Search

Facial emotion recognition (FER) is a crucial component of social cognition and is essential in social‐interpersonal behaviour regulation. Although FER impairment is well‐established in advanced PD, data about FER at the time of diagnosis and its relationship with social behavioural problems in daily life are lacking. The aim was to examine FER at the time of PD diagnosis compared to a matched healthy control (HC) group and to associate FER with indices of social behavioural problems. In total, 142 de novo, treatment‐naïve PD patients and 142 HC were included. FER was assessed by the Ekman 60 faces test (EFT). Behavioural problems in PD patients were assessed using the Dysexecutive Questionnaire (DEX‐self and DEX‐proxy) and the Apathy Evaluation Scale (AES‐self). PD patients had significantly lower EFT‐total scores (p =.001) compared to HC, with worse recognition of Disgust (p =.001) and Sadness (p =.016). Correlational analyses yielded significant correlations between AES‐self and both EFT‐total (rs =.28) and Fear (rs =.22). Significant negative correlations were found between DEX‐proxy and both EFT‐total (rs = −.28) and Anger (rs = −.26). Analyses of DEX‐subscales showed that proxy ratings were significantly higher than patient‐ratings for the Social Conventions subscale (p =.047). This DEX‐proxy subscale had the strongest correlation with EFT‐total (rs = −.29). Results show that de novo PD patients already show impaired FER compared to HC. In addition, lower FER is linked to self‐reported apathy and proxy‐reported social‐behavioural problems, especially concerning social conventions. These findings validate the importance of the inclusion of social cognition measures in the neuropsychological assessment even in early PD. [ABSTRACT FROM AUTHOR]

Background: Parkinson's Disease (PD) is a heterogeneous, progressive neurodegenerative disorder which is characterized by a variety of motor and non-motor symptoms. To date, no disease modifying treatment for PD exists. Here, the study protocol of the Dutch Parkinson Cohort (DUPARC) is described. DUPARC is a longitudinal cohort study aimed at deeply phenotyping de novo PD patients who are treatment-naïve at baseline, to discover and validate biomarkers for PD progression, subtypes and pathophysiology.Methods/design: DUPARC is a prospective cohort study in which 150 de novo PD subjects will be recruited through a collaborative network of PD treating neurologists in the northern part of the Netherlands (Parkinson Platform Northern Netherlands, PPNN). Participants will receive follow-up assessments after 1 year and 3 years, with the intention of an extended follow-up with 3 year intervals. Subjects are extensively characterized to primarily assess objectives within three major domains of PD: cognition, gastrointestinal function and vision. This includes brain magnetic resonance imaging (MRI); brain cholinergic PET-imaging with fluoroethoxybenzovesamicol (FEOBV-PET); brain dopaminergic PET-imaging with fluorodopa (FDOPA-PET); detailed neuropsychological assessments, covering all cognitive domains; gut microbiome composition; intestinal wall permeability; optical coherence tomography (OCT); genotyping; motor and non-motor symptoms; overall clinical status and lifestyle factors, including a dietary assessment; storage of blood and feces for additional analyses of inflammation and metabolic parameters. Since the start of the inclusion, at the end of 2017, over 100 PD subjects with a confirmed dopaminergic deficit on FDOPA-PET have been included.Discussion: DUPARC is the first study to combine data within, but not limited to, the non-motor domains of cognition, gastrointestinal function and vision in PD subjects over time. As a de novo PD cohort, with treatment naïve subjects at baseline, DUPARC provides a unique opportunity for biomarker discovery and validation without the possible confounding influences of dopaminergic medication.Trial Registration: NCT04180865; registered retrospectively, November 28th 2019. [ABSTRACT FROM AUTHOR]

Background: In the newly proposed research criteria for Alzheimer’s disease (AD), patients are defined as having memory dysfunction in addition to either hippocampal atrophy or an abnormal cerebrospinal fluid (CSF) profile. This study applies the criteria in a memory clinic population, using clinical criteria as the reference criterion. Methods: 138 AD patients, 145 nondemented subjects, 78 patients with other dementias and 91 patients with mild cognitive impairment (MCI) were included. Dichotomized medial temporal lobe atrophy (MTA) score on MRI and dichotomized CSF profiles (based on beta-amyloid1–42, tau and phosphorylated tau at threonine 181 levels) were used in combination with an episodic memory test to assess sensitivity, specificity and likelihood ratios (LR) of the newly proposed criteria and their components separately. Results: We found specificities of 95 and 49% for comparison with nondemented subjects and other demented patients, respectively, with a sensitivity of 86% for AD. Specificity was highest (100 and 77%, respectively, LR+ = 48) when both MTA score and CSF profile were abnormal in addition to the episodic memory test, at the cost of a low sensitivity (48%). Conclusion: The newly proposed research criteria for AD yield a good specificity for comparison with nondemented subjects. When the type of dementia is clinically doubted, however, at least two supportive features should be considered (i.e. abnormal MTA score and CSF profile) in addition to memory impairment as core diagnostic criterion. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background and Objectives: The slow and variable disease progression of Becker muscular dystrophy (BMD) urges the development of biomarkers to facilitate clinical trials. We explored changes in 3 muscle-enriched biomarkers in serum of patients with BMD over 4-year time and studied associations with disease severity, disease progression, and dystrophin levels in BMD., Methods: We quantitatively measured creatine kinase (CK) using the International Federation of Clinical Chemistry reference method, creatine/creatinine ratio (Cr/Crn) using liquid chromatography-tandem mass spectrometry, and myostatin with ELISA in serum and assessed functional performance using the North Star Ambulatory Assessment (NSAA), 10-meter run velocity (TMRv), 6-Minute Walking Test (6MWT), and forced vital capacity in a 4-year prospective natural history study. Dystrophin levels were quantified in the tibialis anterior muscle using capillary Western immunoassay. The correlation between biomarkers, age, functional performance, mean annual change, and prediction of concurrent functional performance was analyzed using linear mixed models., Results: Thirty-four patients with 106 visits were included. Eight patients were nonambulant at baseline. Cr/Crn and myostatin were highly patient specific (intraclass correlation coefficient for both = 0.960). Cr/Crn was strongly negatively correlated, whereas myostatin was strongly positively correlated with the NSAA, TMRv, and 6MWT (Cr/Crn rho = -0.869 to -0.801 and myostatin rho = 0.792 to 0.842, all p < 0.001). CK showed a negative association with age ( p = 0.0002) but was not associated with patients' performance. Cr/Crn and myostatin correlated moderately with the average annual change of the 6MWT (rho = -0.532 and 0.555, p = 0.02). Dystrophin levels did not correlate with the selected biomarkers nor with performance. Cr/Crn, myostatin, and age could explain up to 75% of the variance of concurrent functional performance of the NSAA, TMRv, and 6MWT., Discussion: Both Cr/Crn and myostatin could potentially serve as monitoring biomarkers in BMD, as higher Cr/Crn and lower myostatin were associated with lower motor performance and predictive of concurrent functional performance when combined with age. Future studies are needed to more precisely determine the context of use of these biomarkers., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Mutations in the DMD gene are causative for Duchenne muscular dystrophy (DMD). Antisense oligonucleotide (AON) mediated exon skipping to restore disrupted dystrophin reading frame is a therapeutic approach that allows production of a shorter but functional protein. As DMD causing mutations can affect most of the 79 exons encoding dystrophin, a wide variety of AONs are needed to treat the patient population. Design of AONs is largely guided by trial-and-error, and it is yet unclear what defines the skippability of an exon. Here, we use a library of phosphorodiamidate morpholino oligomer (PMOs) AONs of similar physical properties to test the skippability of a large number of DMD exons. The DMD transcript is non-sequentially spliced, meaning that certain introns are retained longer in the transcript than downstream introns. We tested whether the relative intron retention time has a significant effect on AON efficiency, and found that targeting an out-of-frame exon flanked at its 5'-end by an intron that is retained in the transcript longer ('slow' intron) leads to overall higher exon skipping efficiency than when the 5'-end flanking intron is 'fast'. Regardless of splicing speed of flanking introns, we find that positioning an AON closer to the 5'-end of the target exon leads to higher exon skipping efficiency opposed to targeting an exons 3'-end. The data enclosed herein can be of use to guide future target selection and preferential AON binding sites for both DMD and other disease amenable by exon skipping therapies.

DMD is a rare disorder characterized by progressive muscle degeneration and premature death. Therapy development is delayed by difficulties to monitor efficacy non-invasively in clinical trials. In this study, we used RNA-sequencing to describe the pathophysiological changes in skeletal muscle of 3 dystrophic mouse models. We show how dystrophic changes in muscle are reflected in blood by analyzing paired muscle and blood samples. Analysis of repeated blood measurements followed the dystrophic signature at five equally spaced time points over a period of seven months. Treatment with two antisense drugs harboring different levels of dystrophin recovery identified genes associated with safety and efficacy. Evaluation of the blood gene expression in a cohort of DMD patients enabled the comparison between preclinical models and patients, and the identification of genes associated with physical performance, treatment with corticosteroids and body measures. The presented results provide evidence that blood RNA-sequencing can serve as a tool to evaluate disease progression in dystrophic mice and patients, as well as to monitor response to (dystrophin-restoring) therapies in preclinical drug development and in clinical trials., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)

Dysferlinopathies encompass a spectrum of progressive muscular dystrophies caused by the lack of dysferlin due to missense mutations in the dysferlin gene or mutations causing premature truncation of protein translation. Dysferlin is a modular protein, and dysferlins lacking one or more repetitive domains have been shown to retain functionality. As such, antisense-mediated exon skipping has been proposed as a therapy for dysferlinopathy. By skipping the mutated exon, the reading frame would be maintained, while the mutation would be bypassed, thus allowing production of an internally deleted, but partially functional, dysferlin. We previously showed that dysferlin exon skipping is feasible in control cell lines. We here evaluated exon skipping and dysferlin protein restoration in patient-derived cells requiring the skipping of exon 9, 29, 30, or 34. Exon 30 skipping was possible at high efficiency, but did not result in increased dysferlin. We discovered that the alleged exon 30 mutation was in fact a polymorphism and identified a splicing mutation in intron 28 as the disease-causing mutation. While exon skipping was feasible for each of the other cell lines, no increases in dysferlin protein could be detected by western blotting.

Introduction: We compared the automated Elecsys and manual Innotest immunoassays for cerebrospinal fluid (CSF) Alzheimer's disease biomarkers in a multicenter diagnostic setting., Methods: We collected CSF samples from 137 participants in eight local memory clinics. Amyloid β(1-42) (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) were centrally analyzed with Innotest and Elecsys assays. Concordances between methods were assessed., Results: Biomarker results strongly correlated between assays with Spearman's ρ 0.94 for Aβ42, 0.98 for t-tau, and 0.98 for p-tau. Using Gaussian mixture modeling, cohort-specific cut-points were estimated at 1092 pg/mL for Aβ42, 235 pg/mL for t-tau, and 24 pg/mL for p-tau. We found an excellent concordance of biomarker abnormality between assays of 97% for Aβ42 and 96% for both t-tau and p-tau., Discussion: The high concordances between Elecsys and Innotest in this nonacademic, multicenter cohort support the use of Elecsys for CSF Alzheimer's disease diagnostics and allow conversion of results between methods.

Alanine expansion mutations in poly(A)-binding protein nuclear 1 (PABPN1) cause muscle weakness in the late-onset disorder oculopharyngeal muscular dystrophy. In affected muscles, expanded PABPN1 forms nuclear aggregates, depleting levels of soluble PABPN1 and inducing a genome-wide shift from distal to proximal polyadenylation site usage. PABPN1 protein accumulation is regulated by the ubiquitin proteasome system, which is highly dysregulated in oculopharyngeal muscular dystrophy. We show that ARIH2 E3-ligase regulates PABPN1 protein accumulation and aggregation. Levels of ARIH2 mRNA are regulated by PABPN1 via proximal polyadenylation site usage. We demonstrate that masking the proximal polyadenylation site in ARIH2 3' untranslated region by antisense oligonucleotides elevates the expression of ARIH2 and PABPN1 and restores myogenic defects that are induced by ARIH2 or PABPN1 down-regulation in cell culture. In vivo ARIH2 mRNA levels significantly decrease from midlife in vastus lateralis muscles and highly correlate with muscle degeneration. We suggest that the expression of both genes is maintained by a feed-forward loop between mRNA stability regulated by PABPN1 and protein turnover regulated by ARIH2., (Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Immuno-assays are increasingly used for quantification of protein biomarkers for neurodegeneration. It has been proposed to use such cerebrospinal fluid (CSF) protein biomarkers as diagnostic tests for Alzheimer's disease. In two recent world-wide validation studies we found the analytical accuracy to be poor (inter-laboratory coefficient of variation, CV>10%) for CSF tau protein, CSF phospho-tau protein, CSF amyloid beta protein and the CSF neurofilament light chain protein. Retrospectively we suspected that the lack of preparation of accurate and consistent protein standards may have been one reason for the poor inter-laboratory CV. Here we confirm this hypothesis prospectively under standardised and optimised conditions. The CVs for CSF tau, CSF phospho-tau and CSF amyloid beta of individually prepared standards are 8%, 12% and 12% compared to significantly lower CVs for batch prepared standards (5%, 8%, 7%, respectively, p<0.05). This issue will need to be solved in order to ensure that the attempts to include these CSF protein biomarkers either as a diagnostic tool or a secondary outcome measure for treatment trials will be successful., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The primary objective of this study was to assess the intra-rater reliability of the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS-III) in patients with advanced Parkinson's disease (PD). The secondary objective was to assess the intra-rater reliability of standard timed motor tests and dyskinesia scales to determine the necessity of multiple baseline core evaluations before surgery for PD. We carried out two standardized preoperative core evaluations of patients with advanced PD scheduled to undergo deep brain stimulation. Patients were examined in the defined off and on conditions by the same rater. UPDRS-III, timed tests, and dyskinesia scores from the two evaluations were compared using Wilcoxon Signed Ranks tests and intraclass correlation coefficients (ICC). Differences in UPDRS-III scores for the two visits were clinically and statistically nonsignificant, and the ICC was 0.9. Similarly, there were no significant differences in timed motor tests or dyskinesia scores, with a median ICC of 0.8. The results indicate that previous findings of high test-retest reliability of UPDRS-III in early untreated PD patients can now be extended to those with advanced disease complicated by motor fluctuations. In addition, test-retest reliability of dyskinesia scales and timed motor tests was high. Taken together, these findings challenge the need for multiple baseline assessments as currently stipulated in core assessment protocols for surgical intervention in PD.