause disorders of consciousness (DoC) in patients with severe brain injuries. Structural, functional, metabolic, and perfusion imaging studies have revealed specific neuroanatomic regions, such as the brainstem tegmentum, thalamus, posterior cingulate cortex, medial prefrontal cortex, and occipital cortex, where lesions correlate with the current or future state of consciousness. Advanced imaging modalities, such as diffusion tensor imaging, resting-state functional magnetic resonance imaging (fMRI), and task-based fMRI, have been used to improve the accuracy of diagnosis and long-term prognosis, culminating in the endorsement of fMRI for the clinical evaluation of patients with DoC in the 2018 US (task-based fMRI) and 2020 European (task-based and resting-state fMRI) guidelines. As diverse neuroimaging techniques are increasingly used for patients with DoC in research and clinical settings, the need for a standardized approach to reporting results is clear. The success of future multicenter collaborations and international trials fundamentally depends on the implementation of a shared nomenclature and infrastructure. METHODS: To address this need, the Neurocritical Care Society's Curing Coma Campaign convened an international panel of DoC neuroimaging experts to propose common data elements (CDEs) for data collection and reporting in this field. RESULTS: We report the recommendations of this CDE development panel and disseminate CDEs to be used in neuroimaging studies of patients with DoC. CONCLUSIONS: These CDEs will support progress in the field of DoC neuroimaging and facilitate international collaboration.
Nightmare frequency is a risk factor for suicidal ideation during the COVID-19 pandemic.
The association between nightmare frequency (NMF) and suicidal ideation (SI) is well known, yet the impact of the COVID-19 pandemic on this relation is inconsistent. This study aimed to investigate changes in NMF, SI, and their association during the COVID-19 pandemic. Data were collected in 16 countries using a harmonised questionnaire. The sample included 9328 individuals (4848 women; age M[SD] = 46.85 [17.75] years), and 17.60% reported previous COVID-19. Overall, SI was significantly 2% lower during the pandemic vs. before, and this was consistent across genders and ages. Most countries/regions demonstrated decreases in SI during this pandemic, with Austria (-9.57%), Sweden (-6.18%), and Bulgaria (-5.14%) exhibiting significant declines in SI, but Italy (1.45%) and Portugal (2.45%) demonstrated non-significant increases. Suicidal ideation was more common in participants with long-COVID (21.10%) vs. short-COVID (12.40%), though SI did not vary by COVID-19 history. Nightmare frequency increased by 4.50% during the pandemic and was significantly higher in those with previous COVID-19 (14.50% vs. 10.70%), during infection (23.00% vs. 8.10%), and in those with long-COVID (18.00% vs. 8.50%). The relation between NMF and SI was not significantly stronger during the pandemic than prior (rs = 0.18 vs. 0.14; z = 2.80). Frequent nightmares during the pandemic increased the likelihood of reporting SI (OR = 1.57, 95% CI 1.20-2.05), while frequent dream recall during the pandemic served a protective effect (OR = 0.74, 95% CI 0.59-0.94). These findings have important implications for identifying those at risk of suicide and may offer a potential pathway for suicide prevention.
Validity and Reliability of the Turkish Version of the Sleep Condition Indicator: A Clinical Screening Instrument Based on the DSM-5 Criteria for Insomnia.
PURPOSE: We aimed to adapt the Turkish Sleep Condition Indicator (SCI) version and examine its psychometric properties among the general population. METHODS: This study was a cross-sectional study. The item-total correlation, standard error of measurement, Cronbach's α, and McDonald's ω were used for internal consistency. We ran confirmatory factor analysis (CFA) and network analysis to confirm the factor structure. Multigroup CFA was run to assess the measurement invariance across gender, whether clinical insomnia or not, and poor sleep quality. We correlated SCI scores with Insomnia Severity Index (ISI) and Pittsburgh Sleep Quality Index (PSQI) scores to evaluate construct validity. A receiver operating characteristic (ROC) curve analysis was conducted to calculate the cut-off score of the SCI. The temporal stability was examined with the intraclass correlation coefficient. RESULTS: Eight hundred thirty-four participants attended. Over half of the participants were women (63.2% n = 527); the mean age was 36.15 ± 9.64. Confirmatory factor and network analysis results show that the two-factor correlated model had a good model fit for the SCI. The SCI had scalar level invariance across gender, having clinical insomnia and poor sleep quality in the Multigroup CFA. ROC curve analysis shows that the SCI has good sensitivity (90.3%) and specificity (91.8%) for cut-off ≤ 15. The intraclass correlation coefficient computed between the first and second SCI total scores was significant (r=0.80 with a 95% confidence interval from 0.78 to 0.87; p < 0.001). CONCLUSION: The Turkish SCI is a practical self-reported insomnia scale with good psychometric properties that can be used to screen for insomnia disorder.
Acute to long-term characteristics of impedance recordings during neurostimulation in humans.
OBJECTIVE: This study aims to characterize the time course of impedance, a crucial electrophysiological property of brain tissue, in the human thalamus (THL), amygdala-hippocampus (AMG-HPC), and posterior hippocampus (post-HPC) over an extended period. APPROACH: Impedance was periodically sampled every 5-15 minutes over several months in five subjects with drug-resistant epilepsy using an experimental neuromodulation device. Initially, we employed descriptive piecewise and continuous mathematical models to characterize the impedance response for approximately three weeks post-electrode implantation. We then explored the temporal dynamics of impedance during periods when electrical stimulation was temporarily halted, observing a monotonic increase (rebound) in impedance before it stabilized at a higher value. Lastly, we assessed the stability of amplitude and phase over the 24-hour impedance cycle throughout the multi-month recording. MAIN RESULTS: Immediately post-implantation, the impedance decreased, reaching a minimum value in all brain regions within approximately two days, and then increased monotonically over about 14 days to a stable value. The models accounted for the variance in short-term impedance changes. Notably, the minimum impedance of the THL in the most epileptogenic hemisphere was significantly lower than in other regions. During the gaps in electrical stimulation, the impedance rebound decreased over time and stabilized around 200 days post-implant, likely indicative of the foreign body response and fibrous tissue encapsulation around the electrodes. The amplitude and phase of the 24-hour impedance oscillation remained stable throughout the multi-month recording, with circadian variation in impedance dominating the long-term measures. SIGNIFICANCE: Our findings illustrate the complex temporal dynamics of impedance in implanted electrodes and the impact of electrical stimulation. We discuss these dynamics in the context of the known biological foreign body response of the brain to implanted electrodes. The data suggest that the temporal dynamics of impedance are dependent on the anatomical location and tissue epileptogenicity. These insights may offer additional guidance for the delivery of therapeutic stimulation at various time points post-implantation for neuromodulation therapy.
Clinical and cost-effectiveness of DREAMS START (Dementia RElAted Manual for Sleep; STrAtegies for RelaTives) for people living with dementia and their carers: a study protocol for a parallel multicentre randomised controlled trial.
INTRODUCTION: Many people living with dementia experience sleep disturbance and there are no known effective treatments. Non-pharmacological treatment options should be the first-line sleep management. For family carers, relatives' sleep disturbance leads to interruption of their sleep, low mood and breakdown of care. Our team developed and delivered DREAMS START (Dementia RElAted Manual for Sleep; STrAtegies for RelaTives), a multimodal non-pharmacological intervention, showing it to be feasible and acceptable. The aim of this randomised controlled trial is to establish whether DREAMS START is clinically cost-effective in reducing sleep disturbances in people living with dementia living at home compared with usual care. METHODS AND ANALYSIS: We will recruit 370 participant dyads (people living with dementia and family carers) from memory services, community mental health teams and the Join Dementia Research Website in England. Those meeting inclusion criteria will be randomised (1:1) either to DREAMS START or to usual treatment. DREAMS START is a six-session (1 hour/session), manualised intervention delivered every 1-2 weeks by supervised, non-clinically trained graduates. Outcomes will be collected at baseline, 4 months and 8 months with the primary outcome being the Sleep Disorders Inventory score at 8 months. Secondary outcomes for the person with dementia (all proxy) include quality of life, daytime sleepiness, neuropsychiatric symptoms and cost-effectiveness. Secondary outcomes for the family carer include quality of life, sleep disturbance, mood, burden and service use and caring/work activity. Analyses will be intention-to-treat and we will conduct a process evaluation. ETHICS AND DISSEMINATION: London-Camden & Kings Cross Ethics Committee (20/LO/0894) approved the study. We will disseminate our findings in high-impact peer-reviewed journals and at national and international conferences. This research has the potential to improve sleep and quality of life for people living with dementia and their carers, in a feasible and scalable intervention. TRIAL REGISTRATION NUMBER: ISRCTN13072268.