401 results on '"Matthis Synofzik"'
Search Results
52. Correction to: A guide to writing systematic reviews of rare disease treatments to generate FAIRcompliant datasets: building a Treatabolome
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Antonio Atalaia, Rachel Thompson, Alberto Corvo, Leigh Carmody, Davide Piscia, Leslie Matalonga, Alfons Macaya, Angela Lochmuller, Bertrand Fontaine, Birte Zurek, Carles Hernandez-Ferrer, Carola Reinhard, David Gómez-Andrés, Jean-François Desaphy, Katherine Schon, Katja Lohmann, Matthew J. Jennings, Matthis Synofzik, Olaf Riess, Rabah Ben Yaou, Teresinha Evangelista, Thiloka Ratnaike, Virginie Bros-Facer, Gulcin Gumus, Rita Horvath, Patrick Chinnery, Steven Laurie, Holm Graessner, Peter Robinson, Hanns Lochmuller, Sergi Beltran, and Gisèle Bonne
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Medicine - Abstract
An amendment to this paper has been published and can be accessed via the original article.
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- 2021
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53. Hemodialysis in MNGIE transiently reduces serum and urine levels of thymidine and deoxyuridine, but not CSF levels and neurological function
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Benjamin Röeben, Justus Marquetand, Benjamin Bender, Heiko Billing, Tobias B. Haack, Iciar Sanchez-Albisua, Ludger Schöls, Henk J. Blom, and Matthis Synofzik
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MNGIE ,Haemodialysis ,Mitochondriopathy ,Thymidine phosphorylases ,Medicine - Abstract
Abstract Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare, autosomal-recessive mitochondrial disorder caused by TYMP mutations presenting with a multisystemic, often lethal syndrome of progressive leukoencephalopathy, ophthalmoparesis, demyelinating neuropathy, cachexia and gastrointestinal dysmotility. Hemodialysis (HMD) has been suggested as a treatment to reduce accumulation of thymidine and deoxyuridine. However, all studies so far have failed to measure the toxic metabolites in cerebrospinal fluid (CSF), which is the crucial compartment for CNS damage. Our study is the first prospective, longitudinal investigation, exploiting detailed serial testing of predefined clinical and molecular outcome parameters (including serial CSF assessments) in a 29-year-old MNGIE patient undergoing 1 year of extensive HMD. We demonstrate that HMD only transiently restores increased serum and urine levels of thymidine and deoxyuridine, but fails to reduce CSF levels of the toxic metabolites and is ineffective to influence neurological function. These findings have direct important implications for clinical practice: They prevent a burdensome, long-term invasive, but ultimately probably ineffective procedure in future MNGIE patients.
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- 2017
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54. Effects of Exergaming on Attentional Deficits and Dual-Tasking in Parkinson's Disease
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Eva Schaeffer, Jan-Hinrich Busch, Benjamin Roeben, Sascha Otterbein, Pavel Saraykin, Edyta Leks, Inga Liepelt-Scarfone, Matthis Synofzik, Morad Elshehabi, Walter Maetzler, Clint Hansen, Sarah Andris, and Daniela Berg
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Parkinson's disease ,exergaming ,dual-tasking ,cognition ,quantitative motor assessment ,attention ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Introduction: Impairment of dual-tasking, as an attention-based primary cognitive dysfunction, is frequently observed in Parkinson's Disease (PD). The Training-PD study investigated the efficiency of exergaming, as a novel cognitive-motor training approach, to improve attention-based deficits and dual-tasking in PD when compared to healthy controls.Methods: Eighteen PD patients and 17 matched healthy controls received a 6-week home-based training period of exergaming. Treatment effects were monitored using quantitative motor assessment of gait and cognitive testing as baseline and after 6 weeks of training.Results: At baseline PD patients showed a significantly worse performance in several quantitative motor assessment parameters and in two items of cognitive testing. After 6 weeks of exergames training, the comparison of normal gait vs. dual-tasking in general showed an improvement of stride length in the PD group, without a gait-condition specific improvement. In the direct comparison of three different gait conditions (normal gait vs. dual-tasking calculating while walking vs. dual-tasking crossing while walking) PD patients showed a significant improvement of stride length under the dual-tasking calculating condition. This corresponded to a significant improvement in one parameter of the D2 attention test.Conclusions: We conclude, that exergaming, as an easy to apply, safe technique, can improve deficits in cognitive-motor dual-tasking and attention in PD.
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- 2019
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55. White matter hyperintensities in progranulin-associated frontotemporal dementia: A longitudinal GENFI study
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Carole H. Sudre, Martina Bocchetta, Carolin Heller, Rhian Convery, Mollie Neason, Katrina M. Moore, David M. Cash, David L. Thomas, Ione O.C. Woollacott, Martha Foiani, Amanda Heslegrave, Rachelle Shafei, Caroline Greaves, John van Swieten, Fermin Moreno, Raquel Sanchez-Valle, Barbara Borroni, Robert Laforce, Jr, Mario Masellis, Maria Carmela Tartaglia, Caroline Graff, Daniela Galimberti, James B. Rowe, Elizabeth Finger, Matthis Synofzik, Rik Vandenberghe, Alexandre de Mendonça, Fabrizio Tagliavini, Isabel Santana, Simon Ducharme, Chris Butler, Alex Gerhard, Johannes Levin, Adrian Danek, Giovanni B. Frisoni, Sandro Sorbi, Markus Otto, Henrik Zetterberg, Sebastien Ourselin, M. Jorge Cardoso, and Jonathan D. Rohrer
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Computer applications to medicine. Medical informatics ,R858-859.7 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders with both sporadic and genetic forms. Mutations in the progranulin gene (GRN) are a common cause of genetic FTD, causing either a behavioural presentation or, less commonly, language impairment. Presence on T2-weighted images of white matter hyperintensities (WMH) has been previously shown to be more commonly associated with GRN mutations rather than other forms of FTD. The aim of the current study was to investigate the longitudinal change in WMH and the associations of WMH burden with grey matter (GM) loss, markers of neurodegeneration and cognitive function in GRN mutation carriers.336 participants in the Genetic FTD Initiative (GENFI) study were included in the analysis: 101 presymptomatic and 32 symptomatic GRN mutation carriers, as well as 203 mutation-negative controls. 39 presymptomatic and 12 symptomatic carriers, and 73 controls also had longitudinal data available. Participants underwent MR imaging acquisition including isotropic 1 mm T1-weighted and T2-weighted sequences. WMH were automatically segmented and locally subdivided to enable a more detailed representation of the pathology distribution. Log-transformed WMH volumes were investigated in terms of their global and regional associations with imaging measures (grey matter volumes), biomarker concentrations (plasma neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP), genetic status (TMEM106B risk genotype) and cognition (tests of executive function).Analyses revealed that WMH load was higher in both symptomatic and presymptomatic groups compared with controls and this load increased over time. In particular, lesions were seen periventricularly in frontal and occipital lobes, progressing to medial layers over time. However, there was variability in the WMH load across GRN mutation carriers – in the symptomatic group 25.0% had none/mild load, 37.5% had medium and 37.5% had a severe load – a difference not fully explained by disease duration. GM atrophy was strongly associated with WMH load both globally and in separate lobes, and increased WMH burden in the frontal, periventricular and medial regions was associated with worse executive function. Furthermore, plasma NfL and to a lesser extent GFAP concentrations were seen to be associated with increased lesion burden. Lastly, the presence of the homozygous TMEM106B rs1990622 TT risk genotypic status was associated with an increased accrual of WMH per year.In summary, WMH occur in GRN mutation carriers and accumulate over time, but are variable in their severity. They are associated with increased GM atrophy and executive dysfunction. Furthermore, their presence is associated with markers of WM damage (NfL) and astrocytosis (GFAP), whilst their accrual is modified by TMEM106B genetic status. WMH load may represent a target marker for trials of disease modifying therapies in individual patients but the variability across the GRN population would prevent use of such markers as a global outcome measure across all participants in a trial. Keywords: Frontotemporal dementia, White matter hyperintensities, Dementia, Progranulin
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- 2019
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56. Generation of optic atrophy 1 patient-derived induced pluripotent stem cells (iPS-OPA1-BEHR) for disease modeling of complex optic atrophy syndromes (Behr syndrome)
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Stefan Hauser, Stefanie Schuster, Yvonne Theurer, Matthis Synofzik, and Ludger Schöls
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Biology (General) ,QH301-705.5 - Abstract
Human skin fibroblasts were isolated from a 48-year-old patient carrying compound heterozygous mutations (c.610+364G>A and c.1311A>G) in OPA1, responsible for early onset optic atrophy complicated by ataxia and pyramidal signs (Behr syndrome; OMIM #210000). Fibroblasts were reprogrammed using episomal plasmids carrying hOCT4, hSOX2, hKLF4, hL-MYC and hLIN28. The generated transgene-free line iPS-OPA1-BEHR showed no additional genomic aberrations, maintained the disease-relevant mutations, expressed important pluripotency markers and was capable to differentiate into cells of all three germ layers in vitro. The generated iPS-OPA1-BEHR line might be a useful platform to study the pathomechanism of early onset complicated optic atrophy syndromes.
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- 2016
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57. Abnormal Paraplegin Expression in Swollen Neurites, τ- and α-Synuclein Pathology in a Case of Hereditary Spastic Paraplegia SPG7 with an Ala510Val Mutation
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Dietmar R. Thal, Stephan Züchner, Stephan Gierer, Claudia Schulte, Ludger Schöls, Rebecca Schüle, and Matthis Synofzik
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SPG7 ,neurofibrillary tangles ,tau ,spastic paraplegia ,ataxia ,spastic ataxia ,coiled bodies ,Lewy bodies ,paraplegin ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Mutations in the SPG7 gene are the most frequent cause of autosomal recessive hereditary spastic paraplegias and spastic ataxias. Ala510Val is the most common SPG7 mutation, with a frequency of up to 1% in the general population. Here we report the clinical, genetic, and neuropathological findings in a homozygous Ala510Val SPG7 case with spastic ataxia. Neuron loss with associated gliosis was found in the inferior olivary nucleus, the dentate nucleus of the cerebellum, the substantia nigra and the basal nucleus of Meynert. Neurofilament and/or paraplegin accumulation was observed in swollen neurites in the cerebellar and cerebral cortex. This case also showed subcortical τ-pathology in an unique distribution pattern largely restricted to the brainstem. α-synuclein containing Lewy bodies (LBs) were observed in the brainstem and the cortex, compatible with a limbic pattern of Braak LB-Disease stage 4. Taken together, this case shows that the spectrum of pathologies in SPG7 can include neuron loss of the dentate nucleus and the inferior olivary nucleus as well as neuritic pathology. The progressive supranuclear palsy-like brainstem predominant pattern of τ pathology and α-synuclein containing Lewy bodies in our SPG7 cases may be either coincidental or related to SPG7 in addition to neuron loss and neuritic pathology.
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- 2015
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58. Validation of a Step Detection Algorithm during Straight Walking and Turning in Patients with Parkinson’s Disease and Older Adults Using an Inertial Measurement Unit at the Lower Back
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Minh H. Pham, Morad Elshehabi, Linda Haertner, Silvia Del Din, Karin Srulijes, Tanja Heger, Matthis Synofzik, Markus A. Hobert, Gert S. Faber, Clint Hansen, Dina Salkovic, Joaquim J. Ferreira, Daniela Berg, Álvaro Sanchez-Ferro, Jaap H. van Dieën, Clemens Becker, Lynn Rochester, Gerhard Schmidt, and Walter Maetzler
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accelerometer ,gait analysis ,home-like activities ,older adults ,Parkinson’s disease ,turning ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
IntroductionInertial measurement units (IMUs) positioned on various body locations allow detailed gait analysis even under unconstrained conditions. From a medical perspective, the assessment of vulnerable populations is of particular relevance, especially in the daily-life environment. Gait analysis algorithms need thorough validation, as many chronic diseases show specific and even unique gait patterns. The aim of this study was therefore to validate an acceleration-based step detection algorithm for patients with Parkinson’s disease (PD) and older adults in both a lab-based and home-like environment.MethodsIn this prospective observational study, data were captured from a single 6-degrees of freedom IMU (APDM) (3DOF accelerometer and 3DOF gyroscope) worn on the lower back. Detection of heel strike (HS) and toe off (TO) on a treadmill was validated against an optoelectronic system (Vicon) (11 PD patients and 12 older adults). A second independent validation study in the home-like environment was performed against video observation (20 PD patients and 12 older adults) and included step counting during turning and non-turning, defined with a previously published algorithm.ResultsA continuous wavelet transform (cwt)-based algorithm was developed for step detection with very high agreement with the optoelectronic system. HS detection in PD patients/older adults, respectively, reached 99/99% accuracy. Similar results were obtained for TO (99/100%). In HS detection, Bland–Altman plots showed a mean difference of 0.002 s [95% confidence interval (CI) −0.09 to 0.10] between the algorithm and the optoelectronic system. The Bland–Altman plot for TO detection showed mean differences of 0.00 s (95% CI −0.12 to 0.12). In the home-like assessment, the algorithm for detection of occurrence of steps during turning reached 90% (PD patients)/90% (older adults) sensitivity, 83/88% specificity, and 88/89% accuracy. The detection of steps during non-turning phases reached 91/91% sensitivity, 90/90% specificity, and 91/91% accuracy.ConclusionThis cwt-based algorithm for step detection measured at the lower back is in high agreement with the optoelectronic system in both PD patients and older adults. This approach and algorithm thus could provide a valuable tool for future research on home-based gait analysis in these vulnerable cohorts.
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- 2017
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59. Absence of EEG correlates of self-referential processing depth in ALS.
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Tatiana Fomina, Sebastian Weichwald, Matthis Synofzik, Jenifer Just, Ludger Schöls, Bernhard Schölkopf, and Moritz Grosse-Wentrup
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Medicine ,Science - Abstract
Self-referential processing is a key cognitive process, associated with the serotonergic system and the default mode network (DMN). Decreased levels of serotonin and reduced activations of the DMN observed in amyotrophic lateral sclerosis (ALS) suggest that self-referential processing might be altered in patients with ALS. Here, we investigate the effects of ALS on the electroencephalography correlates of self-referential thinking. We find that electroencephalography (EEG) correlates of self-referential thinking are present in healthy individuals, but not in those with ALS. In particular, thinking about themselves or others significantly modulates the bandpower in the medial prefrontal cortex in healthy individuals, but not in ALS patients. This finding supports the view of ALS as a complex multisystem disorder which, as shown here, includes dysfunctional processing of the medial prefrontal cortex. It points towards possible alterations of self-consciousness in ALS patients, which might have important consequences for patients' self-conceptions, personal relations, and decision-making.
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- 2017
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60. Rare Variants in Neurodegeneration Associated Genes Revealed by Targeted Panel Sequencing in a German ALS Cohort
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Stefanie Krüger, Florian Battke, Andrea Sprecher, Marita Munz, Matthis Synofzik, Ludger Schöls, Thomas Gasser, Torsten Grehl, Johannes Prudlo, and Saskia Biskup
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Amyotrophic Lateral Sclerosis ,Genetic Heterogeneity ,neurodegeneration ,next generation sequencing ,polygenic inheritance ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive fatal multisystemic neurodegenerative disorder caused by preferential degeneration of upper and lower motor neurons. To further delineate the genetic architecture of the disease, we used comprehensive panel sequencing in a cohort of 80 German ALS patients. The panel covered 39 confirmed ALS genes and candidate genes, as well as 238 genes associated with other entities of the neurodegenerative disease spectrum. In addition, we performed repeat length analysis for C9orf72. Our aim was to (1) identify potentially disease-causing variants, to (2) assess a proposed model of polygenic inheritance in ALS and to (3) connect ALS with other neurodegenerative entities.We identified 79 rare potentially pathogenic variants in 27 ALS associated genes in familial and sporadic cases. Five patients had pathogenic C9orf72 repeat expansions, a further four patients harbored intermediate length repeat expansions. Our findings demonstrate that a genetic background of the disease can actually be found in a large proportion of seemingly sporadic cases and that it is not limited to putative most frequently affected genes such as C9orf72 or SOD1. Assessing the polygenic nature of ALS, we identified 15 patients carrying at least two rare potentially pathogenic variants in ALS associated genes including pathogenic or intermediate C9orf72 repeat expansions. Multiple variants might influence severity or duration of disease or could account for intrafamilial phenotypic variability or reduced penetrance. However, we could not observe a correlation with age of onset in this study. We further detected potentially pathogenic variants in other neurodegeneration associated genes in 12 patients, supporting the hypothesis of common pathways in neurodegenerative diseases and linking ALS to other entities of the neurodegenerative spectrum. Most interestingly we found variants in GBE1 and SPG7 which might represent differential diagnoses. Based on our findings, we recommend two-staged genetic testing for ALS in Germany in patients with familial and sporadic ALS, comprising C9orf72 repeat analysis followed by comprehensive panel sequencing including differential diagnoses that impair motor neuron function to meet the complexity of ALS genetics.
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- 2016
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61. Antisense Oligonucleotide Mediated Splice Correction of a Deep Intronic Mutation in OPA1
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Tobias Bonifert, Irene Gonzalez Menendez, Florian Battke, Yvonne Theurer, Matthis Synofzik, Ludger Schöls, and Bernd Wissinger
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antisense oligonucleotides ,deep intronic mutation ,OPA1 ,optic neuropathies ,splice correction ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Inherited optic neuropathies (ION) present an important cause of blindness in the European working-age population. Recently we reported the discovery of four independent families with deep intronic mutations in the main inherited optic neuropathies gene OPA1. These deep intronic mutations cause mis-splicing of the OPA1 pre-messenger-RNA transcripts by creating cryptic acceptor splice sites. As a rescue strategy we sought to prevent mis-splicing of the mutant pre-messenger-RNA by applying 2′O-methyl-antisense oligonucleotides (AONs) with a full-length phosphorothioate backbone that target the cryptic acceptor splice sites and the predicted novel branch point created by the deep intronic mutations, respectively. Transfection of patient-derived primary fibroblasts with these AONs induced correct splicing of the mutant pre-messenger-RNA in a time and concentration dependent mode of action, as detected by pyrosequencing of informative heterozygous variants. The treatment showed strong rescue effects (≃55%) using the cryptic acceptor splice sites targeting AON and moderate rescue (≃16%) using the branch point targeting AON. The highest efficacy of Splice correction could be observed 4 days after treatment however, significant effects were still seen 14 days post-transfection. Western blot analysis revealed increased amounts of OPA1 protein with maximum amounts at ≃3 days post-treatment. In summary, we provide the first mutation-specific in vitro rescue strategy for OPA1 deficiency using synthetic AONs.
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- 2016
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62. Effects of Cellular Pathway Disturbances on Misfolded Superoxide Dismutase-1 in Fibroblasts Derived from ALS Patients.
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Isil Keskin, Elin Forsgren, Dale J Lange, Markus Weber, Anna Birve, Matthis Synofzik, Jonathan D Gilthorpe, Peter M Andersen, and Stefan L Marklund
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Medicine ,Science - Abstract
Mutations in superoxide dismutase-1 (SOD1) are a common known cause of amyotrophic lateral sclerosis (ALS). The neurotoxicity of mutant SOD1s is most likely caused by misfolded molecular species, but disease pathogenesis is still not understood. Proposed mechanisms include impaired mitochondrial function, induction of endoplasmic reticulum stress, reduction in the activities of the proteasome and autophagy, and the formation of neurotoxic aggregates. Here we examined whether perturbations in these cellular pathways in turn influence levels of misfolded SOD1 species, potentially amplifying neurotoxicity. For the study we used fibroblasts, which express SOD1 at physiological levels under regulation of the native promoter. The cells were derived from ALS patients expressing 9 different SOD1 mutants of widely variable molecular characteristics, as well as from patients carrying the GGGGCC-repeat-expansion in C9orf72 and from non-disease controls. A specific ELISA was used to quantify soluble, misfolded SOD1, and aggregated SOD1 was analysed by western blotting. Misfolded SOD1 was detected in all lines. Levels were found to be much lower in non-disease control and the non-SOD1 C9orf72 ALS lines. This enabled us to validate patient fibroblasts for use in subsequent perturbation studies. Mitochondrial inhibition, endoplasmic reticulum stress or autophagy inhibition did not affect soluble misfolded SOD1 and in most cases, detergent-resistant SOD1 aggregates were not detected. However, proteasome inhibition led to uniformly large increases in misfolded SOD1 levels in all cell lines and an increase in SOD1 aggregation in some. Thus the ubiquitin-proteasome pathway is a principal determinant of misfolded SOD1 levels in cells derived both from patients and controls and a decline in activity with aging could be one of the factors behind the mid-to late-life onset of inherited ALS.
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- 2016
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63. Sensorimotor recalibration depends on attribution of sensory prediction errors to internal causes.
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Carlo Wilke, Matthis Synofzik, and Axel Lindner
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Medicine ,Science - Abstract
Sensorimotor learning critically depends on error signals. Learning usually tries to minimise these error signals to guarantee optimal performance. Errors can, however, have both internal causes, resulting from one's sensorimotor system, and external causes, resulting from external disturbances. Does learning take into account the perceived cause of error information? Here, we investigated the recalibration of internal predictions about the sensory consequences of one's actions. Since these predictions underlie the distinction of self- and externally produced sensory events, we assumed them to be recalibrated only by prediction errors attributed to internal causes. When subjects were confronted with experimentally induced visual prediction errors about their pointing movements in virtual reality, they recalibrated the predicted visual consequences of their movements. Recalibration was not proportional to the externally generated prediction error, but correlated with the error component which subjects attributed to internal causes. We also revealed adaptation in subjects' motor performance which reflected their recalibrated sensory predictions. Thus, causal attribution of error information is essential for sensorimotor learning.
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- 2013
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64. SARAspeech - Feasibility of automated assessment of ataxic speech disturbance.
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Marcus Grobe-Einsler, Jennifer Faber, A. Taheri, J. Kybelka, J. Raue, J. Volkening, F. Helmhold, Matthis Synofzik, and Thomas Klockgether
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- 2023
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65. Early Recognition of Ball Catching Success in Clinical Trials with RNN-Based Predictive Classification.
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Jana Lang, Martin A. Giese, Matthis Synofzik, Winfried Ilg, and Sebastian Otte
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- 2021
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66. The inner fluctuations of the brain in presymptomatic Frontotemporal Dementia: The chronnectome fingerprint.
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Enrico Premi, Vince D. Calhoun, Matteo Diano, Stefano Gazzina, Maura Cosseddu, Antonella Alberici, Silvana Archetti, Donata Paternicò, Roberto Gasparotti, John van Swieten, Daniela Galimberti, Raquel Sánchez-Valle, Robert Laforce Jr., Fermin Moreno, Matthis Synofzik, Caroline Graff, Mario Masellis, Maria Carmela Tartaglia, and Miren Zulaica
- Published
- 2019
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67. Corrigendum to 'Dissemination in time and space in presymptomatic granulin mutation carriers: A spatial chronnectome study' [Neurobiology of Aging Volume 108, December 2021, Pages 155–167]
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Enrico Premi, Marcello Giunta, Armin Iraji, Srinivas Rachakonda, VinceD. Calhoun, Stefano Gazzina, Alberto Benussi, Roberto Gasparotti, Silvana Archetti, Martina Bocchetta, Dave Cash, Emily Todd, Georgia Peakman, Rhian Convery, John C. van Swieten, Lize Jiskoot, Raquel Sanchez-Valle, Fermin Moreno, Robert Laforce, Caroline Graff, Matthis Synofzik, Daniela Galimberti, JamesB. Rowe, Mario Masellis, Carmela Tartaglia, Elizabeth Finger, Rik Vandenberghe, Alexandre de Mendonça, Fabrizio Tagliavini, Chris R. Butler, Isabel Santana, Alexander Gerhard, Isabelle Le Ber, Florence Pasquier, Simon Ducharme, Johannes Levin, Adrian Danek, Sandro Sorbi, Markus Otto, Jonathan D. Rohrer, and Barbara Borroni
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Aging ,General Neuroscience ,Neurology (clinical) ,Geriatrics and Gerontology ,Developmental Biology - Abstract
Refers to Enrico Premi, Marcello Giunta, Armin Iraji, Srinivas Rachakonda, Vince D. Calhoun, Stefano Gazzina, Alberto Benussi, Roberto Gasparotti, Silvana Archetti, Martina Bocchetta, Dave Cash, Emily Todd, Georgia Peakman, Rhian Convery, John C. van Swieten, Lize Jiskoot, Raquel Sanchez-Valle, Fermin Moreno, Robert Laforce, Caroline Graff, Matthis Synofzik, Daniela Galimberti, James B. Rowe, Mario Masellis, Carmela Tartaglia, Elizabeth Finger, Rik Vandenberghe, Alexandre de Mendonça, Fabrizio Tagliavini, Chris R. Butler, Isabel Santana, Alexander Gerhard, Isabelle Le Ber, Florence Pasquier, Simon Ducharme, Johannes Levin, Adrian Danek, Sandro Sorbi, Markus Otto, Jonathan D. Rohrer, Barbara Borroni Dissemination in time and space in presymptomatic granulin mutation carriers: a GENFI spatial chronnectome study. Neurobiology of Aging, Volume 108, December 2021, Pages 155-167 DOI of original article: 10.1016/j.neurobiolaging.2021.09.001. © 2022 Elsevier Inc. The authors regret that the GENFI authors were listed at the end of the article in the Appendix. The GENFI authors are also part of co-authors. The updated author list is below. The authors would like to apologise for any inconvenience caused.
- Published
- 2022
68. A common flanking variant is associated with enhanced meiotic stability of theFGF14-SCA27B locus
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David Pellerin, Giulia Del Gobbo, Madeline Couse, Egor Dolzhenko, Marie-Josée Dicaire, Adriana Rebelo, Virginie Roth, Marion Wandzel, Céline Bonnet, Catherine Ashton, Phillipa J. Lamont, Nigel G. Laing, Mathilde Renaud, Gianina Ravenscroft, Henry Houlden, Matthis Synofzik, Michael A. Eberle, Kym M. Boycott, Tomi Pastinen, Bernard Brais, Stephan Zuchner, and Matt C. Danzi
- Abstract
The factors driving initiation of pathological expansion of tandem repeats remain largely unknown. Here, we assessed theFGF14-SCA27B (GAA)•(TTC) repeat locus in 2,530 individuals by long-read and Sanger sequencing and identified a 5’-flanking 17-bp deletion-insertion in 70.34% of alleles (3,463/4,923). This common sequence variation was present nearly exclusively on alleles with fewer than 30 GAA-pure repeats and was associated with enhanced meiotic stability of the repeat locus.
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- 2023
69. A Review of Brain and Pituitary Gland MRI Findings in Patients with Ataxia and Hypogonadism
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Alessandra Scaravilli, Mario Tranfa, Giuseppe Pontillo, Bernard Brais, Giovanna De Michele, Roberta La Piana, Francesco Saccà, Filippo Maria Santorelli, Matthis Synofzik, Arturo Brunetti, and Sirio Cocozza
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Neurology ,Neurology (clinical) - Published
- 2023
70. Stage-dependent biomarker changes in spinocerebellar ataxia type 3
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Jennifer Faber, Moritz Berger, Wilke Carlo, Jeannette Hübener-Schmid, Tamara Schaprian, Magda M Santana, Marcus Grobe-Einsler, Dement Onder, Berkan Koyak, Paola Giunti, Hector Garcia-Moreno, Cristina Gonzalez-Robles, Manuela Lima, Mafalda Raposo, Ana Rosa Vieira Melo, Luís Pereira de Almeida, Patrick Silva, Maria M Pinto, Bart P. van de Warrenburg, Judith van Gaalen, Jeroen Jeroen de Vries, Gulin Oz, James M. Joers, Matthis Synofzik, Ludger Schöls, Olaf Riess, Jon Infante, Leire Manrique, Dagmar Timmann, Andreas Thieme, Heike Jacobi, Kathrin Reetz, Imis Dogan, Chiadikaobi Onyike, Michal Povazan, Jeremy Schmahmann, Eva-Maria Ratai, Matthias Schmid, and Thomas Klockgether
- Abstract
Spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3) is the most common autosomal dominant ataxia. In view of the development of targeted therapies for SCA3, precise knowledge of stage-dependent fluid and MRI biomarker changes is needed.We analyzed cross-sectional data of 292 SCA3 mutation carriers including 57 pre-ataxic individuals, and 108 healthy controls from the European Spinocerebellar ataxia type 3/Machado-Joseph Disease Initiative (ESMI) cohort. Blood concentrations of mutant ATXN3 and neurofilament light (NfL) were determined, and volumes of pons, cerebellar white matter (CWM) and cerebellar grey matter (CGM) were measured on MRI.Mutant ATXN3 concentrations were high before and after ataxia onset, while NfL continuously increased and deviated from normal 11.9 years before onset. Pons and CWM volumes decreased, but the deviation from normal was only 2.0 years (pons) and 0.3 years (CWM) before ataxia onset. We propose a staging model of SCA3 that includes an initial asymptomatic carrier stage followed by the biomarker stage defined by absence of ataxia, but a significant rise of NfL. The biomarker stage leads into the ataxia stage, defined by manifest ataxia.The present analysis provides a robust framework for further studies aiming at elaboration and differentiation of the staging model of SCA3.
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- 2023
71. Brain-computer interfacing in amyotrophic lateral sclerosis: Implications of a resting-state EEG analysis.
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Vinay Jayaram, Natalie Widmann, Christian Forster, Tatiana Fomina, Matthias Hohmann, Jennifer Muller vom Hagen, Matthis Synofzik, Bernhard Schölkopf, Ludger Schöls, and Moritz Grosse-Wentrup
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- 2015
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72. A Cognitive Brain-Computer Interface for Patients with Amyotrophic Lateral Sclerosis.
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Matthias R. Hohmann, Tatiana Fomina, Vinay Jayaram, Natalie Widmann, Christian Forster, Jennifer Muller vom Hagen, Matthis Synofzik, Bernhard Schölkopf, Ludger Schöls, and Moritz Grosse-Wentrup
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- 2015
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73. A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia
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Ione O.C. Woollacott, Cristina Polito, Philip Van Damme, Mathieu Vandenbulcke, Rose Bruffaerts, Diana Duro, Chiara Fenoglio, David M. Cash, Maria Rosário Almeida, Sonja Schönecker, C. Ferreira, Sónia Afonso, Matthis Synofzik, Sara Prioni, Marta Cañada, Mikel Tainta, Miguel Tábuas-Pereira, Christin Andersson, Caroline Graff, Miguel Castelo-Branco, Enrico Premi, Håkan Thonberg, Fabrizio Tagliavini, Rachelle Shafei, Benjamin Bender, Ana Gorostidi, Maria João Leitão, Jennifer M. Nicholas, Elise G.P. Dopper, Silvana Archetti, Esther E. Bron, Ana Verdelho, Ron Keren, Isabel Santana, Christen Shoesmith, Pietro Tiraboschi, Sergi Borrego-Écija, Michela Pievani, Sandro Sorbi, Rick van Minkelen, Hans-Otto Karnath, Albert Lladó, Caroline V. Greaves, Jaume Olives, Alessandro Padovani, Miren Zulaica, Giuliano Binetti, Martin Rosser, Pedro Rosa-Neto, Vesna Jelic, Alexander Gerhard, Rosa Rademakers, Sandra E. Black, Wiro J. Niessen, Tobias Hoegen, Rhian S Convery, Janne M. Papma, Maria Carmela Tartaglia, Emily Todd, Adrian Danek, Rita Guerreiro, Robart Bartha, Linn Öijerstedt, Giuseppe Di Fede, Sebastien Ourselin, Núria Bargalló, James B. Rowe, Christopher C Butler, Giorgio G. Fumagalli, Valentina Bessi, Alberto Benussi, Nick C. Fox, Beatriz Santiago, Ekaterina Rogaeva, Alazne Gabilondo, Giacomina Rossi, Mircea Balasa, David L. Thomas, Benedetta Nacmias, Veronica Redaelli, Anna Antonell, Vikram Venkatraghavan, Jonathan D. Rohrer, Jackie M. Poos, Yolande A.L. Pijnenburg, Lieke H.H. Meeter, Carlo Wilke, Sandra V. Loosli, Elio Scarpini, Tobias Langheinrich, Alina Díez, Elisa Semler, Elizabeth Finger, Begoña Indakoetxea, Jessica L. Panman, Carolyn Timberlake, Gemma Lombardi, Luisa Benussi, Morris Freedman, Barbara Borroni, Ricardo Taipa, Johannes Levin, Thomas E. Cope, Paul M. Thompson, Giorgio Giaccone, Valentina Cantoni, Arabella Bouzigues, Jose Bras, Serge Gauthier, Andrea Arighi, Stefan Klein, Fermin Moreno, Markus Otto, Georgia Peakman, Emma L. van der Ende, David F. Tang-Wai, Sarah Anderl-Straub, Jason D. Warren, Alexandre de Mendonça, Camilla Ferrari, Elisabeth Wlasich, Catharina Prix, Michele Veldsman, Raquel Sánchez-Valle, Sara Mitchell, Carolina Maruta, Robert Laforce, Paola Caroppo, Jorge Villanua, Imogen J Swift, Harro Seelaar, Henrik Zetterberg, Simon Mead, Simon Ducharme, Myriam Barandiaran, Katrina M. Moore, John C. van Swieten, Gabriel Miltenberger, Mario Masellis, Timothy Rittman, Lize C. Jiskoot, Daniela Galimberti, Rik Vandenberghe, Carolin Heller, Stefano Gazzina, Aitana Sogorb-Esteve, Roberto Gasparotti, Martina Bocchetta, Neurology, Amsterdam Neuroscience - Neurodegeneration, Repositório da Universidade de Lisboa, Radiology & Nuclear Medicine, and Neurosurgery
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Oncology ,medicine.medical_specialty ,Medizin ,tau Proteins ,Disease ,medicine.disease_cause ,frontotemporal dementia ,biomarker ,disease progression model ,event-based modelling ,neurofilament light chain ,Biomarkers ,C9orf72 Protein ,Complement C1q ,Cross-Sectional Studies ,Disease Progression ,Glial Fibrillary Acidic Protein ,Humans ,Longitudinal Studies ,Mutation ,Frontotemporal Dementia ,diagnosis [Frontotemporal Dementia] ,Settore BIO/13 - Biologia Applicata ,C9orf72 ,Internal medicine ,Medicine ,ddc:610 ,genetics [C9orf72 Protein] ,genetics [Frontotemporal Dementia] ,business.industry ,medicine.disease ,Astrogliosis ,genetics [tau Proteins] ,Cohort ,Biomarker (medicine) ,Neurology (clinical) ,Sample collection ,business ,Frontotemporal dementia - Abstract
© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com, Several CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions., This study was supported in the Netherlands by two Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050813,733050103 and 733050513), the Bluefield Project to Cure Frontotemporal Dementia, the Dioraphte foundation (grant number 1402 1300), the European Joint Programme—Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024); V.V. and S.K. have received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 666992 (EuroPOND). E.B. was supported by the Hartstichting (PPP Allowance, 2018B011); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the MRC UK GENFI grant (MR/M023664/1); J.D.R. is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH); I.J.S. is supported by the Alzheimer’s Association; J.B.R. is supported by the Wellcome Trust (103838); in Spain by the Fundació Marató de TV3 (20143810 to R.S.V.); in Germany by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and by grant 779357 ‘Solve-RD’ from the Horizon 2020 Research and Innovation Programme (to MS); in Sweden by grants from the Swedish FTD Initiative funded by the Schörling Foundation, grants from JPND PreFrontALS Swedish Research Council (VR) 529–2014-7504, Swedish Research Council (VR) 2015–02926, Swedish Research Council (VR) 2018–02754, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Swedish Demensfonden, Stohnes foundation, Gamla Tjänarinnor, Karolinska Institutet Doctoral Funding and StratNeuro. H.Z. is a Wallenberg Scholar.
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- 2022
74. Consensus Paper: Ataxic Gait
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Pierre Cabaraux, Sunil K. Agrawal, Huaying Cai, Rocco Salvatore Calabro, Carlo Casali, Loic Damm, Sarah Doss, Christophe Habas, Anja K. E. Horn, Winfried Ilg, Elan D. Louis, Hiroshi Mitoma, Vito Monaco, Maria Petracca, Alberto Ranavolo, Ashwini K. Rao, Serena Ruggieri, Tommaso Schirinzi, Mariano Serrao, Susanna Summa, Michael Strupp, Olivia Surgent, Matthis Synofzik, Shuai Tao, Hiroo Terasi, Diego Torres-Russotto, Brittany Travers, Jaimie A. Roper, and Mario Manto
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Neurology ,Cerebellum ,Therapies ,Posture ,Rehabilitation ,Cerebellar ataxia ,Gait ,Neurology (clinical) - Abstract
The aim of this consensus paper is to discuss the roles of the cerebellum in human gait, as well as its assessment and therapy. Cerebellar vermis is critical for postural control. The cerebellum ensures the mapping of sensory information into temporally relevant motor commands. Mental imagery of gait involves intrinsically connected fronto-parietal networks comprising the cerebellum. Muscular activities in cerebellar patients show impaired timing of discharges, affecting the patterning of the synergies subserving locomotion. Ataxia of stance/gait is amongst the first cerebellar deficits in cerebellar disorders such as degenerative ataxias and is a disabling symptom with a high risk of falls. Prolonged discharges and increased muscle coactivation may be related to compensatory mechanisms and enhanced body sway, respectively. Essential tremor is frequently associated with mild gait ataxia. There is growing evidence for an important role of the cerebellar cortex in the pathogenesis of essential tremor. In multiple sclerosis, balance and gait are affected due to cerebellar and spinal cord involvement, as a result of disseminated demyelination and neurodegeneration impairing proprioception. In orthostatic tremor, patients often show mild-to-moderate limb and gait ataxia. The tremor generator is likely located in the posterior fossa. Tandem gait is impaired in the early stages of cerebellar disorders and may be particularly useful in the evaluation of pre-ataxic stages of progressive ataxias. Impaired inter-joint coordination and enhanced variability of gait temporal and kinetic parameters can be grasped by wearable devices such as accelerometers. Kinect is a promising low cost technology to obtain reliable measurements and remote assessments of gait. Deep learning methods are being developed in order to help clinicians in the diagnosis and decision-making process. Locomotor adaptation is impaired in cerebellar patients. Coordinative training aims to improve the coordinative strategy and foot placements across strides, cerebellar patients benefiting from intense rehabilitation therapies. Robotic training is a promising approach to complement conventional rehabilitation and neuromodulation of the cerebellum. Wearable dynamic orthoses represent a potential aid to assist gait. The panel of experts agree that the understanding of the cerebellar contribution to gait control will lead to a better management of cerebellar ataxias in general and will likely contribute to use gait parameters as robust biomarkers of future clinical trials.
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- 2022
75. Blood neurofilament light chain levels are associated with disease progression in a transgenic SCA3 mouse model
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David Mengel, Isabel G. Wellik, Kristen H. Schuster, Sabrina I. Jarrah, Madeleine Wacker, Naila S. Ashraf, Gülin Öz, Matthis Synofzik, Maria do Carmo Costa, and Hayley S. McLoughlin
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Increased neurofilament light (NfL) protein in biofluids is reflective of neurodegeneration and has gained interest as a biomarker across neurodegenerative diseases. In spinocerebellar ataxia type 3 (SCA3), the most common dominantly inherited ataxia, patients exhibit progressive NfL increases in peripheral blood when becoming symptomatic, remaining stably elevated throughout further disease course. However, progressive NfL changes are not yet validated in relevant preclinical SCA3 animal models, hindering its application as a biomarker during therapeutic development. We used ultra-sensitive single-molecule array (Simoa) to measure blood NfL over disease progression in the YACQ84 mouse, assessing relationships with measures of disease severity including age, CAG repeat size, and magnetic resonance spectroscopy. We show that YACQ84 mice exhibit increased blood NfL, concomitant with ataxia-related motor deficits and correlated with neurometabolite abnormalities. Our findings establish natural history progression of NfL increases in the preclinical YACQ84 mouse, further supporting the utility of blood NfL as a peripheral neurodegeneration biomarker and informing coinciding timelines of different measures of SCA3 pathogenesis.Summary statementPeripheral blood of SCA3 YACQ84 mice exhibits increased abundance of neuronal-specific NfL protein directly associating with disease progression, providing an accessible disease biofluid biomarker to interrogate in preclinical therapeutic studies.
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- 2023
76. The Benson Complex Figure Test detects deficits in visuoconstruction and visual memory in symptomatic familial frontotemporal dementia: A GENFI study
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Lize C. Jiskoot, Lucy L. Russell, Georgia Peakman, Rhian S. Convery, Caroline V. Greaves, Martina Bocchetta, Jackie M. Poos, Harro Seelaar, Lucia A.A. Giannini, John C. van Swieten, Rick van Minkelen, Yolande A.L. Pijnenburg, James B. Rowe, Barbara Borroni, Daniela Galimberti, Mario Masellis, Carmela Tartaglia, Elizabeth Finger, Chris R. Butler, Caroline Graff, Robert Laforce, Raquel Sanchez-Valle, Alexandre de Mendonça, Fermin Moreno, Matthis Synofzik, Rik Vandenberghe, Simon Ducharme, Isabelle le Ber, Johannes Levin, Markus Otto, Florence Pasquier, Isabel Santana, David M. Cash, David Thomas, Jonathan D. Rohrer, Neurology, Amsterdam Neuroscience - Neurodegeneration, Repositório da Universidade de Lisboa, and Clinical Genetics
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cognition ,marker ,neuropsychology ,Presymptomatic ,Marker ,frontotemporal dementia ,presymptomatic ,Cognition ,Neurology ,Genetic ,Neuropsychology ,Frontotemporal dementia ,Neurology (clinical) ,genetic - Abstract
© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/), Objective: Sensitive cognitive markers are still needed for frontotemporal dementia (FTD). The Benson Complex Figure Test (BCFT) is an interesting candidate test, as it assesses visuospatial, visual memory, and executive abilities, allowing the detection of multiple mechanisms of cognitive impairment. To investigate differences in BCFT Copy, Recall and Recognition in presymptomatic and symptomatic FTD mutation carriers, and to explore its cognitive and neuroimaging correlates. Method: We included cross-sectional data from 332 presymptomatic and 136 symptomatic mutation carriers (GRN, MAPT or C9orf72 mutations), and 290 controls in the GENFI consortium. We examined gene-specific differences between mutation carriers (stratified by CDR® NACC-FTLD score) and controls using Quade's / Pearson Χ2 tests. We investigated associations with neuropsychological test scores and grey matter volume using partial correlations and multiple regression models respectively. Results: No significant differences were found between groups at CDR® NACC-FTLD 0-0.5. Symptomatic GRN and C9orf72 mutation carriers had lower Copy scores at CDR® NACC-FTLD ≥2. All three groups had lower Recall scores at CDR® NACC-FTLD ≥2, with MAPT mutation carriers starting at CDR® NACC-FTLD ≥1. All three groups had lower Recognition scores at CDR® NACC FTLD ≥2. Performance correlated with tests for visuoconstruction, memory, and executive function. Copy scores correlated with frontal-subcortical grey matter atrophy, while Recall scores correlated with temporal lobe atrophy. Conclusions: In the symptomatic stage, the BCFT identifies differential mechanisms of cognitive impairment depending on the genetic mutation, corroborated by gene-specific cognitive and neuroimaging correlates. Our findings suggest that impaired performance on the BCFT occurs relatively late in the genetic FTD disease process. Therefore its potential as cognitive biomarker for upcoming clinical trials in presymptomatic to early-stage FTD is most likely limited., The Dementia Research Centre is supported by Alzheimer's Research UK, Alzheimer's Society, Brain Research UK, and The Wolfson Foundation. This work was supported by the NIHR UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility, and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd., funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. JDR is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project, the JPND GENFI-PROX grant (2019–02248), the Dioraphte Foundation [grant numbers 09–02-00], the Association for Frontotemporal Dementias Research Grant 2009, The Netherlands Organization for Scientific Research (NWO) (grant HCMI 056–13-018), ZonMw Memorabel (Deltaplan Dementie; project numbers 733050103 and 733050813), JPND PreFrontAls Consortium (project number 733051042) and Instituto de Salud Carlos III, Spain, and FEDER funds (grant number 20/00448). JBR is supported by the Wellcome Trust (103838), Medical Research Council (SUAG092 G116768) and the NIHR Cambridge Biomedical Research Centre (BRC-1215 − 20014: the views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care). This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198). JMP is supported by a fellowship award from Alzheimer Nederland (WE.15–2019.02). This work was conducted using the MRC Dementias Platform UK (MR/L023784/1 and MR/009076/1).
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- 2023
77. Optimized testing strategy for the diagnosis of GAA-FGF14ataxia
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Céline Bonnet, David Pellerin, Virginie Roth, Guillemette Clément, Marion Wandzel, Laëtitia Lambert, Solène Frismand, Marian Douarinou, Anais Grosset, Ines Bekkour, Frédéric Weber, Florent Girardier, Clément Robin, Stéphanie Cacciatore, Myriam Bronner, Carine Pourié, Natacha Dreumont, Salomé Puisieux, Marie-Josée Dicaire, François Evoy, Marie-France Rioux, Armand Hocquel, Roberta La Piana, Matthis Synofzik, Henry Houlden, Matt C. Danzi, Stephan Zuchner, Bernard Brais, and Mathilde Renaud
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BackgroundDominantly inherited GAA repeat expansions inFGF14are a common cause of spinocerebellar ataxia (GAA-FGF14ataxia; SCA27B, late-onset). Molecular confirmation ofFGF14GAA repeat expansions has thus far mostly relied on long-read sequencing, a technology that is not yet widely available in clinical laboratories.MethodsWe developed and validated a strategy to detectFGF14GAA repeat expansions using long-range PCR, bidirectional repeat-primed PCRs, and Sanger sequencing. We compared this strategy to targeted nanopore sequencing in a cohort of 22 French Canadian patients and next validated it in a cohort of 53 French index patients with unsolved ataxia.ResultsDiagnosis was accurately confirmed for all 22 French Canadian patients using this strategy. Method comparison showed that capillary electrophoresis of long-range PCR products significantly underestimated expansion sizes compared to nanopore sequencing (slope, 0.87 [95% CI, 0.81 to 0.93]; intercept, 14.58 [95% CI, -2.48 to 31.12]) and gel electrophoresis (slope, 0.84 [95% CI, 0.78 to 0.97]; intercept, 21.34 [95% CI, -27.66 to 40.22]). The latter techniques yielded similar size estimates. Following calibration with internal controls, expansion size estimates were similar between capillary electrophoresis and nanopore sequencing (slope: 0.98 [95% CI, 0.92 to 1.04]; intercept: 10.62 [95% CI, -7.49 to 27.71]), and gel electrophoresis (slope: 0.94 [95% CI, 0.88 to 1.09]; intercept: 18.81 [95% CI, -41.93 to 39.15]). We identified 9 French patients (9/53; 17%) and 2 of their relatives who carried anFGF14(GAA)≥250expansion.ConclusionThis novel strategy reliably detected and sizedFGF14GAA expansions. It compared favorably to long-read sequencing and can readily be implemented in clinical laboratories.
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- 2023
78. TR-FRET-Based Immunoassay to Measure Ataxin-2 as a Target Engagement Marker in Spinocerebellar Ataxia Type 2
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Jessica Bux, Nesli Ece Sen, Isa-Maria Klink, Stefan Hauser, Matthis Synofzik, Ludger Schöls, Georg Auburger, Olaf Riess, and Jeannette Hübener-Schmid
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Target engagement ,Cellular and Molecular Neuroscience ,Neurology ,ddc:570 ,Neuroscience (miscellaneous) ,Biomarker ,Time-resolved fluorescence energy transfer ,Spinocerebellar ataxia type 2 ,Ataxin-2 - Abstract
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited neurodegenerative disease, which belongs to the trinucleotide repeat disease group with a CAG repeat expansion in exon 1 of the ATXN2 gene resulting in an ataxin-2 protein with an expanded polyglutamine (polyQ)-stretch. The disease is late manifesting leading to early death. Today, therapeutic interventions to cure the disease or even to decelerate disease progression are not available yet. Furthermore, primary readout parameter for disease progression and therapeutic intervention studies are limited. Thus, there is an urgent need for quantifiable molecular biomarkers such as ataxin-2 becoming even more important due to numerous potential protein-lowering therapeutic intervention strategies. The aim of this study was to establish a sensitive technique to measure the amount of soluble polyQ-expanded ataxin-2 in human biofluids to evaluate ataxin-2 protein levels as prognostic and/or therapeutic biomarker in SCA2. Time-resolved fluorescence energy transfer (TR-FRET) was used to establish a polyQ-expanded ataxin-2-specific immunoassay. Two different ataxin-2 antibodies and two different polyQ-binding antibodies were validated in three different concentrations and tested in cellular and animal tissue as well as in human cell lines, comparing different buffer conditions to evaluate the best assay conditions. We established a TR-FRET-based immunoassay for soluble polyQ-expanded ataxin-2 and validated measurements in human cell lines including iPSC-derived cortical neurons. Additionally, our immunoassay was sensitive enough to monitor small ataxin-2 expression changes by siRNA or starvation treatment. We successfully established the first sensitive ataxin-2 immunoassay to measure specifically soluble polyQ-expanded ataxin-2 in human biomaterials.
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- 2023
79. Autosomal Recessive Cerebellar Ataxias in Europe: Frequency, Onset, and Severity in 677 Patients
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Andreas Traschütz, Astrid D. Adarmes‐Gomez, Mathieu Anheim, Jonathan Baets, Björn H. Falkenburger, Janina Gburek‐Augustat, Sarah Doss, Christoph Kamm, Peter Klivenyi, Marcus Grobe‐Einsler, Thomas Klopstock, Martina Minnerop, Alexander Münchau, Chiara Pane, Mathilde Renaud, Filippo M. Santorelli, Ludger Schöls, Dagmar Timmann, Stefan Vielhaber, Tobias B. Haack, Bart P. van de Warrenburg, Ginevra Zanni, and Matthis Synofzik
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Neurology ,Medizin ,03.01. Általános orvostudomány ,Human medicine ,Neurology (clinical) ,ddc:610 - Abstract
in press
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- 2023
80. Evolution of Clinical Outcome Measures and Biomarkers in Sporadic Adult-Onset Degenerative Ataxia
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Demet Oender, Jennifer Faber, Carlo Wilke, Tamara Schaprian, Asadeh Lakghomi, David Mengel, Ludger Schöls, Andreas Traschütz, Zofia Fleszar, Claudia Dufke, Stefan Vielhaber, Judith Machts, Ilaria Giordano, Marcus Grobe‐Einsler, Thomas Klopstock, Claudia Stendel, Sylvia Boesch, Wolfgang Nachbauer, Dagmar Timmann‐Braun, Andreas Gustafsson Thieme, Christoph Kamm, Ales Dudesek, Chantal Tallaksen, Iselin Wedding, Alessandro Filla, Matthias Schmid, Matthis Synofzik, and Thomas Klockgether
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Adult ,multiple system atrophy ,Medizin ,volumetric MRI ,genetics [Ataxia] ,sporadic ataxia ,diagnosis [Cerebellar Ataxia] ,neurofilament light chain ,diagnosis [Multiple System Atrophy] ,Neurology ,natural history ,Cerebellum ,Humans ,ddc:610 ,Neurology (clinical) ,Biomarkers - Abstract
Background: Sporadic adult-onset ataxias without known genetic or acquired cause are subdivided into multiple system atrophy of cerebellar type (MSA-C) and sporadic adult-onset ataxia of unknown etiology (SAOA). Objectives: To study the differential evolution of both conditions including plasma neurofilament light chain (NfL) levels and magnetic resonance imaging (MRI) markers. Methods: SPORTAX is a prospective registry of sporadic ataxia patients with an onset >40 years. Scale for the Assessment and Rating of Ataxia was the primary outcome measure. In subgroups, blood samples were taken and MRIs performed. Plasma NfL was measured via a single molecule assay. Regional brain volumes were automatically measured. To assess signal changes, we defined the pons and middle cerebellar peduncle abnormality score (PMAS). Using mixed-effects models, we analyzed changes on a time scale starting with ataxia onset. Results: Of 404 patients without genetic diagnosis, 130 met criteria of probable MSA-C at baseline and 26 during follow-up suggesting clinical conversion to MSA-C. The remaining 248 were classified as SAOA. At baseline, NfL, cerebellar white matter (CWM) and pons volume, and PMAS separated MSA-C from SAOA. NfL decreased in MSA-C and did not change in SAOA. CWM and pons volume decreased faster, whereas PMAS increased faster in MSA-C. In MSA-C, pons volume had highest sensitivity to change, and PMAS was a predictor of faster progression. Fulfillment of possible MSA criteria, NfL and PMAS were risk factors, CWM and pons volume protective factors for conversion to MSA-C. Conclusions: This study provides detailed information on differential evolution and prognostic relevance of biomarkers in MSA-C and SAOA. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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- 2023
81. The prodromal phase of hereditary spastic paraplegia type 4: the preSPG4 cohort study
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Tim W Rattay, Maximilian Völker, Maren Rautenberg, Christoph Kessler, Isabel Wurster, Natalie Winter, Tobias B Haack, Tobias Lindig, Holger Hengel, Matthis Synofzik, Rebecca Schüle, Peter Martus, and Ludger Schöls
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genetics [Mutation] ,SPG4 ,NfL ,Cohort Studies ,genetics [Paraplegia] ,neurofilament light chain ,prodromal phase ,genetics [Spastic Paraplegia, Hereditary] ,Humans ,genetics [Amyloid beta-Peptides] ,genetics [Spastin] ,Neurology (clinical) ,ddc:610 ,preSPG4 study ,hereditary spastic paraplegia - Abstract
This cohort study aimed to characterize the prodromal phase of hereditary spastic paraplegia type 4 (SPG4) using biomarkers and clinical signs and symptoms that develop before manifest gait abnormalities. Fifty-six first-degree relatives at risk of developing SPG4 underwent blinded genotyping and standardized phenotyping, including the Spastic Paraplegia Rating Scale (SPRS), complicating symptoms, non-motor affection, Three-Minute Walk, and neurophysiological assessment. Automated MR image analysis was used to compare volumetric properties. CSF of 33 probands was analysed for neurofilament light chain (NfL), tau, and amyloid-β (Aβ). Thirty participants turned out to be SPAST mutation carriers, whereas 26 did not inherit a SPAST mutation. Increased reflexes, ankle clonus, and hip abduction weakness were more frequent in prodromal mutation carriers but were also observed in non-mutation carriers. Only Babinski's sign differentiated reliably between the two groups. Timed walk and non-motor symptoms did not differ between groups. Whereas most mutation carriers had total SPRS scores of 2 points or more, only two non-mutation carriers reached more than 1 point. Motor evoked potentials revealed no differences between mutation and non-mutation carriers. We found NfL but not tau or Aβ to rise in CSF of mutation carriers when approaching the time point of predicted disease manifestation. Serum NfL did not differ between groups. Volumetric MRI analyses did not reveal group differences apart from a smaller cingulate gyrus in mutation carriers. This study depicts subtle clinical signs which develop before gait abnormalities in SPG4. Long-term follow-up is needed to study the evolution of SPG4 in the prodromal stage and conversion into manifest disease. NfL in CSF is a promising fluid biomarker that may indicate disease activity in prodromal SPG4 but needs further evaluation in longitudinal studies.
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- 2023
82. Development of tailored splice-switching oligonucleotides for progressive brain disorders in Europe: development, regulation, and implementation considerations
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Annemieke Aartsma-Rus, Willeke van Roon-Mom, Marlen Lauffer, Christine Siezen, Britt Duijndam, Tineke Coenen-de Roo, Rebecca Schüle, Matthis Synofzik, and Holm Graessner
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regulators ,treatment ,therapeutic use [Oligonucleotides, Antisense] ,Oligonucleotides ,Brain ,genetics [Oligonucleotides, Antisense] ,Oligonucleotides, Antisense ,Europe ,genetics [Oligonucleotides] ,therapeutic use [Oligonucleotides] ,drug therapy [Brain Diseases] ,Humans ,ddc:610 ,N = 1 ,antisense oligonucleotides ,Molecular Biology - Abstract
Splice-modulating antisense oligonucleotides (ASOs) offer treatment options for rare neurological diseases, including those with very rare mutations, where patient-specific, individualized ASOs have to be developed. Inspired by the development of milasen, the 1 Mutation 1 Medicine (1M1M) and Dutch Center for RNA Therapeutics (DCRT) aim to develop patient-specific ASOs and treat eligible patients within Europe and the Netherlands, respectively. Treatment will be provided under a named patient setting. Our initiatives benefited from regulatory advice from the European Medicines Agency (EMA) with regard to preclinical proof-of-concept studies, safety studies, compounding and measuring benefit and safety in treated patients. We here outline the most important considerations from these interactions and how we implemented this advice into our plan to develop and treat eligible patients within Europe.
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- 2023
83. Short-read genome sequencing allows 'en route' diagnosis of patients with atypical Friedreich ataxia
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Zofia Fleszar, Claudia Dufke, Marc Sturm, Rebecca Schüle, Ludger Schöls, Tobias B. Haack, and Matthis Synofzik
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Neurology ,Neurology (clinical) ,ddc:610 - Published
- 2023
84. Repeat expansions nested within tandem CNVs: A unique structural change in GLS exemplifies the diagnostic challenges of non-coding pathogenic variation
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Sarah Fazal, Matt C Danzi, André B P van Kuilenburg, Selina Reich, Andreas Traschütz, Benjamin Bender, René Leen, Camilo Toro, Karen Usdin, Bruce Hayward, David R Adams, Clara D M van Karnebeek, Carlos R Ferreira, Precilla D’Sousa, Undiagnosed Diseases Network, Mustafa Tekin, Stephan Züchner, Matthis Synofzik, Laboratory Genetic Metabolic Diseases, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, AII - Cancer immunology, Paediatrics, Paediatric Metabolic Diseases, Paediatric Pulmonology, APH - Personalized Medicine, and ANS - Cellular & Molecular Mechanisms
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Ataxia/diagnosis ,ddc:570 ,Proteins/genetics ,Genetics ,Humans ,General Medicine ,diagnosis [Ataxia] ,genetics [Ataxia] ,5' Untranslated Regions ,genetics [Glutaminase] ,Molecular Biology ,Glutaminase/genetics ,Genetics (clinical) - Abstract
Glutaminase deficiency has recently been associated with ataxia and developmental delay due to repeat expansions in the 5′UTR of the glutaminase (GLS) gene. Patients with the described GLS repeat expansion may indeed remain undiagnosed due to the rarity of this variant, the challenge of its detection and the recency of its discovery. In this study, we combined advanced bioinformatics screening of ~3000 genomes and ~1500 exomes with optical genome mapping and long-read sequencing for confirmation studies. We identified two GLS families, previously intensely and unsuccessfully analyzed. One family carries an unusual and complex structural change involving a homozygous repeat expansion nested within a quadruplication event in the 5′UTR of GLS. Glutaminase deficiency and its metabolic consequences were validated by in-depth biochemical analysis. The identified GLS patients showed progressive early-onset ataxia, cognitive deficits, pyramidal tract damage and optic atrophy, thus demonstrating susceptibility of several specific neuron populations to glutaminase deficiency. This large-scale screening study demonstrates the ability of bioinformatics analysis—validated by latest state-of-the-art technologies (optical genome mapping and long-read sequencing)—to effectively flag complex repeat expansions using short-read datasets and thus facilitate diagnosis of ultra-rare disorders.
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- 2023
85. Dissemination in time and space in presymptomatic granulin mutation carriers: a GENFI spatial chronnectome study
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Sandro Sorbi, Vince D. Calhoun, James B. Rowe, Isabelle Le Ber, Matthis Synofzik, Roberto Gasparotti, Martina Bocchetta, Enrico Premi, Dave Cash, Alexandre de Mendonça, Armin Iraji, Johannes Levin, Stefano Gazzina, A. Danek, Lize C. Jiskoot, Marcello Giunta, Alexander Gerhard, Markus Otto, Raquel Sánchez-Valle, Emily Todd, Genetic Frontotemporal dementia Initiative, Isabel Santana, Silvana Archetti, Rhian S Convery, Robert Laforce, Srinivas Rachakonda, Florence Pasquier, Fermin Moreno, John C. van Swieten, Georgia Peakman, Elizabeth Finger, Jonathan D. Rohrer, Christopher C Butler, Daniela Galimberti, Alberto Benussi, Carmela Tartaglia, Rik Vandenberghe, Caroline Graff, Mario Masellis, Fabrizio Tagliavini, Barbara Borroni, Simon Ducharme, Genetic Frontotemporal dementia Initiative (GENFI), Neurology, and Clinical Genetics
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Adult ,Male ,resting-state functional MRI ,Heterozygote ,Aging ,Time Factors ,Dissemination in time ,Spatial Behavior ,spatial chronnectome ,Granulin ,Biology ,Research initiative ,frontotemporal dementia ,Executive Function ,dynamic functional network connectivity ,Frontotemporal Dementia ,GRN mutation ,medicine ,Humans ,Default mode network ,Granulins ,General Neuroscience ,Brain ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Asymptomatic Diseases ,Mutation ,Mutation (genetic algorithm) ,Female ,Neurology (clinical) ,Geriatrics and Gerontology ,Neuroscience ,Insula ,Language network ,Developmental Biology ,Frontotemporal dementia - Abstract
The presymptomatic brain changes of granulin (GRN) disease, preceding by years frontotemporal dementia, has not been fully characterized. New approaches focus on the spatial chronnectome can capture both spatial network configurations and their dynamic changes over time. To investigate the spatial dynamics in 141 presymptomatic GRN mutation carriers and 282 noncarriers from the Genetic Frontotemporal dementia research Initiative cohort. We considered time-varying patterns of the default mode network, the language network, and the salience network, each summarized into 4 distinct recurring spatial configurations. Dwell time (DT) (the time each individual spends in each spatial state of each network), fractional occupacy (FO) (the total percentage of time spent by each individual in a state of a specific network) and total transition number (the total number of transitions performed by each individual in a specifict state) were considered. Correlations between DT, FO, and transition number and estimated years from expected symptom onset (EYO) and clinical performances were assessed. Presymptomatic GRN mutation carriers spent significantly more time in those spatial states characterised by greater activation of the insula and the parietal cortices, as compared to noncarriers (p < 0.05, FDR-corrected). A significant correlation between DT and FO of these spatial states and EYO was found, the longer the time spent in the spatial states, the closer the EYO. DT and FO significantly correlated with performances at tests tapping processing speed, with worse scores associated with increased spatial states’ DT. Our results demonstrated that presymptomatic GRN disease presents a complex dynamic reorganization of brain connectivity. Change in both the spatial and temporal aspects of brain network connectivity could provide a unique glimpse into brain function and potentially allowing a more sophisticated evaluation of the earliest disease changes and the understanding of possible mechanisms in GRN disease.
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- 2021
86. Deep Intronic
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David, Pellerin, Matt C, Danzi, Carlo, Wilke, Mathilde, Renaud, Sarah, Fazal, Marie-Josée, Dicaire, Carolin K, Scriba, Catherine, Ashton, Christopher, Yanick, Danique, Beijer, Adriana, Rebelo, Clarissa, Rocca, Zane, Jaunmuktane, Joshua A, Sonnen, Roxanne, Larivière, David, Genís, Laura, Molina Porcel, Karine, Choquet, Rawan, Sakalla, Sylvie, Provost, Rebecca, Robertson, Xavier, Allard-Chamard, Martine, Tétreault, Sarah J, Reiling, Sara, Nagy, Vikas, Nishadham, Meera, Purushottam, Seena, Vengalil, Mainak, Bardhan, Atchayaram, Nalini, Zhongbo, Chen, Jean, Mathieu, Rami, Massie, Colin H, Chalk, Anne-Louise, Lafontaine, François, Evoy, Marie-France, Rioux, Jiannis, Ragoussis, Kym M, Boycott, Marie-Pierre, Dubé, Antoine, Duquette, Henry, Houlden, Gianina, Ravenscroft, Nigel G, Laing, Phillipa J, Lamont, Mario A, Saporta, Rebecca, Schüle, Ludger, Schöls, Roberta, La Piana, Matthis, Synofzik, Stephan, Zuchner, and Bernard, Brais
- Abstract
The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis.We sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disease in two independent case-control series - one French Canadian (66 patients and 209 controls) and the other German (228 patients and 199 controls). We also genotyped the repeat in 20 Australian and 31 Indian index patients. We assayed gene and protein expression in two postmortem cerebellum specimens and two induced pluripotent stem-cell (iPSC)-derived motor-neuron cell lines.In the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron ofA dominantly inherited deep intronic GAA repeat expansion in
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- 2022
87. Soluble TAM receptor biomarkers: Neuroprotection in AD neuroinflammation?'
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Frederic Brosseron, Anne Maass, Luca Kleineidam, Kishore Aravind Ravichandran, Oliver Peters, Josef Priller, Anja Schneider, Klaus Fließbach, Jens Wiltfang, Emrah Duzel, Katharina Buerger, Robert Perneczky, Stefan Teipel, Christoph Laske, Annika Spottke, Charlotte E. Teunissen, Matthis Synofzik, Michael Wagner, Frank Jessen, Alfredo Ramirez, Agustin Ruiz, and Michael T. Heneka
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2022
88. French Translation and Cross-cultural Adaptation of the Scale for the Assessment and Rating of Ataxia
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Dax Bourcier, Nicolas Bélair, Élyse-Anne Pedneault-Tremblay, Isabelle Lessard, Thomas Klockgether, Matthis Synofzik, Caroline Rahn, Bernard Brais, Elise Duchesne, and Cynthia Gagnon
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Cross-cultural adaptation ,Psychometric properties ,Translation ,Neurology ,ISPOR guidelines ,Ataxia ,ddc:610 ,Neurology (clinical) - Abstract
The Scale for the Assessment and Rating of Ataxia (SARA) is a widely used scale for assessing the severity of ataxia in clinics, natural history studies, and treatment trials worldwide. However, no French translation with validated cross-cultural adaptation is available. This study aimed to translate and adapt the SARA into French. The translation process was conducted according to the ISPOR guidelines for the translation and cultural adaptation process for patient-reported outcomes. A total of five translators, an expert committee, and two physiotherapists took part in the process to assess and ensure comprehension and language equivalences of the final French version. A few misinterpretations were pointed out during the translation process and were changed accordingly by the translation team. The French version of the SARA is ready to be used in clinical and research settings with French-speaking populations living with ataxia.
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- 2022
89. F57 Quantitative motor assessment of upper limb ataxia with q-motor: a cross-sectional validation study including novel ataxia tasks – lessons learnt for HD
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Pascal Barallon, Andreas Traschütz, Dominik Hermle, Robin Schubert, Rebecca Schüle, Ralf Reilmann, and Matthis Synofzik
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- 2022
90. F56 Quantifying fine-motor impairment in ataxia: digital parameters of q-motor spiral drawing correlate with clinical severity, function & ADLs – lessons for HD
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Robin Schubert, Dominik Hermle, Pascal Barallon, Rebecca Schüle, Ralf Reilmann, Matthis Synofzik, and Andreas Traschütz
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- 2022
91. Progressive Spinal Cord Degeneration in Friedreich's Ataxia: Results from ENIGMA-Ataxia
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Thiago J.R. Rezende, Isaac M. Adanyeguh, Filippo Arrigoni, Benjamin Bender, Fernando Cendes, Louise A. Corben, Andreas Deistung, Martin Delatycki, Imis Dogan, Gary F. Egan, Sophia L. Göricke, Nellie Georgiou‐Karistianis, Pierre‐Gilles Henry, Diane Hutter, Neda Jahanshad, James M. Joers, Christophe Lenglet, Tobias Lindig, Alberto R.M. Martinez, Andrea Martinuzzi, Gabriella Paparella, Denis Peruzzo, Kathrin Reetz, Sandro Romanzetti, Ludger Schöls, Jörg B. Schulz, Matthis Synofzik, Sophia I. Thomopoulos, Paul M. Thompson, Dagmar Timmann, Ian H. Harding, and Marcondes C. França
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Movement Disorders ,pathology [Friedreich Ataxia] ,Pyramidal Tracts ,Medizin ,Friedreich's ataxia ,spinal cord ,complications [Friedreich Ataxia] ,methods [Magnetic Resonance Imaging] ,Neurology ,Humans ,Ataxia ,ddc:610 ,Neurology (clinical) ,ENIGMA-ataxia ,MRI ,SCT - Abstract
Movement disorders 38(1), 45-56 (2023). doi:10.1002/mds.29261, Published by Wiley, New York, NY
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- 2022
92. A de novo STUB1 variant associated with an early adult-onset multisystemic ataxia phenotype
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Friedemann Bender, Tobias B. Haack, Alejandra Leyva-Gutiérrez, Stefan Hauser, Selina Reich, Matthis Synofzik, Andreas Traschütz, and David Mengel
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Adult ,0301 basic medicine ,Spastic gait ,Ataxia ,Cerebellar Ataxia ,Ubiquitin-Protein Ligases ,Early-onset ataxia ,Disease ,030105 genetics & heredity ,Biology ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,SCA48 ,medicine ,Humans ,Spinocerebellar Ataxias ,Dominant ,ddc:610 ,Index case ,Exome sequencing ,genetics [Ubiquitin-Protein Ligases] ,Genetics ,Sanger sequencing ,Original Communication ,CHIP ,genetics [Ataxia] ,medicine.disease ,Phenotype ,Pedigree ,Neurology ,symbols ,Neurology (clinical) ,medicine.symptom ,STUB1 ,Myoclonus ,030217 neurology & neurosurgery - Abstract
Background Biallelic STUB1 variants are a well-established cause of autosomal-recessive early-onset multisystemic ataxia (SCAR16). Evidence for STUB1 variants causing autosomal-dominant ataxia (SCA48) so far largely relies on segregation data in larger families. Presenting the first de novo occurrence of a heterozygous STUB1 variant, we here present additional qualitative evidence for STUB1-disease as an autosomal-dominant disorder. Methods Whole exome sequencing on an index patient with sporadic early-onset ataxia, followed by Sanger sequencing in all family members, was used to identify causative variants as well as to rule out alternative genetic hits and intronic STUB1 variants. STUB1 mRNA and protein levels in PBMCs in all family members were analysed using qRT-PCR and Western Blot. Results A previously unreported start-lost loss-of-function variant c.3G>A in the start codon of STUB1 was identified in the index case, occurring de novo and without evidence for a second (potentially missed) variant (e.g., intronic or copy number) in STUB1. The patient showed an early adult-onset multisystemic ataxia complicated by spastic gait disorder, distal myoclonus and cognitive dysfunction, thus closely mirroring the systems affected in autosomal-recessive STUB1-associated disease. In line with the predicted start-lost effect of the variant, functional investigations demonstrated markedly reduced STUB1 protein expression in PBMCs, whereas mRNA levels were intact. Conclusion De novo occurrence of the loss-of-function STUB1 variant in our case with multisystemic ataxia provides a qualitatively additional line of evidence for STUB1-disease as an autosomal-dominant disorder, in which the same neurological systems are affected as in its autosomal-recessive counterpart. Moreover, this finding adds support for loss-of-function as a mechanism underlying autosomal-dominant STUB1-disease, thus mirroring its autosomal-recessive counterpart also in terms of the underlying mutational mechanism.
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- 2021
93. Clinical and Molecular Findings of Autosomal Recessive Spastic Ataxia of Charlevoix Saguenay: an Iranian Case Series Expanding the Genetic and Neuroimaging Spectra
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Mahmoud Reza Ashrafi, Pouria Mohammadi, Ali Reza Tavasoli, Morteza Heidari, Sareh Hosseinpour, Maryam Rasulinejad, Mohammad Rohani, Masoud Ghahvechi Akbari, Reza Azizi Malamiri, Reza Shervin Badv, Davood Fathi, Ali Zare Dehnavi, Shahram Savad, Ali Rabbani, Matthis Synofzik, Nejat Mahdieh, and Zahra Rezaei
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Ataxia of Charlevoix Saguenay ,Neurology ,ARSACS ,Mutation ,Spastic ataxia ,ddc:610 ,Neurology (clinical) - Abstract
Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is now increasingly identified from all countries over the world, possibly rendering it one of the most common autosomal recessive ataxias. Here, we selected patients harboring SACS variants, the causative gene for ARSACS, in a large cohort of 137 patients with early-onset ataxia recruited from May 2019 to May 2021 and were referred to the ataxia clinic. Genetic studies were performed for 111 out of 137 patients (81%) which led to a diagnostic rate of 72.9% (81 out of 111 cases). Ten patients with the molecular diagnosis of ARSACS were identified. We investigated the phenotypic and imaging spectra of all confirmed patients with ARSACS. We also estimated the frequency of ARSACS in this cohort and described their clinical and genetic findings including seven novel variants as well as novel neuroimaging findings. While the classic clinical triad of ARSACS is progressive cerebellar ataxia, spasticity, and sensorimotor polyneuropathy, it is not a constant feature in all patients. Sensorimotor axonal-demyelinating neuropathy was detected in all of our patients, but spasticity and extensor plantar reflex were absent in 50% (5/10). In all patients, brain magnetic resonance imaging (MRI) showed symmetric linear hypointensities in the pons (pontine stripes) and anterior superior cerebellar atrophy as well as a hyperintense rim around the thalami (thalamic rim). Although infratentorial arachnoid cyst has been reported in ARSACS earlier, we report anterior temporal arachnoid cyst in two patients for the first time, indicating that arachnoid cyst may be an associated imaging feature of ARSACS. We also extended molecular spectrum of ARSACS by presenting 8 pathogenic and one variant of unknown significance (VUS) sequence variants, which 7 of them have not been reported previously. MetaDome server confirmed that the identified VUS variant was in the intolerant regions of sacsin protein encoded by SACS.
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- 2022
94. Spinal cord damage in Friedreich’s ataxia: Results from the ENIGMA-Ataxia
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Thiago JR Rezende, Isaac M Adanyeguh, Filippo Arrigoni, Benjamin Bender, Fernando Cendes, Louise A Corben, Andreas Deistung, Martin Delatycki, Imis Dogan, Gary F Egan, Sophia L Göricke, Nellie Georgiou-Karistianis, Pierre-Gilles Henry, Diane Hutter, Neda Jahanshad, James M Joers, Christophe Lenglet, Tobias Lindig, Alberto RM Martinez, Andrea Martinuzzi, Gabriella Paparella, Denis Peruzzo, Kathrin Reetz, Sandro Romanzetti, Ludger Schöls, Jörg B Schulz, Matthis Synofzik, Sophia I Thomopoulos, Paul M Thompson, Dagmar Timmann, Ian H Harding, and Marcondes C. França
- Abstract
ObjectiveSpinal cord damage is a hallmark of Friedreich ataxia (FRDA), but its progression and clinical correlates remain unclear. Here we performed a characterization of cervical spinal cord structural abnormalities in a large multisite FRDA cohort.MethodsWe performed a cross-sectional analysis of cervical spinal cord (C1 to C4) cross-sectional area (CSA) and eccentricity using MRI data from eight sites within the ENIGMA-Ataxia initiative, including 256 individuals with FRDA and 223 age- and sex-matched controls. Correlations and subgroup analyses within the FRDA cohort were undertaken based on disease duration, ataxia severity, and onset age.ResultsIndividuals with FRDA, relative to controls, had significantly reduced CSA at all examined levels, with large effect sizes (d>2.1) and significant correlations with disease severity (rd>1.2), but without significant clinical correlations. Subgroup analyses showed that CSA and eccentricity are abnormal at all disease stages. However, while CSA appears to decrease progressively, eccentricity remains stable over time.InterpretationPrevious research has shown that increased eccentricity reflects dorsal column (DC) damage, while decreased CSA reflects either DC or corticospinal tract (CST) damage or both. Hence, our data support the hypothesis that damage to DC and CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, whereas CST alterations may be both developmental and degenerative. These results provide new insights about FRDA pathogenesis and indicate that CSA of the cervical spinal cord should be investigated further as a potential biomarker of disease progression.
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- 2022
95. Tau and neurofilament light-chain as fluid biomarkers in spinocerebellar ataxia type 3
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Hector Garcia‐Moreno, Mercedes Prudencio, Gilbert Thomas‐Black, Nita Solanky, Karen R. Jansen‐West, Rana Hanna AL‐Shaikh, Amanda Heslegrave, Henrik Zetterberg, Magda M. Santana, Luis Pereira de Almeida, Ana Vasconcelos‐Ferreira, Cristina Januário, Jon Infante, Jennifer Faber, Thomas Klockgether, Kathrin Reetz, Mafalda Raposo, Ana F. Ferreira, Manuela Lima, Ludger Schöls, Matthis Synofzik, Jeannette Hübener‐Schmid, Andreas Puschmann, Sorina Gorcenco, Zbigniew K. Wszolek, Leonard Petrucelli, Paola Giunti, and Universidad de Cantabria
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blood [tau Proteins] ,Heterozygote ,blood [Neurofilament Proteins] ,Mice, Transgenic ,tau Proteins ,blood [Machado-Joseph Disease] ,Mice ,Neurofilament Proteins ,genetics [Machado-Joseph Disease] ,Cerebellum ,Animals ,Humans ,ddc:610 ,blood [Biomarkers] ,Neurofilaments ,Machado-Joseph Disease ,cerebrospinal fluid [Neurofilament Proteins] ,Neurofilaments, Tau ,Spinocerebellar ataxias ,genetics [tau Proteins] ,cerebrospinal fluid [Biomarkers] ,cerebrospinal fluid [tau Proteins] ,Neurology ,cerebrospinal fluid [Machado-Joseph Disease] ,Neurology (clinical) ,Tau ,Biomarkers ,chemistry [Cerebellum] - Abstract
Background and purpose: Clinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures. Methods: To evaluate total tau (t-tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCHL1) and neurofilament light-chain (NfL) as fluid biomarkers in SCA3, ATXN3 mutation carriers (n = 143) and controls (n = 172) were clinically assessed, and the plasma concentrations of the four proteins were analysed on the Simoa HD-1 platform. Eleven ATXN3 mutation carrier cerebrospinal fluid samples were analysed for t-tau and phosphorylated tau (p-tau181 ). A transgenic SCA3 mouse model (MJDTg) was used to measure cerebellar t-tau levels. Results: Plasma t-tau levels were higher in mutation carriers below the age of 50 compared to controls, and the Inventory of Non-Ataxia Signs was associated with t-tau in ataxic patients (p = 0.004). Pre-ataxic carriers showed higher cerebrospinal fluid t-tau and p-tau181 concentrations compared to ataxic patients (p = 0.025 and p = 0.014, respectively). Cerebellar t-tau was elevated in MJDTg mice compared to wild-type (p = 0.033) only in the early stages of the disease. GFAP and UCHL1 did not show higher levels in mutation carriers compared to controls. Plasma NfL concentrations were higher in mutation carriers compared to controls, and differences were greater for younger carriers. The Scale for the Assessment and Rating of Ataxia was the strongest predictor of NfL in ataxic patients (p < 0.001). Conclusion: Our results suggest that tau might be a marker of early disease stages in SCA3. NfL can discriminate mutation carriers from controls and is associated with different clinical variables. Longitudinal studies are required to confirm their potential role as biomarkers in clinical trials. Federal Ministry of Education and Research, Grant/Award Number: 01ED1602A/B; The Netherlands Organisation for Health Research and Development; Fundação para a Ciência e a Tecnologia (FCT); Medical Research Council, Grant/Award Number: MR/N028767/1; Department of Health’s National Institute for Health Research Biomedical Research Centre’s funding scheme; National Institute for Health Research University College London Hospitals Biomedical Research Centre UCLH; Swedish Research Council, Grant/Award Number: 2018-02532; European Research Council, Grant/Award Number: 681712; Swedish State Support for Clinical Research, Grant/Award Number: ALFGBG-720931; Alzheimer Drug Discovery Foundation (ADDF), Grant/Award Number: 201809-2016862; National Ataxia Foundation; Hertie Academy for Clinical Neuroscience; German Federal Ministry of Education and Research, Grant/Award Number: 01GQ1402 and 01DN18022; German Research Foundation, Grant/Award Number: IRTG 2150 and ZUK32/1; NIH/National Institute of Neurological Disorder and Stroke, Grant/Award Number: P01NS084974, R01NS088689, R35NS097273 and R21NS084528; Department of Defense, Grant/Award Number: ALSRP AL130125; Mayo Clinic Foundation; Amyotrophic Lateral Sclerosis Association; Robert Packard Center for ALS Research at Johns Hopkins; Target ALS Foundation; Mayo Clinic Center for Regenerative Medicine; Mayo Clinic Neuroscience Focused Research Team; Albertson Parkinson’s Research Foundation; European Union’s Horizon 2020 research and innovation programme, Grant/Award Number: 643417; CureSCA3; Regional Fund for Science and Technology (FRCT), PRO-SCIENTIA program, Azores Government; SCA-network, Sweden; Region Skåne, Sweden; Sol Goldman Charitable Trust; Donald G and Jodi P Heeringa Family; The Haworth Family Professorship in Neurodegenerative Diseases fund; Alzheimer Forschung Initiative e.V., Grant/Award Number: AFI13812 and NL-18002CB; Fundo Social Europeu (FSE); ALF, Sweden
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- 2022
96. Effects of Levodopa on quality of sleep and nocturnal movements in Parkinson’s Disease
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Walter Maetzler, Jan-Hinrich Busch, Laura Zaunbrecher, Thomas Vaterrodt, Susanne Nussbaum, Clint Hansen, Benjamin Roeben, Matthis Synofzik, Eva Schaeffer, Morad Elshehabi, Kirsten Emmert, Inga Liepelt-Scarfone, Sara Becker, and Daniela Berg
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Sleep Wake Disorders ,medicine.medical_specialty ,Levodopa ,Neurology ,Parkinson's disease ,Movement ,etiology [Sleep Wake Disorders] ,therapeutic use [Levodopa] ,Hypokinesia ,Disease ,Nocturnal ,050105 experimental psychology ,drug therapy [Sleep Wake Disorders] ,Antiparkinson Agents ,03 medical and health sciences ,0302 clinical medicine ,Physical medicine and rehabilitation ,medicine ,Humans ,0501 psychology and cognitive sciences ,ddc:610 ,therapeutic use [Antiparkinson Agents] ,pharmacology [Antiparkinson Agents] ,Original Communication ,business.industry ,05 social sciences ,Parkinson Disease ,medicine.disease ,Sleep in non-human animals ,drug therapy [Parkinson Disease] ,nervous system diseases ,Cohort ,sense organs ,Neurology (clinical) ,complications [Parkinson Disease] ,medicine.symptom ,Sleep ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Background Sleep disturbances are common in Parkinson’s Disease (PD), with nocturnal akinesia being one of the most burdensome. Levodopa is frequently used in clinical routine to improve nocturnal akinesia, although evidence is not well proven. Methods We assessed associations of Levodopa intake with quality of sleep and perception of nocturnal akinesia in three PD cohorts, using the Parkinson’s Disease Sleep Scale (PDSS-2) in two cohorts and a question on nocturnal immobility in one cohort. In one cohort also objective assessment of mobility during sleep was performed, using mobile health technology. Results In an independent analysis of all three cohorts (in total n = 1124 PD patients), patients taking Levodopa CR reported a significantly higher burden by nocturnal akinesia than patients without Levodopa. Higher Levodopa intake and MDS-UPDRS part IV scores (indicating motor fluctuations) predicted worse PDSS-2 and higher subjective nocturnal immobility scores, while disease duration and severity were not predictive. Levodopa intake was not associated with objectively changed mobility during sleep. Conclusion Our results showed an association of higher Levodopa intake with perception of worse quality of sleep and nocturnal immobility in PD, indicating that Levodopa alone might not be suitable to improve subjective feeling of nocturnal akinesia in PD. In contrast, Levodopa intake was not relevantly associated with objectively measured mobility during sleep. PD patients with motor fluctuations may be particularly affected by subjective perception of nocturnal mobility. This study should motivate further pathophysiological and clinical investigations on the cause of perception of immobility during sleep in PD.
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- 2021
97. Fluid biomarkers in frontotemporal dementia: past, present and future
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Matthis Synofzik, Jonathan D. Rohrer, Daniela Galimberti, Aitana Sogorb-Esteve, John C. van Swieten, Carolin Heller, Imogen Swift, Markus Otto, Henrik Zetterberg, Caroline Graff, Emily Todd, Emma L. van der Ende, Amanda Heslegrave, and Neurology
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blood [Frontotemporal Dementia] ,Neurofilament light ,CSF ,cerebrospinal fluid [Frontotemporal Dementia] ,Disease ,Proteomics ,frontotemporal dementia ,Diagnosis, Differential ,03 medical and health sciences ,diagnosis [Frontotemporal Dementia] ,0302 clinical medicine ,Neuroimaging ,SDG 3 - Good Health and Well-being ,mental disorders ,Medicine ,Humans ,ddc:610 ,030304 developmental biology ,0303 health sciences ,blood [Biomarkers] ,business.industry ,Neurodegeneration ,Omics ,medicine.disease ,Psychiatry and Mental health ,cerebrospinal fluid [Biomarkers] ,Frontotemporal Dementia ,Biomarker (medicine) ,Surgery ,Neurology (clinical) ,business ,Neuroscience ,030217 neurology & neurosurgery ,Biomarkers ,Frontotemporal dementia ,Forecasting - Abstract
The frontotemporal dementia (FTD) spectrum of neurodegenerative disorders includes a heterogeneous group of conditions. However, following on from a series of important molecular studies in the early 2000s, major advances have now been made in the understanding of the pathological and genetic underpinnings of the disease. In turn, alongside the development of novel methodologies for measuring proteins and other molecules in biological fluids, the last 10 years have seen a huge increase in biomarker studies within FTD. This recent past has focused on attempting to develop markers that will help differentiate FTD from other dementias (particularly Alzheimer’s disease (AD)), as well as from non-neurodegenerative conditions such as primary psychiatric disorders. While cerebrospinal fluid, and more recently blood, markers of AD have been successfully developed, specific markers identifying primary tauopathies or TDP-43 proteinopathies are still lacking. More focus at the moment has been on non-specific markers of neurodegeneration, and in particular, multiple studies of neurofilament light chain have highlighted its importance as a diagnostic, prognostic and staging marker of FTD. As clinical trials get under way in specific genetic forms of FTD, measures of progranulin and dipeptide repeat proteins in biofluids have become important potential measures of therapeutic response. However, understanding of whether drugs restore cellular function will also be important, and studies of key pathophysiological processes, including neuroinflammation, lysosomal function and synaptic health, are also now becoming more common. There is much still to learn in the fluid biomarker field in FTD, but the creation of large multinational cohorts is facilitating better powered studies and will pave the way for larger omics studies, including proteomics, metabolomics and lipidomics, as well as investigations of multimodal biomarker combinations across fluids, brain imaging and other domains. Here we provide an overview of the past, present and future of fluid biomarkers within the FTD field.
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- 2021
98. Apathy in presymptomatic genetic frontotemporal dementia predicts cognitive decline and is driven by structural brain changes
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Matthis Synofzik, Alexandre de Mendonça, Giovanni B. Frisoni, Maura Malpetti, Fermin Moreno, Christopher C Butler, Roberta Ghidoni, Daniela Galimberti, Rik Vandenberghe, Elizabeth Finger, Isabel Santana, Alexander Gerhard, Georgia Peakman, Emily Todd, Carolin Heller, Jonathan D. Rohrer, Katrina M. Moore, Kamen A. Tsvetanov, Rhian S Convery, P. Simon Jones, Johannes Levin, James B. Rowe, Caroline Graff, Markus Otto, Barbara Borroni, Raquel Sánchez-Valle, Sandro Sorbi, Fabrizio Tagliavini, John C. van Swieten, Maria Carmela Tartaglia, Rogier A. Kievit, Simon Ducharme, Robert Laforce, Mario Masellis, Timothy Rittman, Adrian Danek, David M. Cash, Martina Bocchetta, Apollo - University of Cambridge Repository, Repositório da Universidade de Lisboa, Neurology, Malpetti, Maura [0000-0001-8923-9656], Jones, Simon [0000-0001-9695-0702], Tsvetanov, Kamen A. [0000-0002-3178-6363], Rittman, Timothy [0000-0003-1063-6937], and Rowe, James [0000-0001-7216-8679]
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Male ,longitudinal design ,SYMPTOMS ,pathology [Cognitive Dysfunction] ,Epidemiology ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,Medizin ,apathy ,DISEASE ,0302 clinical medicine ,pathology [Brain] ,pathology [Gray Matter] ,C9orf72 ,presymptomatic carriers ,cognitive decline ,genetic frontotemporal dementia ,MRI ,Apathy ,Gray Matter ,Cognitive decline ,genetics [Frontotemporal Dementia] ,pathology [Atrophy] ,0303 health sciences ,Health Policy ,Brain ,Cognition ,IMPAIRMENT ,Middle Aged ,DEPRESSION ,Magnetic Resonance Imaging ,Psychiatry and Mental health ,Frontotemporal Dementia ,Female ,IMPULSIVITY ,medicine.symptom ,Life Sciences & Biomedicine ,Clinical psychology ,Frontotemporal dementia ,Clinical Neurology ,FEATURED ARTICLE ,Prodromal Symptoms ,PHENOTYPES ,genetics [Mutation] ,Impulsivity ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,All institutes and research themes of the Radboud University Medical Center ,Atrophy ,SDG 3 - Good Health and Well-being ,Developmental Neuroscience ,mental disorders ,medicine ,Humans ,Dementia ,Cognitive Dysfunction ,ddc:610 ,BEHAVIORAL-VARIANT ,030304 developmental biology ,Science & Technology ,EXECUTIVE FUNCTION ,business.industry ,DIGIT SYMBOL ,1103 Clinical Sciences ,medicine.disease ,DYSFUNCTION ,Geriatrics ,Mutation ,FEATURED ARTICLES ,Neurosciences & Neurology ,Neurology (clinical) ,Geriatrics and Gerontology ,1109 Neurosciences ,business ,030217 neurology & neurosurgery - Abstract
© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited., Introduction: Apathy adversely affects prognosis and survival of patients with frontotemporal dementia (FTD). We test whether apathy develops in presymptomatic genetic FTD, and is associated with cognitive decline and brain atrophy. Methods: Presymptomatic carriers of MAPT, GRN or C9orf72 mutations (N = 304), and relatives without mutations (N = 296) underwent clinical assessments and MRI at baseline, and annually for 2 years. Longitudinal changes in apathy, cognition, gray matter volumes, and their relationships were analyzed with latent growth curve modeling. Results: Apathy severity increased over time in presymptomatic carriers, but not in non-carriers. In presymptomatic carriers, baseline apathy predicted cognitive decline over two years, but not vice versa. Apathy progression was associated with baseline low gray matter volume in frontal and cingulate regions. Discussion: Apathy is an early marker of FTD-related changes and predicts a subsequent subclinical deterioration of cognition before dementia onset. Apathy may be a modifiable factor in those at risk of FTD., This work is co‐funded by the UK Medical Research Council (MR/M023664/1), the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, a Canadian Institutes of Health Research operating grant and the Bluefield Project, as well as a JPND grant “GENFI‐prox” (by DLR/BMBF to MS, joined with JDR, JvS, MO, BB and CG). MM is supported by the Cambridge Trust & Sidney Sussex College Scholarship. PSJ is supported by the Cambridge Centre for Parkinson Plus. KAT is supported by the British Academy Postdoctoral Fellowship (KAT: PF160048) and Guarantors of Brain (KAT: 101149). TR is supported by the Cambridge Centre for Parkinson Plus and Cambridge Biomedical Resource Centre. RAK is supported by Medical Research Council (RAK: SUAG/047/G101400). JBR reports grants from the NIHR Cambridge Biomedical research centre, Wellcome Trust (103838), and Medical Research Council (SUAG051/G101400; MR/T033371/1); personal fees from Asceneuron, WAVE, Astex, and Biogen; and grants from Janssen, AZ Medimmune, and Eli Lilly, outside the submitted work. JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). MB is supported by a Fellowship award from the Alzheimer's Society, UK (AS‐JF‐19a‐004‐517), and by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society, and Alzheimer's Research UK.
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- 2020
99. Fampridine and Acetazolamide in EA2 and Related Familial EA
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Carolin Muth, Julian Teufel, Ludger Schöls, Ulrich Mansmann, Michael Strupp, Christiana Franke, Dagmar Timmann, and Matthis Synofzik
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business.industry ,Research ,Placebo-controlled study ,Placebo ,Crossover study ,Anesthesia ,Clinical endpoint ,Medicine ,In patient ,ddc:610 ,Neurology (clinical) ,Family history ,Adverse effect ,business ,Acetazolamide ,medicine.drug - Abstract
ObjectiveTo determine the efficacy and safety of the treatment with prolonged-release 4-aminopyridine (fampridine) and acetazolamide for patients with episodic ataxia type 2 (EA2), patients with EA2 were treated with a random sequence of fampridine, acetazolamide, and placebo in a 3-period crossover trial.MethodsA total of 30 patients with EA2 (8 female; aged 20–71 years; 18 genetically confirmed, 4 with a positive family history, 8 with the clinical diagnosis) were enrolled in this phase III, randomized, double-blind, placebo-controlled, 3-period crossover trial. Each period lasted 12 weeks with a 4-week washout period. Each patient received a random sequence of 20 mg/d fampridine, 750 mg/d acetazolamide, and placebo. The primary end point was the number of attacks during the last 30 days within the 12-week treatment period. Participants, caregivers, and those assessing the outcomes were blinded to the intervention.ResultsCompared with placebo, fampridine reduced the number of attacks to 63% (95% CI 54%–74%) and acetazolamide to 52% (95% CI 46%–60%). A total of 39 (26.5%) adverse events were observed under treatment with fampridine (mostly tingling paresthesia and fatigue), 66 (44.9%) happened under acetazolamide (mostly taste disturbance and gastrointestinal complaints), and 42 (28.6%) under placebo (mostly gastrointestinal complaints).ConclusionBoth fampridine and acetazolamide significantly reduce the number of attacks in patients with EA2 and related EA in comparison to placebo. Fampridine 10 mg twice daily had fewer side effects than acetazolamide 250 mg 3 times daily. The trial was registered with DRKS.de (DRKS00005258) and EudraCT (2013-000107-17). This study was supported by the Federal Ministry of Education and Research (BMBF) (grant number 01EO0901). Fampridine (study medication) was provided by Biogen Idec.Classification of EvidenceClass II evidence.
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- 2020
100. Soluble TAM receptors sAXL and sTyro3 predict structural and functional protection in Alzheimer's disease
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Frederic Brosseron, Anne Maass, Luca Kleineidam, Kishore Aravind Ravichandran, Pablo García González, Róisín M. McManus, Christina Ising, Francesco Santarelli, Carl-Christian Kolbe, Lisa M. Häsler, Steffen Wolfsgruber, Marta Marquié, Mercè Boada, Adelina Orellana, Itziar de Rojas, Sandra Röske, Oliver Peters, Nicoleta-Carmen Cosma, Arda Cetindag, Xiao Wang, Josef Priller, Eike J. Spruth, Slawek Altenstein, Anja Schneider, Klaus Fliessbach, Jens Wiltfang, Björn H. Schott, Katharina Bürger, Daniel Janowitz, Martin Dichgans, Robert Perneczky, Boris-Stephan Rauchmann, Stefan Teipel, Ingo Kilimann, Doreen Goerss, Christoph Laske, Matthias H. Munk, Emrah Düzel, Renat Yakupov, Laura Dobisch, Coraline D. Metzger, Wenzel Glanz, Michael Ewers, Peter Dechent, John Dylan Haynes, Klaus Scheffler, Nina Roy, Ayda Rostamzadeh, Charlotte E. Teunissen, Natalie L. Marchant, Annika Spottke, Mathias Jucker, Eicke Latz, Michael Wagner, David Mengel, Matthis Synofzik, Frank Jessen, Alfredo Ramirez, Agustín Ruiz, Michael T. Heneka, Clinical chemistry, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Amsterdam Neuroscience
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Inflammation ,metabolism [Inflammation] ,Amyloid beta-Peptides ,General Neuroscience ,TAM receptor ,tau Proteins ,Alzheimer's disease ,neuroinflammation ,Cohort Studies ,cerebrospinal fluid [Biomarkers] ,cerebrospinal fluid [tau Proteins] ,Alzheimer Disease ,biomarker ,Humans ,Cognitive Dysfunction ,ddc:610 ,metabolism [Alzheimer Disease] ,Biomarkers - Abstract
There is an urgent need to improve the understanding of neuroinflammation in Alzheimer's disease (AD). We analyzed cerebrospinal fluid inflammatory biomarker correlations to brain structural volume and longitudinal cognitive outcomes in the DELCODE study and in a validation cohort of the F.ACE Alzheimer Center Barcelona. We investigated whether respective biomarker changes are evident before onset of cognitive impairment. YKL-40; sTREM2; sAXL; sTyro3; MIF; complement factors C1q, C4, and H; ferritin; and ApoE protein were elevated in pre-dementia subjects with pathological levels of tau or other neurodegeneration markers, demonstrating tight interactions between inflammation and accumulating neurodegeneration even before onset of symptoms. Intriguingly, higher levels of ApoE and soluble TAM receptors sAXL and sTyro3 were related to larger brain structure and stable cognitive outcome at follow-up. Our findings indicate a protective mechanism relevant for intervention strategies aiming to regulate neuroinflammation in subjects with no or subjective symptoms but underlying AD pathology profile.
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- 2022
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