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An abstract of the article "Emergency Department Evaluation of Sudden, Severe Headache," by D.P. Breen, C.W. Duncan, A.J. Gray, and R. Al-Shahi Salman is presented.

Background: A simple prognostic model was previously developed to predict the probability of recently-diagnosed patients reaching negative outcomes (postural instability, dementia or death) in a 5-year period., Objectives: To validate this model in an independent cohort and establish utility at later time points., Methods: Validation was performed using data collected in an incident cohort at baseline, 2 and 4 years. Predicted negative outcome probabilities were compared to actual 5-year outcomes., Results: The model, based on age, MDS-UPDRS axial score and 60-second animal fluency, predicted poor 5-year outcome when applied at baseline, (area under the curve (AUC) 0.80), 2 years (AUC 0.82) and 4 years (AUC 0.71). Power calculations showed that selecting a subgroup with prognostic score >0.5 reduced the sample size required for a disease-modifying trial., Conclusions: This 5-year prognostic model has good accuracy when employed up to 4 years from diagnosis and may help stratification for disease-modifying trials., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Introduction: Cerebral small vessel disease (SVD) is common in patients with cognitive impairment and neurodegenerative diseases such as Alzheimer's and Parkinson's. This study investigated the burden of magnetic resonance imaging (MRI)-based markers of SVD in patients with neurodegenerative diseases as a function of rare genetic variant carrier status., Methods: The Ontario Neurodegenerative Disease Research Initiative study included 520 participants, recruited from 14 tertiary care centers, diagnosed with various neurodegenerative diseases and determined the carrier status of rare non-synonymous variants in five genes (ABCC6, COL4A1/COL4A2, NOTCH3/HTRA1)., Results: NOTCH3/HTRA1 were found to significantly influence SVD neuroimaging outcomes; however, the mechanisms by which these variants contribute to disease progression or worsen clinical correlates are not yet understood., Discussion: Further studies are needed to develop genetic and imaging neurovascular markers to enhance our understanding of their potential contribution to neurodegenerative diseases., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Neuropsychiatric symptoms (NPS) are a core feature of most neurodegenerative and cerebrovascular diseases. White matter hyperintensities and brain atrophy have been implicated in NPS. We aimed to investigate the relative contribution of white matter hyperintensities and cortical thickness to NPS in participants across neurodegenerative and cerebrovascular diseases., Methods: Five hundred thirteen participants with one of these conditions, i.e. Alzheimer's Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Parkinson's Disease, or Cerebrovascular Disease, were included in the study. NPS were assessed using the Neuropsychiatric Inventory - Questionnaire and grouped into hyperactivity, psychotic, affective, and apathy subsyndromes. White matter hyperintensities were quantified using a semi-automatic segmentation technique and FreeSurfer cortical thickness was used to measure regional grey matter loss., Results: Although NPS were frequent across the five disease groups, participants with frontotemporal dementia had the highest frequency of hyperactivity, apathy, and affective subsyndromes compared to other groups, whilst psychotic subsyndrome was high in both frontotemporal dementia and Parkinson's disease. Results from univariate and multivariate results showed that various predictors were associated with neuropsychiatric subsyndromes, especially cortical thickness in the inferior frontal, cingulate, and insula regions, sex(female), global cognition, and basal ganglia-thalamus white matter hyperintensities., Conclusions: In participants with neurodegenerative and cerebrovascular diseases, our results suggest that smaller cortical thickness and white matter hyperintensity burden in several cortical-subcortical structures may contribute to the development of NPS. Further studies investigating the mechanisms that determine the progression of NPS in various neurodegenerative and cerebrovascular diseases are needed., (© 2023. The Author(s).)

Background and Purpose: The pathophysiology of Parkinson's disease (PD) negatively affects brain network connectivity, and in the presence of brain white matter hyperintensities (WMHs) cognitive and motor impairments seem to be aggravated. However, the role of WMHs in predicting accelerating symptom worsening remains controversial. The objective was to investigate whether location and segmental brain WMH burden at baseline predict cognitive and motor declines in PD after 2 years., Methods: Ninety-eight older adults followed longitudinally from Ontario Neurodegenerative Diseases Research Initiative with PD of 3-8 years in duration were included. Percentages of WMH volumes at baseline were calculated by location (deep and periventricular) and by brain region (frontal, temporal, parietal, occipital lobes and basal ganglia + thalamus). Cognitive and motor changes were assessed from baseline to 2-year follow-up. Specifically, global cognition, attention, executive function, memory, visuospatial abilities and language were assessed as were motor symptoms evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III, spatial-temporal gait variables, Freezing of Gait Questionnaire and Activities Specific Balance Confidence Scale., Results: Regression analysis adjusted for potential confounders showed that total and periventricular WMHs at baseline predicted decline in global cognition (p < 0.05). Also, total WMH burden predicted the decline of executive function (p < 0.05). Occipital WMH volumes also predicted decline in global cognition, visuomotor attention and visuospatial memory declines (p < 0.05). WMH volumes at baseline did not predict motor decline., Conclusion: White matter hyperintensity burden at baseline predicted cognitive but not motor decline in early to mid-stage PD. The motor decline observed after 2 years in these older adults with PD is probably related to the primary neurodegenerative process than comorbid white matter pathology., (© 2023 European Academy of Neurology.)

Objectives: Caregiving burdens are a substantial concern in the clinical care of persons with neurodegenerative disorders. In the Ontario Neurodegenerative Disease Research Initiative, we used the Zarit's Burden Interview (ZBI) to examine: (1) the types of burdens captured by the ZBI in a cross-disorder sample of neurodegenerative conditions (2) whether there are categorical or disorder-specific effects on caregiving burdens, and (3) which demographic, clinical, and cognitive measures are related to burden(s) in neurodegenerative disorders?, Methods/design: N = 504 participants and their study partners (e.g., family, friends) across: Alzheimer's disease/mild cognitive impairment (AD/MCI; n = 120), Parkinson's disease (PD; n = 136), amyotrophic lateral sclerosis (ALS; n = 38), frontotemporal dementia (FTD; n = 53), and cerebrovascular disease (CVD; n = 157). Study partners provided information about themselves, and information about the clinical participants (e.g., activities of daily living (ADL)). We used Correspondence Analysis to identify types of caregiving concerns in the ZBI. We then identified relationships between those concerns and demographic and clinical measures, and a cognitive battery., Results: We found three components in the ZBI. The first was "overall burden" and was (1) strongly related to increased neuropsychiatric symptoms (NPI severity r = 0.586, NPI distress r = 0.587) and decreased independence in ADL (instrumental ADLs r = -0.566, basic ADLs r = -0.43), (2) moderately related to cognition (MoCA r = -0.268), and (3) showed little-to-no differences between disorders. The second and third components together showed four types of caregiving concerns: current care of the person with the neurodegenerative disease, future care of the person with the neurodegenerative disease, personal concerns of study partners, and social concerns of study partners., Conclusions: Our results suggest that the experience of caregiving in neurodegenerative and cerebrovascular diseases is individualized and is not defined by diagnostic categories. Our findings highlight the importance of targeting ADL and neuropsychiatric symptoms with caregiver-personalized solutions., (© 2022 John Wiley & Sons Ltd.)

Change in empathy is an increasingly recognised symptom of neurodegenerative diseases and contributes to caregiver burden and patient distress. Empathy impairment has been associated with brain atrophy but its relationship to white matter hyperintensities (WMH) is unknown. We aimed to investigate the relationships amongst WMH, brain atrophy, and empathy deficits in neurodegenerative and cerebrovascular diseases. Five hundred thirteen participants with Alzheimer's disease/mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), Parkinson's disease, or cerebrovascular disease (CVD) were included. Empathy was assessed using the Interpersonal Reactivity Index. WMH were measured using a semi-automatic segmentation and FreeSurfer was used to measure cortical thickness. A heterogeneous pattern of cortical thinning was found between groups, with FTD showing thinning in frontotemporal regions and CVD in left superior parietal, left insula, and left postcentral. Results from both univariate and multivariate analyses revealed that several variables were associated with empathy, particularly cortical thickness in the fronto-insulo-temporal and cingulate regions, sex (female), global cognition, and right parietal and occipital WMH. Our results suggest that cortical atrophy and WMH may be associated with empathy deficits in neurodegenerative and cerebrovascular diseases. Future work should consider investigating the longitudinal effects of WMH and atrophy on empathy deficits in neurodegenerative and cerebrovascular diseases., (© 2022. The Author(s), under exclusive licence to American Aging Association.)

Background: Although previously thought to be asymptomatic, recent studies have suggested that magnetic resonance imaging-visible perivascular spaces (PVS) in the basal ganglia (BG-PVS) of patients with Parkinson's disease (PD) may be markers of motor disability and cognitive decline. In addition, a pathogenic and risk profile difference between small (≤3-mm diameter) and large (>3-mm diameter) PVS has been suggested., Objective: The aim of this study was to examine associations between quantitative measures of large and small BG-PVS, global cognition, and motor/nonmotor features in a multicenter cohort of patients with PD., Methods: We performed a cross-sectional study examining the association between large and small BG-PVS with Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I-IV and cognition (Montreal Cognitive Assessment) in 133 patients with PD enrolled in the Ontario Neurodegenerative Disease Research Initiative study., Results: Patients with PD with small BG-PVS demonstrated an association with MDS-UPDRS Parts I (P = 0.008) and II (both P = 0.02), whereas patients with large BG-PVS demonstrated an association with MDS-UPDRS Parts III (P < 0.0001) and IV (P < 0.001). BG-PVS were not correlated with cognition., Conclusions: Small BG-PVS are associated with motor and nonmotor aspects of experiences in daily living, while large BG-PVS are associated with the motor symptoms and motor complications. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

Introduction: Malignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan proteomics (Somalogic, Boulder, CO) and fibulin-3 seemed highly accurate, but SOMAscan has not been validated prospectively and subsequent fibulin-3 data have been contradictory., Methods: A multicenter prospective observational study was performed in 22 centers, generating a large intention-to-diagnose cohort. Blood sampling, processing, and diagnostic assessment were standardized, including a 1-year follow-up. Plasma fibulin-3 was measured using two enzyme-linked immunosorbent assays (CloudClone [used in previous studies] and BosterBio, Pleasanton, CA). Serum proteomics was measured using the SOMAscan assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve [AUC]) was benchmarked against serum mesothelin (Mesomark, Fujirebio Diagnostics, Malvern, PA). Biomarkers were correlated against primary tumor volume, inflammatory markers, and asbestos exposure., Results: A total of 638 patients with suspected pleural malignancy (SPM) and 110 asbestos-exposed controls (AECs) were recruited. SOMAscan reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in patients with differentiating non-MPM SPM. Fibulin-3 (by BosterBio after failed CloudClone validation) revealed 7.4% and 11.9% sensitivity at 95% specificity in MPM versus non-MPM SPM and AECs, respectively (associated AUCs 0.611 [0.557-0.664], p = 0.0015) and 0.516 [0.443-0.589], p = 0.671), both inferior to mesothelin. SOMAscan proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumor volume., Conclusions: SOMAscan may prove useful as a future screening test for MPM in asbestos-exposed persons. Neither fibulin-3 nor SOMAscan should be used for diagnosis or pathway stratification., (Copyright © 2021 International Association for the Study of Lung Cancer. All rights reserved.)

Disordered cholesterol metabolism is linked to neurodegeneration. In this study we investigated the profile of cholesterol metabolites found in the cerebrospinal fluid (CSF) of Parkinson's disease (PD) patients. When adjustments were made for confounding variables of age and sex, 7α,(25R)26-dihydroxycholesterol and a second oxysterol 7α,x,y-trihydroxycholest-4-en-3-one (7α,x,y-triHCO), whose exact structure is unknown, were found to be significantly elevated in PD CSF. The likely location of the additional hydroxy groups on the second oxysterol are on the sterol side-chain. We found that CSF 7α-hydroxycholesterol levels correlated positively with depression in PD patients, while two presumptively identified cholestenoic acids correlated negatively with depression., Competing Interests: WG, PC, and YW were listed as inventors on the Swansea University patent “Kit and method for quantitative detection of steroids,” US9851368B2, licensed to Avanti Polar Lipids Inc., and Cayman Chemical Company by Swansea University. WG, JA-K, PC, EY, ST, EA, and YW were shareholders in CholesteniX Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Griffiths, Abdel-Khalik, Moore, Wijeyekoon, Crick, Yutuc, Farrell, Breen, Williams-Gray, Theofilopoulos, Arenas, Trupp, Barker and Wang.)

Constipation is a common but not a universal feature in early PD, suggesting that gut involvement is heterogeneous and may be part of a distinct PD subtype with prognostic implications. We analysed data from the Parkinson's Incidence Cohorts Collaboration, composed of incident community-based cohorts of PD patients assessed longitudinally over 8 years. Constipation was assessed with the MDS-UPDRS constipation item or a comparable categorical scale. Primary PD outcomes of interest were dementia, postural instability and death. PD patients were stratified according to constipation severity at diagnosis: none (n = 313, 67.3%), minor (n = 97, 20.9%) and major (n = 55, 11.8%). Clinical progression to all three outcomes was more rapid in those with more severe constipation at baseline (Kaplan-Meier survival analysis). Cox regression analysis, adjusting for relevant confounders, confirmed a significant relationship between constipation severity and progression to dementia, but not postural instability or death. Early constipation may predict an accelerated progression of neurodegenerative pathology.

Background: Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study., Objectives: We examined sex associations to PD phenotypes cross-sectionally and longitudinally in large-scale data., Methods: We tested 40 clinical phenotypes, using longitudinal, clinic-based patient cohorts, consisting of 5946 patients, with a median follow-up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex-associated differences in presentation, and linear mixed-effects models to test sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD., Results: Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the online-only cohort., Conclusions: We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Background: Cognitive impairment is common in Parkinson's disease (PD), with 80% cumulatively developing dementia (PDD)., Objective: We sought to identify tests that are sensitive to change over time above normal ageing so as to refine the neuropsychological tests predictive of PDD., Methods: Participants with newly diagnosed PD (n = 211) and age-matched controls (n = 99) completed a range of clinical and neuropsychological tests as part of the ICICLE-PD study at 18-month intervals over 72 months. Impairments on tests were determined using control means (<1-2SD) and median scores. Mild cognitive impairment (PD-MCI) was classified using 1-2SD below normative values. Linear mixed effects modelling assessed cognitive decline, while Cox regression identified baseline predictors of PDD., Results: At 72 months, 46 (cumulative probability 33.9%) participants had developed PDD; these participants declined at a faster rate in tests of global cognition, verbal fluency, memory and attention (p < 0.05) compared to those who remained dementia-free. Impaired baseline global cognition, visual memory and attention using median cut-offs were the best predictors of early PDD (area under the curve [AUC] = 0.88, p < 0.001) compared to control-generated cut-offs (AUC = 0.76-0.84,p < 0.001) and PD-MCI (AUC = 0.64-0.81, p < 0.001). Impaired global cognition and semantic fluency were the most useful brief tests employable in a clinical setting (AUC = 0.79, p < 0.001)., Conclusion: Verbal fluency, attention and memory were sensitive to change in early PDD and may be suitable tests to measure therapeutic response in future interventions. Impaired global cognition, attention and visual memory were the most accurate predictors for developing a PDD. Future studies could consider adopting these tests for patient clinical trial stratification.

Background: White matter hyperintensities (WMH) on magnetic resonance imaging may influence clinical presentation in patients with Parkinson's disease (PD), although their significance and pathophysiological origins remain unresolved. Studies examining WMH have identified pathogenic variants in NOTCH3 as an underlying cause of inherited forms of cerebral small vessel disease., Methods: We examined NOTCH3 variants, WMH volumes, and clinical correlates in 139 PD patients in the Ontario Neurodegenerative Disease Research Initiative cohort., Results: We identified 13 PD patients (~9%) with rare (<1% of general population), nonsynonymous NOTCH3 variants. Bayesian linear modeling demonstrated a doubling of WMH between variant negative and positive patients (3.1 vs. 6.9 mL), with large effect sizes for periventricular WMH (d = 0.8) and lacunes (d = 1.2). Negative correlations were observed between WMH and global cognition (r = -0.2)., Conclusion: The NOTCH3 rare variants in PD may significantly contribute to increased WMH burden, which in turn may negatively influence cognition. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Introduction: Variants in the GBA1 gene have been identified as a common risk factor for Parkinson's disease (PD). In addition to pathogenic mutations (those associated with Gaucher disease), a number of 'non-pathogenic' variants also occur at increased frequency in PD. Previous studies have reported that pathogenic variants adversely affect the clinical course of PD. The role of 'non-pathogenic' GBA1 variants on PD course is less clear. In this study, we report the effect of GBA1 variants in incident PD patients with long-term follow-up., Methods: The study population consisted of patients in the Cambridgeshire Incidence of Parkinson's disease from General Practice to Neurologist and Parkinsonism: Incidence, Cognition and Non-motor heterogeneity in Cambridgeshire cohorts. Patients were grouped into non-carriers, carriers of 'non-pathogenic' GBA1 variants and carriers of pathogenic GBA1 mutations. Survival analyses for time to development of dementia, postural instability and death were carried out. Cox regression analysis controlling for potential confounders were used to determine the impact of GBA1 variants on these outcome measures., Results: GBA1 variants were identified in 14.4% of patients. Pathogenic and 'non-pathogenic' GBA1 variants were associated with the accelerated development of dementia and a more aggressive motor course. Pathogenic GBA1 variants were associated with earlier mortality in comparison with non-carriers, independent of the development of dementia., Discussion: GBA1 variants, including those not associated with Gaucher disease, are common in PD and result in a more aggressive disease course., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

The innate immune system is implicated in Parkinson's disease (PD), but peripheral in-vivo clinical evidence of the components and driving mechanisms involved and their relationship with clinical heterogeneity and progression to dementia remain poorly explored. We examined changes in peripheral innate immune-related markers in PD cases (n = 41) stratified according to risk of developing early dementia. 'Higher Risk'(HR) (n = 23) and 'Lower Risk' (LR) (n = 18) groups were defined according to neuropsychological predictors and MAPT H1/H2 genotype, and compared to age, gender and genotype-matched controls. Monocyte subsets and expression of key surface markers were measured using flow cytometry. Serum markers including alpha-synuclein, inflammasome-related caspase-1 and bacterial translocation-related endotoxin were measured using quantitative immuno-based assays. Specific markers were further investigated using monocyte assays and validated in plasma samples from a larger incident PD cohort (n = 95). We found that classical monocyte frequency was elevated in PD cases compared to controls, driven predominantly by the HR group, in whom Toll-Like Receptor (TLR)4+ monocytes and monocyte Triggering Receptor Expressed on Myeloid cells-2 (TREM2) expression were also increased. Monocyte Human Leukocyte Antigen (HLA)-DR expression correlated with clinical variables, with lower levels associated with worse cognitive/motor performance. Notably, monocyte changes were accompanied by elevated serum bacterial endotoxin, again predominantly in the HR group. Serum alpha-synuclein and inflammasome-related caspase-1 were decreased in PD cases compared to controls regardless of group, with decreased monocyte alpha-synuclein secretion in HR cases. Further, alpha-synuclein and caspase-1 correlated positively in serum and monocyte lysates, and in plasma from the larger cohort, though no associations were seen with baseline or 36-month longitudinal clinical data. Principal Components Analysis of all monocyte and significant serum markers indicated 3 major components. Component 1 (alpha-synuclein, caspase-1, TLR2+ monocytes) differentiated PD cases and controls in both groups, while Component 2 (endotoxin, monocyte TREM2, alpha-synuclein) did so predominantly in the HR group. Component 3 (classical monocytes, alpha-synuclein) also differentiated cases and controls overall in both groups. These findings demonstrate that systemic innate immune changes are present in PD and are greatest in those at higher risk of rapid progression to dementia. Markers associated with PD per-se (alpha-synuclein, caspase-1), differ from those related to cognitive progression and clinical heterogeneity (endotoxin, TREM2, TLR4, classical monocytes, HLA-DR), with mechanistic and therapeutic implications. Alpha-synuclein and caspase-1 are associated, suggesting inflammasome involvement common to all PD, while bacterial translocation associated changes may contribute towards progression to Parkinson's dementia. Additionally, HLA-DR-associated variations in antigen presentation/clearance may modulate existing clinical disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Immune markers are altered in Parkinson's disease (PD), but relationships between cerebrospinal fluid (CSF) and plasma cytokines and associations with neurodegeneration-associated proteins remain unclear., Methods: CSF and plasma samples and demographic/clinical measures were obtained from 35 PD patients. CSF samples were analyzed for cytokines (together with plasma) and for α-synuclein, amyloid β(1-42) peptide, total tau, and phospho(Thr231)-tau., Results: There were no CSF-plasma cytokine correlations. Interleukin (IL)-8 was higher and interferon-γ, IL-10, and tumor necrosis factor-α were lower in CSF versus plasma. In CSF, total tau correlated positively with IL-8 and IL-1β, whereas α-synuclein correlated positively with amyloid β(1-42) and negatively with semantic fluency (a known marker of PD dementia risk)., Discussion: CSF and peripheral cytokine profiles in PD are not closely related. Associations between CSF IL-8 and IL-1β and tau suggest that CSF inflammatory changes may relate to tau pathology within PD. CSF α-synuclein/amyloid β may reflect the risk of developing PD dementia. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

Toxic epidermal necrolysis and Staphylococcal scalded skin syndrome (SSSS) are potentially life-threatening dermatological emergencies that present in a similar clinical fashion. Toxic epidermal necrolysis is typically triggered by anticonvulsant and other neurological medications and reports clindamycin inducing the disease is exceedingly rare. SSSS seldomly occurs in adult patients. We present the case of a 60-year-old male presenting with dermatological rash covering >80% his body surface. Diagnosis and therapy involved multidisciplinary contribution from medical physicians, dermatologists, microbiologists and histopathologists to provide a favourable outcome., (© The Author(s) 2020. Published by Oxford University Press.)

Background: Cross-sectional studies have identified that the prevalence of neuropsychiatric symptoms (NPS) in Parkinson's disease (PD) ranges from 70-89%. However, there are few longitudinal studies determining the impact of NPS on quality of life (QoL) in PD patients and their caregivers. We seek to determine the progression of NPS in early PD., Methods: Newly diagnosed idiopathic PD cases ( n = 212) and age-matched controls ( n = 99) were recruited into a longitudinal study. NPS were assessed using the Neuropsychiatric Inventory with Caregiver Distress scale (NPI-D). Further neuropsychological and clinical assessments were completed by participants, with reassessment at 18 and 36 months. Linear mixed-effects modelling determined factors associated with NPI-D and QoL over 36 months., Results: Depression, anxiety, apathy and hallucinations were more frequent in PD than controls at all time points ( p < 0.05). Higher motor severity at baseline was associated with worsening NPI-D scores over time (β = 0.1, p < 0.05), but not cognition. A higher NPI total score was associated with poorer QoL at any time point (β = 0.3, p < 0.001), but not changed in QoL scores., Conclusion: NPS are significantly associated with poorer QoL, even in early PD. Screening for NPS from diagnosis may allow efficient delivery of better support and treatment to patients and their families.

The non-motor features of Parkinson's disease (PD) are increasingly being recognised. This review deals with the spectrum of sleep disorders associated with PD, which have a multifactorial aetiology and can significantly have an impact on the quality of life of patients and their carers. Some sleep disorders represent a prodromal phase of PD, with REM sleep behaviour disorder (RBD) being of particular interest in this regard, whereas others become more common as the disease advances. Understanding the pathophysiology of these sleep disturbances will hopefully lead to new treatment opportunities in the future. The recent discovery of the glymphatic system for removal of waste products from the brain has also raised the possibility that sleep disruption may cause or accelerate the underlying disease process.

Endobronchial metastasis from extrapulmonary malignancies are rare and include malignant melanoma. Cases that are complicated by central airway obstruction should follow a patient-centred approach, guided by patient and tumour characteristics. http://bit.ly/32baZvo., Competing Interests: Conflict of interest: S. Cullivan has nothing to disclose. Conflict of interest: J. Bruzzi has nothing to disclose. Conflict of interest: T. McHale has nothing to disclose. Conflict of interest: R. Shatwan has nothing to disclose. Conflict of interest: P. Donnellan has nothing to disclose. Conflict of interest: D.P. Breen has nothing to disclose., (Copyright ©ERS 2019.)

Background: Several reports have identified different patterns of Parkinson's disease progression in individuals carrying missense variants in GBA or LRRK2 genes. The overall contribution of genetic factors to the severity and progression of Parkinson's disease, however, has not been well studied., Objectives: To test the association between genetic variants and the clinical features of Parkinson's disease on a genomewide scale., Methods: We accumulated individual data from 12 longitudinal cohorts in a total of 4093 patients with 22,307 observations for a median of 3.81 years. Genomewide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently identified disease-risk variants, were also investigated post hoc for candidate associations with these phenotypes., Results: Two variants were genomewide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (hazard ratio 2.04 [1.58-2.62]; P value = 3.46E-8). Rs61863020(G>A), an intergenic variant and expression quantitative trait loci for α-2A adrenergic receptor, was associated with a lower prevalence of insomnia at baseline (odds ratio 0.63 [0.52-0.75]; P value = 4.74E-8). In the targeted analysis, we found 9 associations between known Parkinson's risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports of GBA coding variants (rs2230288: p.E365K; rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, and an APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients., Conclusions: We identified novel genetic factors associated with heterogeneity of Parkinson's disease. The results can be used for validation or hypothesis tests regarding Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Introduction: To explore the prevalence, clinical course and associated features of lower limb tremor in the most common tremor syndromes., Methods: This retrospective chart review studied lower limb tremor patients as defined by a Tremor Rating Scale score ≥1 in either lower limb. We compared and correlated their characteristics, also comparing them with patients without lower limb tremor., Results: Of the 283 patients with lower limb tremor (58.3% males, age: 65.0 ± 16.0 years, tremor duration: 25.6 ± 17.9 years), 255 patients within six tremor syndrome groups were included in the final analysis. Prevalence of patients with lower limb tremor (either rest, postural or kinetic) was lowest (28.6%) in the essential tremor (ET) group and highest (69%) in the parkinsonian tremor (PT) group. Lower limb tremor score was higher in patients classified as having intention tremor (IT) compared to ET and dystonic tremor (DT). Total tremor score was highest in IT and lowest in ET. We found a positive correlation between total lower limb tremor score and total tremor score in most groups. In addition, there was a positive correlation between lower limb tremor score and upper limb tremor score. Finally, compared to patients without lower limb tremor, all diagnostic groups with lower limb tremor, with the exception of functional tremor (FT), had worse total tremor score; and disease duration was longer in ET-plus, DT and PT patients with lower limb tremor compared to those without., Conclusions: Lower limb tremor is less commonly observed in ET than other tremor syndromes, is a marker of symptom severity of the underlying disease condition in all tremor syndromes except FT, and reflects longer disease duration in ET-plus, DT and PT., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To determine if any association between previously identified alleles that confer risk for Parkinson disease and variables measuring disease progression., Methods: We evaluated the association between 31 risk variants and variables measuring disease progression. A total of 23,423 visits by 4,307 patients of European ancestry from 13 longitudinal cohorts in Europe, North America, and Australia were analyzed., Results: We confirmed the importance of GBA on phenotypes. GBA variants were associated with the development of daytime sleepiness (p.N370S: hazard ratio [HR] 3.28 [1.69-6.34]) and possible REM sleep behavior (p.T408M: odds ratio 6.48 [2.04-20.60]). We also replicated previously reported associations of GBA variants with motor/cognitive declines. The other genotype-phenotype associations include an intergenic variant near LRRK2 and the faster development of motor symptom (Hoehn and Yahr scale 3.0 HR 1.33 [1.16-1.52] for the C allele of rs76904798) and an intronic variant in PMVK and the development of wearing-off effects (HR 1.66 [1.19-2.31] for the C allele of rs114138760). Age at onset was associated with TMEM175 variant p.M393T (-0.72 [-1.21 to -0.23] in years), the C allele of rs199347 (intronic region of GPNMB , 0.70 [0.27-1.14]), and G allele of rs1106180 (intronic region of CCDC62 , 0.62 [0.21-1.03])., Conclusions: This study provides evidence that alleles associated with Parkinson disease risk, in particular GBA variants, also contribute to the heterogeneity of multiple motor and nonmotor aspects. Accounting for genetic variability will be a useful factor in understanding disease course and in minimizing heterogeneity in clinical trials.

Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG) exp ] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG) 11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

We examined associations between self-reported sleep measures and cognitive level and change (age 70-76 years) in a longitudinal, same-year-of-birth cohort study (baseline N = 1091; longitudinal N = 664). We also leveraged GWAS summary data to ascertain whether polygenic scores (PGS) of chronotype and sleep duration related to self-reported sleep, and to cognitive level and change. Shorter sleep latency was associated with significantly higher levels of visuospatial ability, processing speed, and verbal memory (β ≥ |0.184|, SE ≤ 0.075, p ≤ 0.003). Longer daytime sleep duration was significantly associated slower processing speed (β = -0.085, SE = 0.027, p = 0.001), and with steeper 6-year decline in visuospatial reasoning (β = -0.009, SE = 0.003, p = 0.008), and processing speed (β = -0.009, SE = 0.002, p < 0.001). Only longitudinal associations between longer daytime sleeping and steeper cognitive declines survived correction for important health covariates and false discovery rate (FDR). PGS of chronotype and sleep duration were nominally associated with specific self-reported sleep characteristics for most SNP thresholds (standardized β range = |0.123 to 0.082|, p range = 0.003 to 0.046), but neither PGS predicted cognitive level or change following FDR. Daytime sleep duration is a potentially important correlate of cognitive decline in visuospatial reasoning and processing speed in older age, whereas cross-sectional associations are partially confounded by important health factors. A genetic propensity toward morningness and sleep duration were weakly, but consistently, related to self-reported sleep characteristics, and did not relate to cognitive level or change., (© Sleep Research Society 2019. Published by Oxford University Press [on behalf of the Sleep Research Society].)

Spread of α-synuclein pathology from the peripheral to central nervous system may be an important etiological factor in Parkinson's disease, although there are some unanswered questions about its correlation with neuronal loss. Experimental evidence has highlighted the gastrointestinal tract as a potential starting point for aggregated α-synuclein, with the vagus nerve acting as a "highway" by which pathology may be transmitted to the lower brain stem. This review begins by highlighting the key studies demonstrating that α-synuclein pathology has the ability to spread from certain sites in the gastrointestinal tract to the brain (and vice versa). We go on to assess the recent epidemiological studies that have shown that vagotomy and appendectomy may have the potential to reduce the risk of developing Parkinson's disease. Finally, we discuss the factors in the gastrointestinal tract (such as dysbiosis of the gut microbiota, infection, and inflammation) that may trigger α-synuclein aggregation in the first place, as well as other potential mechanisms underlying the distribution of α-synuclein pathology in the brain. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Background: Population-based, prospective studies can provide important insights into Parkinson's disease (PD) and other parkinsonian disorders. Participant follow-up in such studies is often achieved through linkage to routinely collected healthcare datasets. We systematically reviewed the published literature on the accuracy of these datasets for this purpose., Methods: We searched four electronic databases for published studies that compared PD and parkinsonism cases identified using routinely collected data to a reference standard. We extracted study characteristics and two accuracy measures: positive predictive value (PPV) and/or sensitivity., Results: We identified 18 articles, resulting in 27 measures of PPV and 14 of sensitivity. For PD, PPV ranged from 56-90% in hospital datasets, 53-87% in prescription datasets, 81-90% in primary care datasets and was 67% in mortality datasets. Combining diagnostic and medication codes increased PPV. For parkinsonism, PPV ranged from 36-88% in hospital datasets, 40-74% in prescription datasets, and was 94% in mortality datasets. Sensitivity ranged from 15-73% in single datasets for PD and 43-63% in single datasets for parkinsonism., Conclusions: In many settings, routinely collected datasets generate good PPVs and reasonable sensitivities for identifying PD and parkinsonism cases. However, given the wide range of identified accuracy estimates, we recommend cohorts conduct their own context-specific validation studies if existing evidence is lacking. Further research is warranted to investigate primary care and medication datasets, and to develop algorithms that balance a high PPV with acceptable sensitivity., Competing Interests: The authors have declared that no competing interests exist.

Patients with sleep-related motor and behavioral disorders present to a variety of subspecialty clinics (neurology, sleep medicine, respiratory medicine, psychiatry). Diagnosing these disorders can be difficult, and sometimes they have a significant impact on quality of life. Alongside a number of common and well-recognized conditions, several new disease entities have been described in recent years that present with abnormal nocturnal motor phenomena (such as ADCY5-associated disease and anti-IgLON5 disease). Our understanding of the neural basis and prognostic significance of other sleep-related disorders has also grown, particularly rapid eye movement sleep behavior disorder. This review (along with a collection of previously unpublished videos) is intended to aid in the recognition and treatment of these patients. The recent change in terminology from nocturnal frontal lobe epilepsy to sleep-related hypermotor epilepsy is also discussed. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Background: Mediastinal and central large vessels (T4) invasion by lung cancer is often difficult to assess preoperatively due to the limited accuracy of computed tomography (CT) scan of the chest. Esophageal ultrasound (EUS) can visualize the relationship of para-esophageally located lung tumors to surrounding mediastinal structures., Aim: To assess the value of EUS for detecting mediastinal invasion (T4) of centrally located lung tumors., Methods: Patients who underwent EUS for the diagnosis and staging of lung cancer and in whom the primary tumor was detected by EUS and who subsequently underwent surgical- pathological staging (2000-2016) were retrospectively selected from two university hospitals in The Netherlands. T status of the lung tumor was reviewed based on EUS, CT and thoracotomy findings. Surgical- pathological staging was the reference standard., Results: In 426 patients, a lung malignancy was detected by EUS of which 74 subjects subsequently underwent surgical- pathological staging. 19 patients (26%) were diagnosed with stage T4 based on vascular (n=8, 42%) or mediastinal (n=8, 42%) invasion or both (n=2, 11%), one patient (5%) had vertebral involvement. Sensitivity, specificity, PPV and NPV for assessing T4 status were: for EUS (n=74); 42%, 95%, 73%, 83%, for chest CT (n=66); 76%, 61%, 41%, 88% and the combination of EUS and chest CT (both positive or negative for T4, (n=34); 83%, 100%, 100% 97%., Conclusion: EUS has a high specificity and NPV for the T4 assessment of lung tumors located para-esophageally and offers further value to chest CT scan., (Copyright © 2017 Elsevier B.V. All rights reserved.)