Lack of Association Between GBA Mutations and Motor Complications in European and American Parkinson's Disease Cohorts

Background: Motor complications are a consequence of the chronic dopaminergic treatment of Parkinson’s disease (PD) and include levodopa-induced dyskinesia (LIDs) and motor fluctuations (MF). Currently, evidence is on lacking whether patients with GBA-associated PD differ in their risk of developing motor complications compared to the general PD population. Objective: To evaluate the association of GBA carrier status with the development of LIDS and MFs from early PD. Methods: Motor complications were recorded prospectively in 884 patients with PD from four longitudinal cohorts using part IV of the UPDRS or MDS-UPDRS. Subjects were followed for up to 11 years and the associations of GBA mutations with the development of motor complications were assessed using parametric accelerated failure time models. Results: In 439 patients from Europe, GBA mutations were detected in 53 (12.1%) patients and a total of 168 cases of LIDs and 258 cases of MF were observed. GBA carrier status was not associated with the time to develop LIDs (HR 0.78, 95%CI 0.47 to 1.26, p = 0.30) or MF (HR 1.19, 95%CI 0.84 to 1.70, p = 0.33). In the American cohorts, GBA mutations were detected in 36 (8.1%) patients and GBA carrier status was also not associated with the progression to LIDs (HR 1.08, 95%CI 0.55 to 2.14, p = 0.82) or MF (HR 1.22, 95%CI 0.74 to 2.04, p = 0.43). Conclusion: This study does not provide evidence that GBA-carrier status is associated with a higher risk of developing motor complications. Publication of studies with null results is vital to develop an accurate summary of the clinical features that impact patients with GBA-associated PD.publishedVersio

Lack of Association Between GBA Mutations and Motor Complications in European and American Parkinson's Disease Cohorts

ACKNOWLEDGMENTS The authors would like to thank all of the patients and controls for participation in each of the studies. Equally, we thank all members of each of the study groups and other personnel for their contributions. Funding sources for the respective studies are as follows: The Norwegian ParkWest study has been funded by the Research Council of Norway (177966), the Western Norway Regional Health Authority (911218), the Norwegian Parkinson’s Research Foundation, and Rebergs Legacy. PINE study was supported by Parkinson’s UK (G0502, G0914, G1302), Scottish Government Chief Scientist Office, BMA Doris Hillier Award, the BUPA Foundation, NHS Grampian Endowments, and RS MacDonald Trust. The NYPUM study has been funded by the Swedish Medical Research Council, the Swedish Parkinson’s disease Association, the Swedish Parkinson’s Foundation, Parkinson Research Foundation, Erling Persson Foundation, Kempe Foundation, the Swedish Brain Foundation (Hjarnfonden), and the Vasterbotten County Council. AAS, JMG and GA are supported by the Research Council of Norway (287842). BLF acknowledges support through donations to the UCLA Clinical Neurogenomics Research Center. CK is supported by the NIH grant F32AG063442. The PEG study was supported by NIH/NIEHS grants R01-ES010544 and U54-ES012078. Publication of this manuscript was supported under the The Michael J. Fox Foundation: 2021 RFA: Accelerating Publication of Parkinson’s Disease Replication Data.Peer reviewedPublisher PD

Deep mining of oxysterols and cholestenoic acids in human plasma and cerebrospinal fluid: Quantification using isotope dilution mass spectrometry

Both plasma and cerebrospinal fluid (CSF) are rich in cholesterol and its metabolites. Here we describe in detail a methodology for the identification and quantification of multiple sterols including oxysterols and sterol-acids found in these fluids. The method is translatable to any laboratory with access to liquid chromatography – tandem mass spectrometry. The method exploits isotope-dilution mass spectrometry for absolute quantification of target metabolites. The method is applicable for semi-quantification of other sterols for which isotope labelled surrogates are not available and approximate quantification of partially identified sterols. Values are reported for non-esterified sterols in the absence of saponification and total sterols following saponification. In this way absolute quantification data is reported for 17 sterols in the NIST SRM 1950 plasma along with semi-quantitative data for 8 additional sterols and approximate quantification for one further sterol. In a pooled (CSF) sample used for internal quality control, absolute quantification was performed on 10 sterols, semi-quantification on 9 sterols and approximate quantification on a further three partially identified sterols. The value of the method is illustrated by confirming the sterol phenotype of a patient suffering from ACOX2 deficiency, a rare disorder of bile acid biosynthesis, and in a plasma sample from a patient suffering from cerebrotendinous xanthomatosis, where cholesterol 27-hydroxylase is deficient

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Low level of phosphate in male patients reporting swallowing disturbances in early Parkinson's disease

Background & aim: Swallowing disturbances are associated with older age as well as with other subclinical disturbances of multifactorial origin in patients with Parkinson's disease (PD). This study assesses nutritional markers and whole-body impedance data to better understand swallowing disturbances in Parkinson's disease. Design and patients included: This cross-sectional study includes baseline data from a cohort of newly diagnosed patients identified in the New Parkinsonism in Umeå study (NYPUM) (n = 75). Methods: Swallowing disturbance was registered as a score of one or more on the Unified Parkinson's Disease Rating Scale (UPDRS) section II question number 7 on swallowing. The analysis used nutritional markers in plasma and anthropometry from bioimpedance. Results: Bivariate analysis revealed that swallowing disturbances were associated with low plasma phosphate levels for males (r = −0.428; p = 0.005) and for all patients with PD (r = −0.241; p = 0.037). In males but not in females, a negative association was found between age and albumin and amount of intra-cellular water (ICW, l). Plasma albumin was associated with plasma phosphate (r = 0.315; p = 0.006; n = 75, r = 0.361; p = 0.036; n = 34, r = 0.310; p = 0.049; n = 41). Another risk pattern indicating swallowing disturbance in females was revealed by an association with visceral adiposity index (VAI), plasma triglycerides (TG), and triglyceride/high density lipoprotein (TG/HDL) ratio. The adjusted logistic regression revealed that low phosphate in males and low magnesium in females were risk factors for swallowing disturbance. Conclusion: The age-related decline in plasma phosphate in males with PD may be an important nutritional marker for swallowing disturbances. Body composition measurements and nutritional markers provide information for the study of swallowing dysfunction as part of sarcopenia

Early Recognition of Cognitive Ability and Nutritional Markers for Dementia in Parkinson’s Disease

Background: Cognitive decline and dementia are common non-motor problems in Parkinson’s disease (PD). The underlying aetiology is multifaceted and both chronic and reversible causes for cognitive decline are likely to be present. Malnutrition is frequent in the Parkinson population, both early and late in the disease, and nutritional deficiencies could play a role in some cognitive deficits. Objectives: The objective is to study the association between nutritional status with focus on iron intake and homeostasis, mild cognitive impairment (MCI), and PD dementia (PDD). Setting and Participants: This study included 73 out of 145 patients with PD participating in a population-based study in northern Sweden. Measurements: Registration of nutritional status by laboratory analyses of blood plasma and neuropsychological assessments at time of diagnosis were performed. MCI and PDD were assessed yearly up to ten years after diagnosis. Mini Nutritional Assessments (Full-MNA score) and plasma variables detecting iron homeostasis were compared between patients with MCI and patients with normal cognition (NC). Motor severity was measured using the Unified Parkinson´s disease rating scale III, (UPDRS III) and Hoehn and Yahr (H&Y) staging scale. Cox proportional Hazard model were performed to see if any variables that differed between MCI and NC could predict PDD at follow-up. Results: Patients with MCI at time of diagnosis had lower levels of plasma iron (P-Fe) and albumin (P-Albumin) as well as a lower score on Full-MNA score. Dietary intake of iron was higher in patients with MCI than in patients with NC (p = 0.012). In logistic regression models adjusted for age, sex, and UPDRS III, lower levels of P-Fe (p = 0.025) and P-Albumin (p = 0.011) and higher dietary iron intake (p = 0.019) were associated with MCI at baseline. A Cox regression model with dementia as endpoint revealed that lower levels of P-Fe increase the risk of dementia at follow-up with adjustments for age, sex, UPDRS III, and MCI at baseline (HR 95% CI = 0.87 (0.78-0.98), p = 0.021). Conclusions: Low P-Fe was associated with cognitive disturbance at baseline and predicted dementia up to ten years after diagnosis in patients with PD. Low P-Albumin and malnutrition assessed with Full-MNA score were associated with MCI at baseline but did not predict dementia at follow-up

On the function of female ornaments: male bluethroats prefer colourful females

Female ornaments in animals with conventional sex roles have traditionally been considered non-functional, being merely a genetically correlated response to selection for male ornamentation. Alternatively, female ornaments may be influenced by selection acting directly on the females, either through female–female competition or male choice. We tested the latter hypothesis in mate choice experiments with bluethroats (Luscinia s. svecica), a passerine bird in which females vary considerably in coloration of an ornamental throat patch. In outdoor aviaries placed in prime breeding habitat, males were allowed to choose between a colourful and a drab female. We found that males associated more with, and performed more sexual behaviours towards, colourful females. Female coloration was not age-related, but correlated significantly with body mass and tarsus length. Thus, we have demonstrated both a male preference for female ornamentation, and a relationship between ornament expression and female body size, which may be indicative of quality. Our results refute the correlated response hypothesis and support the hypothesis that female ornamentation is sexually selected

Moist smokeless tobacco (Snus) use and risk of Parkinson's disease

Background: Cigarette smoking is associated with a lower risk of Parkinson's disease. It is unclear what constituent of tobacco smoke may lower the risk. Use of Swedish moist smokeless tobacco (snus) can serve as a model to disentangle what constituent of tobacco smoke may lower the risk. The aim of this study was to determine whether snus use was associated with a lower risk of Parkinson's disease. Methods: Individual participant data were collected from seven prospective cohort studies, including 348 601 men. We used survival analysis with multivariable Cox regression to estimate study-specific relative risk of Parkinson's disease due to snus use, and random-effects models to pool estimates in a meta-analysis. The primary analyses were restricted to never-smokers to eliminate the potential confounding effect of tobacco smoking. Results: During a mean follow-up time of 16.1 years, 1199 incident Parkinson's disease cases were identified. Among men who never smoked, ever-snus users had about 60% lower Parkinson's disease risk compared with never-snus users [pooled hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.28-0.61]. The inverse association between snus use and Parkinson's disease risk was more pronounced in current (pooled HR 0.38, 95% CI 0.23-0.63), moderate-heavy amount (pooled HR 0.41, 95% CI 0.19-0.90) and long-term snus users (pooled HR 0.44, 95% CI 0.24-0.83). Conclusions: Non-smoking men who used snus had a substantially lower risk of Parkinson's disease. Results also indicated an inverse dose-response relationship between snus use and Parkinson's disease risk. Our findings suggest that nicotine or other components of tobacco leaves may influence the development of Parkinson's disease

Monovalent and divalent saturation level as a function of concentration.

<p>The level of antibody saturation upon binding to oligomers is shown as a black line and binding to monomers is shown as a red line. The vertical dotted lines indicate the concentrations where the saturation level of binding to the oligomer is above 50% while the monovalent saturation level remains below 2%. (A) mAB-O, (B) mAB-M, (C) ASyO2, (D) ASyO5, (E) ASyM.</p

Dot blot enables probing for structural differences between fibrils and oligomers.

<p>An equal amount of fibrils and oligomers from either Aβ_(1–42) or α-synuclein, as indicated in the figure, were applied to a nitrocellulose membrane. Binding specificity of (A) mAB-O, (B) mAB-M, (C) Aβ fibril-specific OC antibody,, (D) ASyO2, (E) ASyO5, and (F) ASyM.</p