Publications by authors named "Matthis Synofzik"

257 Publications

Stratifying the presymptomatic phase of genetic frontotemporal dementia by serum NfL and pNfH: a longitudinal multicentre study.

Ann Neurol 2021 Nov 7. Epub 2021 Nov 7.

Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Switzerland.

Objective: While the presymptomatic stages of frontotemporal dementia (FTD) provide a unique chance to delay or even prevent neurodegeneration by early intervention, they remain poorly defined. Leveraging a large multicentre cohort of genetic FTD mutation carriers, we provide a biomarker-based stratification and biomarker cascade of the likely most treatment-relevant stage within the presymptomatic phase: the conversion stage.

Methods: We longitudinally assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in the GENFI cohort (n = 444), using single-molecule array technique. Subjects comprised 91 symptomatic and 179 presymptomatic subjects with mutations in the FTD genes C9orf72, GRN or MAPT, and 174 mutation-negative within-family controls.

Results: In a biomarker cascade, NfL increase preceded the hypothetical clinical onset by 15 years and concurred with brain atrophy onset, while pNfH increase started close to clinical onset. The conversion stage was marked by increased NfL, but still normal pNfH levels, while both were increased at the symptomatic stage. Intra-individual change rates were increased for NfL at the conversion stage and for pNfH at the symptomatic stage, highlighting their respective potential as stage-dependent dynamic biomarkers within the biomarker cascade. Increased NfL levels and NfL change rates allowed identification of presymptomatic subjects converting to symptomatic disease and capture of proximity-to-onset. We estimate stage-dependent sample sizes for trials aiming to decrease neurofilament levels or change rates.

Interpretation: Blood NfL and pNfH provide dynamic stage-dependent stratification and, potentially, treatment response biomarkers in presymptomatic FTD, allowing demarcation of the conversion stage. The proposed biomarker cascade might pave the way towards a biomarker-based precision medicine approach to genetic FTD. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ana.26265DOI Listing
November 2021

Effects of exergaming on hippocampal volume and brain-derived neurotrophic factor levels in Parkinson's disease.

Eur J Neurol 2021 Nov 1. Epub 2021 Nov 1.

Department of Neurology, Christian-Albrecht-University Kiel, Kiel, Germany.

Background And Objective: Cognitive impairment is among the most burdensome non-motor symptoms in Parkinson's disease (PD) and has been associated with hippocampal atrophy. Exercise has been reported to enhance neuroplasticity in the hippocampus in correlation with an improvement of cognitive function. We present data from the Training-PD study, which was designed to evaluate effects of an "" training protocol on neuronal plasticity in PD.

Methods: We initiated a 6-week exergaming training program, combining visually stimulating computer games with physical exercise in 17 PD patients and 18 matched healthy controls. Volumetric segmentation of hippocampal subfields on T1- and T2-weighted magnetic resonance imaging and brain-derived neurotrophic factor (BDNF) serum levels were analyzed before and after the training protocol.

Results: The PD group showed a group-dependent significant volume increase of the left hippocampal subfields CA1, CA4/dentate gyrus (DG) and subiculum after the 6-week training protocol. The effect was most pronounced in the left DG of PD patients, who showed a significantly smaller percentage volume compared to healthy controls at baseline, but not at follow-up. Both groups had a significant increase in serum BDNF levels after training.

Conclusions: The results of the present study indicate that exergaming might be a suitable approach to induce hippocampal volume changes in PD patients. Further and larger studies are needed to verify our findings.
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http://dx.doi.org/10.1111/ene.15165DOI Listing
November 2021

Characterization of Lifestyle in Spinocerebellar Ataxia Type 3 and Association with Disease Severity.

Mov Disord 2021 Oct 29. Epub 2021 Oct 29.

Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

Background: Lifestyle could influence the course of hereditary ataxias, but representative data are missing.

Objective: The objective of this study was to characterize lifestyle in spinocerebellar ataxia type 3 (SCA3) and investigate possible associations with disease parameters.

Methods: In a prospective cohort study, data on smoking, alcohol consumption, physical activity, physiotherapy, and body mass index (BMI) were collected from 243 patients with SCA3 and 119 controls and tested for associations with age of onset, disease severity, and progression.

Results: Compared with controls, patients with SCA3 were less active and consumed less alcohol. Less physical activity and alcohol abstinence were associated with more severe disease, but not with progression rates or age of onset. Smoking, BMI, or physiotherapy did not correlate with disease parameters.

Conclusion: Differences in lifestyle factors of patients with SCA3 and controls as well as associations of lifestyle factors with disease severity are likely driven by the influence of symptoms on behavior. No association between lifestyle and disease progression was detected. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28844DOI Listing
October 2021

Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone .

Front Cell Dev Biol 2021 6;9:710247. Epub 2021 Oct 6.

Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Dortmund, Germany.

Recessive mutations in , an endoplasmic reticulum (ER)-resident BiP co-chaperone, have been identified in patients with multisystemic neurodegeneration and diabetes mellitus. To further unravel these pathomechanisms, we employed a non-biased proteomic approach and identified dysregulation of several key cellular pathways, suggesting a pathophysiological interplay of perturbed lipid metabolism, mitochondrial bioenergetics, ER-Golgi function, and amyloid-beta processing. Further functional investigations in fibroblasts of patients with mutations detected cellular accumulation of lipids and an increased sensitivity to cholesterol stress, which led to activation of the unfolded protein response (UPR), alterations of the ER-Golgi machinery, and a defect of amyloid precursor protein. In line with the results of previous studies, we describe here alterations in mitochondrial morphology and function, as a major contributor to the pathophysiology. Hence, we propose that the loss of affects lipid/cholesterol homeostasis, leading to UPR activation, β-amyloid accumulation, and impairment of mitochondrial oxidative phosphorylation.
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http://dx.doi.org/10.3389/fcell.2021.710247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8526738PMC
October 2021

A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia.

Brain 2021 Oct 11. Epub 2021 Oct 11.

Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, OX3 9DU Oxford, UK.

Several CSF and blood biomarkers for genetic frontotemporal dementia (FTD) have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH)), synapse dysfunction (neuronal pentraxin 2 (NPTX2)), astrogliosis (glial fibrillary acidic protein (GFAP)), 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 FTD, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic FTD using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. 275 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-initialised DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on prior 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 NfL, blood pNfH, blood GFAP, 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 (AUC) of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The AUC to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic FTD revealed that NPTX2 and NfL 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.
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http://dx.doi.org/10.1093/brain/awab382DOI Listing
October 2021

Dissemination in time and space in presymptomatic granulin mutation carriers: a GENFI spatial chronnectome study.

Neurobiol Aging 2021 Dec 8;108:155-167. Epub 2021 Sep 8.

Nueld Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK.

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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http://dx.doi.org/10.1016/j.neurobiolaging.2021.09.001DOI Listing
December 2021

Preparing n-of-1 Antisense Oligonucleotide Treatments for Rare Neurological Diseases in Europe: Genetic, Regulatory, and Ethical Perspectives.

Nucleic Acid Ther 2021 Sep 29. Epub 2021 Sep 29.

Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.

Antisense oligonucleotide (ASO) therapies present a promising disease-modifying treatment approach for rare neurological diseases (RNDs). However, the current focus is on "more common" RNDs, leaving a large share of RND patients still without prospect of disease-modifying treatments. In response to this gap, n-of-1 ASO treatment approaches are targeting ultrarare or even private variants. While highly attractive, this emerging, academia-driven field of ultimately individualized precision medicine is in need of systematic guidance and standards, which will allow global scaling of this approach. We provide here genetic, regulatory, and ethical perspectives for preparing n-of-1 ASO treatments and research programs, with a specific focus on the European context. By example of splice modulating ASOs, we outline genetic criteria for variant prioritization, chart the regulatory field of n-of-1 ASO treatment development in Europe, and propose an ethically informed classification for n-of-1 ASO treatment strategies and level of outcome assessments. To accommodate the ethical requirements of both individual patient benefit and knowledge gain, we propose a stronger integration of patient care and clinical research when developing novel n-of-1 ASO treatments: each single trial of therapy should inherently be driven to generate generalizable knowledge, be registered in a ASO treatment registry, and include assessment of generic outcomes, which allow aggregated analysis across n-of-1 trials of therapy.
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http://dx.doi.org/10.1089/nat.2021.0039DOI Listing
September 2021

Fampridine and Acetazolamide in EA2 and Related Familial EA: A Prospective Randomized Placebo-Controlled Trial.

Neurol Clin Pract 2021 Aug;11(4):e438-e446

Department of Neurology and German Center for Vertigo and Balance Disorders (DSGZ) (CM, JT, M. Strupp), Ludwig Maximilians University, Munich, LMU University Hospital, Campus Grosshadern; Department of Neurology and Hertie-Institute for Clinical Brain Research (LS, M. Synofzik), Eberhard Karls University and German Center for Neurodegenerative Diseases (DZNE), Tübingen; Department of Neurology (CF), Charité-Universitätsmedizin Berlin, Berlin, Germany, Formerly Department of Neurology, University of Dresden; Department of Neurology (DT), Essen University Hospital, University of Duisburg-Essen; and Department of Medical Information Sciences (UM), Biometry, and Epidemiology (IBE), Ludwig Maximilian University, Munich, Germany.

Objective: To 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.

Methods: A 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.

Results: Compared 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).

Conclusion: Both 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 Evidence: Class II evidence.
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http://dx.doi.org/10.1212/CPJ.0000000000001017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382428PMC
August 2021

Polyglutamine-Expanded Ataxin-3: A Target Engagement Marker for Spinocerebellar Ataxia Type 3 in Peripheral Blood.

Mov Disord 2021 Nov 16;36(11):2675-2681. Epub 2021 Aug 16.

Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

Background: Spinocerebellar ataxia type 3 is a rare neurodegenerative disease caused by a CAG repeat expansion in the ataxin-3 gene. Although no curative therapy is yet available, preclinical gene-silencing approaches to reduce polyglutamine (polyQ) toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are of critical importance as pharmacodynamic and particularly as target engagement markers.

Objective: We aimed at developing an ultrasensitive immunoassay to measure specifically polyQ-expanded ataxin-3 in plasma and cerebrospinal fluid (CSF).

Methods: Using the novel single molecule counting ataxin-3 immunoassay, we analyzed cross-sectional and longitudinal patient biomaterials.

Results: Statistical analyses revealed a correlation with clinical parameters and a stability of polyQ-expanded ataxin-3 during conversion from the pre-ataxic to the ataxic phases.

Conclusions: The novel immunoassay is able to quantify polyQ-expanded ataxin-3 in plasma and CSF, whereas ataxin-3 levels in plasma correlate with disease severity. Longitudinal analyses demonstrated a high stability of polyQ-expanded ataxin-3 over a short period. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28749DOI Listing
November 2021

Comparison of clinical rating scales in genetic frontotemporal dementia within the GENFI cohort.

J Neurol Neurosurg Psychiatry 2021 Aug 5. Epub 2021 Aug 5.

Department of Neurofarba, University of Florence, Firenze, Italy.

Background: Therapeutic trials are now underway in genetic forms of frontotemporal dementia (FTD) but clinical outcome measures are limited. The two most commonly used measures, the Clinical Dementia Rating (CDR)+National Alzheimer's Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) and the FTD Rating Scale (FRS), have yet to be compared in detail in the genetic forms of FTD.

Methods: The CDR+NACC FTLD and FRS were assessed cross-sectionally in 725 consecutively recruited participants from the Genetic FTD Initiative: 457 mutation carriers (77 microtubule-associated protein tau (, 187 , 193 ) and 268 family members without mutations (non-carrier control group). 231 mutation carriers (51 92 88 ) and 145 non-carriers had available longitudinal data at a follow-up time point.

Results: Cross-sectionally, the mean FRS score was lower in all genetic groups compared with controls: mutation carriers mean 83.4 (SD 27.0), mutation carriers 78.2 (28.8), mutation carriers 71.0 (34.0), controls 96.2 (7.7), p<0.001 for all comparisons, while the mean CDR+NACC FTLD Sum of Boxes was significantly higher in all genetic groups: mutation carriers mean 2.6 (5.2), mutation carriers 3.2 (5.6), mutation carriers 4.2 (6.2), controls 0.2 (0.6), p<0.001 for all comparisons. Mean FRS score decreased and CDR+NACC FTLD Sum of Boxes increased with increasing disease severity within each individual genetic group. FRS and CDR+NACC FTLD Sum of Boxes scores were strongly negatively correlated across all mutation carriers (r=-0.77, p<0.001) and within each genetic group (r=-0.67 to -0.81, p<0.001 in each group). Nonetheless, discrepancies in disease staging were seen between the scales, and with each scale and clinician-judged symptomatic status. Longitudinally, annualised change in both FRS and CDR+NACC FTLD Sum of Boxes scores initially increased with disease severity level before decreasing in those with the most severe disease: controls -0.1 (6.0) for FRS, -0.1 (0.4) for CDR+NACC FTLD Sum of Boxes, asymptomatic mutation carriers -0.5 (8.2), 0.2 (0.9), prodromal disease -2.3 (9.9), 0.6 (2.7), mild disease -10.2 (18.6), 3.0 (4.1), moderate disease -9.6 (16.6), 4.4 (4.0), severe disease -2.7 (8.3), 1.7 (3.3). Sample sizes were calculated for a trial of prodromal mutation carriers: over 180 participants per arm would be needed to detect a moderate sized effect (30%) for both outcome measures, with sample sizes lower for the FRS.

Conclusions: Both the FRS and CDR+NACC FTLD measure disease severity in genetic FTD mutation carriers throughout the timeline of their disease, although the FRS may be preferable as an outcome measure. However, neither address a number of key symptoms in the FTD spectrum, for example, motor and neuropsychiatric deficits, which future scales will need to incorporate.
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http://dx.doi.org/10.1136/jnnp-2021-326868DOI Listing
August 2021

Natural History of Polymerase Gamma-Related Ataxia.

Mov Disord 2021 Nov 20;36(11):2642-2652. Epub 2021 Jul 20.

Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research & Center of Neurology, University of Tuebingen, Tuebingen, Germany.

Background: Mutations in the mitochondrial DNA polymerase gamma are causing a wide phenotypic spectrum including ataxia as one of the most common presentations.

Objective: The objective of this study was to determine the course of disease of polymerase gamma-related ataxia.

Methods: In a prospective natural history study, we assessed 24 adult ataxia patients with biallelic polymerase gamma mutations for (1) severity of cerebellar dysfunction using the Scale for the Assessment and Rating of Ataxia score, (2) presence of nonataxia signs using the Inventory of Non-Ataxia Symptoms, (3) gray- and white-matter changes in brain MRI, and (4) findings in nerve conduction studies.

Results: Assessment included follow-up visits up to 11.6 years. The Scale for the Assessment and Rating of Ataxia showed a mean annual increase of 1.02 ± 0.78 points/year. Disease progression was faster in patients with age at onset ≤ 30 years (1.5 Scale for the Assessment and Rating of Ataxia points/year) than with later onset (0.5 points/year); P = 0.008. The Inventory of Non-Ataxia Symptoms count increased by 0.30 ± 0.4 points/year. External ophthalmoplegia, brain stem oculomotor signs, areflexia, and sensory deficits were the most common nonataxic features. On MRI cerebellar atrophy was mild. T2 signal alterations affected mostly cerebellar white matter, middle cerebellar peduncles, thalamus, brain stem, and occipital and frontal white matter. Within 4 years, progression was primarily observed in the context of repeated epileptic seizures. Nerve conduction studies revealed axonal sensory peripheral neuropathy with mild motor nerve involvement. Exploratory sample size calculation implied 38 patients per arm as sufficient to detect a reduction of progression by 50% in hypothetical interventions within a 1-year trial.

Conclusion: The results recommend the Scale for the Assessment and Rating of Ataxia as a primary outcome measure for future interventional trials in polymerase gamma-related ataxia. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28713DOI Listing
November 2021

The Revised Self-Monitoring Scale detects early impairment of social cognition in genetic frontotemporal dementia within the GENFI cohort.

Alzheimers Res Ther 2021 07 12;13(1):127. Epub 2021 Jul 12.

Department of Neurology, Ludwig-Maximilians Universität München, Munich, Germany.

Background: Although social cognitive dysfunction is a major feature of frontotemporal dementia (FTD), it has been poorly studied in familial forms. A key goal of studies is to detect early cognitive impairment using validated measures in large patient cohorts.

Methods: We used the Revised Self-Monitoring Scale (RSMS) as a measure of socioemotional sensitivity in 730 participants from the genetic FTD initiative (GENFI) observational study: 269 mutation-negative healthy controls, 193 C9orf72 expansion carriers, 193 GRN mutation carriers and 75 MAPT mutation carriers. All participants underwent the standardised GENFI clinical assessment including the 'CDR® plus NACC FTLD' scale and RSMS. The RSMS total score and its two subscores, socioemotional expressiveness (EX score) and modification of self-presentation (SP score) were measured. Volumetric T1-weighted magnetic resonance imaging was available from 377 mutation carriers for voxel-based morphometry (VBM) analysis.

Results: The RSMS was decreased in symptomatic mutation carriers in all genetic groups but at a prodromal stage only in the C9orf72 (for the total score and both subscores) and GRN (for the modification of self-presentation subscore) groups. RSMS score correlated with disease severity in all groups. The VBM analysis implicated an overlapping network of regions including the orbitofrontal cortex, insula, temporal pole, medial temporal lobe and striatum.

Conclusions: The RSMS indexes socioemotional impairment at an early stage of genetic FTD and may be a suitable outcome measure in forthcoming trials.
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http://dx.doi.org/10.1186/s13195-021-00865-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276486PMC
July 2021

The ARCA Registry: A Collaborative Global Platform for Advancing Trial Readiness in Autosomal Recessive Cerebellar Ataxias.

Front Neurol 2021 25;12:677551. Epub 2021 Jun 25.

Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Autosomal recessive cerebellar ataxias (ARCAs) form an ultrarare yet expanding group of neurodegenerative multisystemic diseases affecting the cerebellum and other neurological or non-neurological systems. With the advent of targeted therapies for ARCAs, disease registries have become a precious source of real-world quantitative and qualitative data complementing knowledge from preclinical studies and clinical trials. Here, we review the , a global collaborative multicenter platform (>15 countries, >30 sites) with the overarching goal to advance trial readiness in ARCAs. It presents a good clinical practice (GCP)- and general data protection regulation (GDPR)-compliant professional-reported registry for multicenter web-based capture of cross-center standardized longitudinal data. Modular electronic case report forms (eCRFs) with core, extended, and optional datasets allow data capture tailored to the participating site's variable interests and resources. The eCRFs cover all key data elements required by regulatory authorities [European Medicines Agency (EMA)] and the European Rare Disease (ERD) platform. They capture genotype, phenotype, and progression and include demographic data, biomarkers, comorbidity, medication, magnetic resonance imaging (MRI), and longitudinal clinician- or patient-reported ratings of ataxia severity, non-ataxia features, disease stage, activities of daily living, and (mental) health status. Moreover, they are aligned to major autosomal-dominant spinocerebellar ataxia (SCA) and sporadic ataxia (SPORTAX) registries in the field, thus allowing for joint and comparative analyses not only across ARCAs but also with SCAs and sporadic ataxias. The registry is at the core of a systematic multi-component ARCA database cluster with a linked biobank and an evolving study database for digital outcome measures. Currently, the registry contains more than 800 patients with almost 1,500 visits representing all ages and disease stages; 65% of patients with established genetic diagnoses capture all the main ARCA genes, and 35% with unsolved diagnoses are targets for advanced next-generation sequencing. The ARCA Registry serves as the backbone of many major European and transatlantic consortia, such as PREPARE, PROSPAX, and the Ataxia Global Initiative, with additional data input from SPORTAX. It has thus become the largest global trial-readiness registry in the ARCA field.
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http://dx.doi.org/10.3389/fneur.2021.677551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267795PMC
June 2021

Developmental Consequences of Defective ATG7-Mediated Autophagy in Humans.

N Engl J Med 2021 06;384(25):2406-2417

From the Wellcome Centre for Mitochondrial Research, (J.J.C., M.O., N.M.-L., A.M.S., A.P., R.M., R.W.T.), the Translational and Clinical Research Institute (J.J.C, M.O., T.M.P., A.M.S., A.P., R.M., R.W.T.), and the NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children (A.M.S., R.M., R.W.T.), Newcastle University, Newcastle Upon Tyne, and the Institute of Child Health, Department of Molecular Neuroscience, University College London Institute of Neurology (D.Z., M.R.), the Division of Genetics and Molecular Medicine, Guy's Hospital, King's College London School of Medicine (I.A.B.), and the Clinical Genetics Unit, Guy's and St. Thomas' NHS Foundation Trust (C.D.), London - all in the United Kingdom; Institut Universitaire de Recherche Clinique and Laboratoire de Génétique Moléculaire, University of Montpellier and Centre Hospitalier Universitaire (CHU) de Montpellier (C.G., S.S., L.L., M.K.), Departments of Neuroradiology (N.L.) and Pediatric Neurology (P.M., F.R.) and Reference Center for Neuromuscular Diseases Atlantic-Occitania-Caribbean (AOC) (P.M., F.R.), CHU de Montpellier, and Laboratoire de Physiologie et Médecine Expérimentale du Cœur et des Muscles (PhyMedExp), INSERM, CNRS, University of Montpellier (P.M., F.R.), Montpellier, and the Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, Alternative Energies and Atomic Energy Commission (CEA), CNRS Gif-sur-Yvette (F.P.-P., A.D.) - all in France; the Translational Stem Cell Biology and Metabolism Program, Research Programs Unit, and the Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki (F.S., T.G.M.); Radiation Oncology, Albert Einstein College of Medicine, New York (N.M.-L.); the Institute of Medical Genetics, University of Zurich, Zurich, Switzerland (A.B., S.A.-B., A.R.); Hertie Institute for Clinical Brain Research and Center of Neurology, and the German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany (S.R., L.S., M.S.); the Departments of Genetics (H.S.A., F.S.A.) and Neuroscience (S.A.), King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; and the Dr. John T. Macdonald Foundation, Department of Human Genetics, and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami (S.Z.).

Background: Autophagy is the major intracellular degradation route in mammalian cells. Systemic ablation of core autophagy-related () genes in mice leads to embryonic or perinatal lethality, and conditional models show neurodegeneration. Impaired autophagy has been associated with a range of complex human diseases, yet congenital autophagy disorders are rare.

Methods: We performed a genetic, clinical, and neuroimaging analysis involving five families. Mechanistic investigations were conducted with the use of patient-derived fibroblasts, skeletal muscle-biopsy specimens, mouse embryonic fibroblasts, and yeast.

Results: We found deleterious, recessive variants in human , a core autophagy-related gene encoding a protein that is indispensable to classical degradative autophagy. Twelve patients from five families with distinct variants had complex neurodevelopmental disorders with brain, muscle, and endocrine involvement. Patients had abnormalities of the cerebellum and corpus callosum and various degrees of facial dysmorphism. These patients have survived with impaired autophagic flux arising from a diminishment or absence of ATG7 protein. Although autophagic sequestration was markedly reduced, evidence of basal autophagy was readily identified in fibroblasts and skeletal muscle with loss of ATG7. Complementation of different model systems by deleterious variants resulted in poor or absent autophagic function as compared with the reintroduction of wild-type .

Conclusions: We identified several patients with a neurodevelopmental disorder who have survived with a severe loss or complete absence of ATG7, an essential effector enzyme for autophagy without a known functional paralogue. (Funded by the Wellcome Centre for Mitochondrial Research and others.).
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http://dx.doi.org/10.1056/NEJMoa1915722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611730PMC
June 2021

Characterizing the Clinical Features and Atrophy Patterns of -Related Frontotemporal Dementia With Disease Progression Modeling.

Neurology 2021 08 22;97(9):e941-e952. Epub 2021 Jun 22.

From the Department of Neuroimaging (A.L.Y., S.C.R.W.), Institute of Psychiatry, Psychology and Neuroscience, King's College London; Departments of Computer Science (A.L.Y., D.C.A.) and Medical Physics and Biomedical Engineering (D.M.C.), Centre for Medical Image Computing, University College London; Dementia Research Centre (M.B., L.L.R., R.S.C., G.P., E.T., D.M.C., C.V.G., L.J., J.D.R.), Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; Department of Neurology (J.v.S., L.J., H.S.), Erasmus Medical Centre, Rotterdam, the Netherlands; Cognitive Disorders Unit (F.M.), Department of Neurology, Donostia University Hospital; Neuroscience Area (F.M.), Biodonostia Health Research Institute, San Sebastian, Gipuzkoa, Spain; Alzheimer's Disease and Other Cognitive Disorders Unit (R.S.-V.), Neurology Service, Hospital Clínic, Institut d'Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Spain; Neurology Unit (B.B.), Department of Clinical and Experimental Sciences, University of Brescia, Italy; Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine (R.L.), Université Laval, Québec; Sunnybrook Health Sciences Centre, Sunnybrook Research Institute (M.M.), and Tanz Centre for Research in Neurodegenerative Diseases (M.C.T.), University of Toronto, Canada; Center for Alzheimer Research (C.G.), Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet; Unit for Hereditary Dementias (C.G.), Theme Aging, Karolinska University Hospital, Solna, Sweden; Fondazione Ca'Granda (D.G.), IRCCS Ospedale Policlinico; University of Milan (D.G.), Centro Dino Ferrari, Italy; Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust (J.B.R.), University of Cambridge, UK; Department of Clinical Neurological Sciences (E.F.), University of Western Ontario, London, Canada; Department of Neurodegenerative Diseases (M.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; Center for Neurodegenerative Diseases (DZNE) (M.S.), Tübingen, Germany; Laboratory for Cognitive Neurology, Department of Neurosciences (R.V.), and Leuven Brain Institute (R.V.), KU Leuven; Neurology Service (R.V.), University Hospitals Leuven, Belgium; Faculty of Medicine (A.d.M.), University of Lisbon, Portugal; Fondazione IRCCS Istituto Neurologico Carlo Besta (F.T.), Milan, Italy; University Hospital of Coimbra (HUC), Neurology Service (I.S.), and Center for Neuroscience and Cell Biology (I.S.), Faculty of Medicine, University of Coimbra, Portugal; Department of Psychiatry, McGill University Health Centre (S.D.), and McConnell Brain Imaging Centre, Montreal Neurological Institute (S.D.), McGill University, Montreal, Canada; Nuffield Department of Clinical Neurosciences (C.B.), Medical Sciences Division, University of Oxford; Division of Neuroscience and Experimental Psychology (A.G.), Wolfson Molecular Imaging Centre, University of Manchester, UK; Departments of Geriatric Medicine and Nuclear Medicine (A.G.), University of Duisburg-Essen; Department of Neurology (J.L., A.D.), Ludwig-Maximilians Universität München; German Center for Neurodegenerative Diseases (DZNE) (J.L.); Munich Cluster of Systems Neurology (SyNergy) (J.L.), Munich; Department of Neurology (M.O.), University of Ulm, Germany; Departments of Neuroscience, Psychology, Drug Research, and Child Health (S.S.), University of Florence; and IRCCS Don Gnocchi (S.S.), Florence, Italy.

Background And Objective: Mutations in the gene cause frontotemporal dementia (FTD). Most previous studies investigating the neuroanatomical signature of mutations have grouped all different mutations together and shown an association with focal atrophy of the temporal lobe. The variability in atrophy patterns between each particular mutation is less well-characterized. We aimed to investigate whether there were distinct groups of mutation carriers based on their neuroanatomical signature.

Methods: We applied Subtype and Stage Inference (SuStaIn), an unsupervised machine learning technique that identifies groups of individuals with distinct progression patterns, to characterize patterns of regional atrophy in associated FTD within the Genetic FTD Initiative (GENFI) cohort study.

Results: Eighty-two mutation carriers were analyzed, the majority of whom had P301L, IVS10+16, or R406W mutations, along with 48 healthy noncarriers. SuStaIn identified 2 groups of mutation carriers with distinct atrophy patterns: a temporal subtype, in which atrophy was most prominent in the hippocampus, amygdala, temporal cortex, and insula; and a frontotemporal subtype, in which atrophy was more localized to the lateral temporal lobe and anterior insula, as well as the orbitofrontal and ventromedial prefrontal cortex and anterior cingulate. There was one-to-one mapping between IVS10+16 and R406W mutations and the temporal subtype and near one-to-one mapping between P301L mutations and the frontotemporal subtype. There were differences in clinical symptoms and neuropsychological test scores between subtypes: the temporal subtype was associated with amnestic symptoms, whereas the frontotemporal subtype was associated with executive dysfunction.

Conclusion: Our results demonstrate that different mutations give rise to distinct atrophy patterns and clinical phenotype, providing insights into the underlying disease biology and potential utility for patient stratification in therapeutic trials.
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http://dx.doi.org/10.1212/WNL.0000000000012410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408507PMC
August 2021

Solving patients with rare diseases through programmatic reanalysis of genome-phenome data.

Eur J Hum Genet 2021 Sep 1;29(9):1337-1347. Epub 2021 Jun 1.

CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Baldiri Reixac 4, Barcelona, Spain.

Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics.
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http://dx.doi.org/10.1038/s41431-021-00852-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440686PMC
September 2021

Solve-RD: systematic pan-European data sharing and collaborative analysis to solve rare diseases.

Eur J Hum Genet 2021 Sep 1;29(9):1325-1331. Epub 2021 Jun 1.

Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient's data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe.
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http://dx.doi.org/10.1038/s41431-021-00859-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440542PMC
September 2021

Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia.

Brain 2021 06;144(5):1422-1434

Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.
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http://dx.doi.org/10.1093/brain/awab041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219359PMC
June 2021

Regional Brain and Spinal Cord Volume Loss in Spinocerebellar Ataxia Type 3.

Mov Disord 2021 10 5;36(10):2273-2281. Epub 2021 May 5.

IXICO Plc, London, United Kingdom.

Background: Given that new therapeutic options for spinocerebellar ataxias are on the horizon, there is a need for markers that reflect disease-related alterations, in particular, in the preataxic stage, in which clinical scales are lacking sensitivity.

Objective: The objective of this study was to quantify regional brain volumes and upper cervical spinal cord areas in spinocerebellar ataxia type 3 in vivo across the entire time course of the disease.

Methods: We applied a brain segmentation approach that included a lobular subsegmentation of the cerebellum to magnetic resonance images of 210 ataxic and 48 preataxic spinocerebellar ataxia type 3 mutation carriers and 63 healthy controls. In addition, cervical cord cross-sectional areas were determined at 2 levels.

Results: The metrics of cervical spinal cord segments C3 and C2, medulla oblongata, pons, and pallidum, and the cerebellar anterior lobe were reduced in preataxic mutation carriers compared with controls. Those of cervical spinal cord segments C2 and C3, medulla oblongata, pons, midbrain, cerebellar lobules crus II and X, cerebellar white matter, and pallidum were reduced in ataxic compared with nonataxic carriers. Of all metrics studied, pontine volume showed the steepest decline across the disease course. It covaried with ataxia severity, CAG repeat length, and age. The multivariate model derived from this analysis explained 46.33% of the variance of pontine volume.

Conclusion: Regional brain and spinal cord tissue loss in spinocerebellar ataxia type 3 starts before ataxia onset. Pontine volume appears to be the most promising imaging biomarker candidate for interventional trials that aim at slowing the progression of spinocerebellar ataxia type 3. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28610DOI Listing
October 2021

Differential early subcortical involvement in genetic FTD within the GENFI cohort.

Neuroimage Clin 2021 29;30:102646. Epub 2021 Mar 29.

Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität, Munich German Center for Neurodegenerative Diseases (DZNE), Munich Munich Cluster of Systems Neurology, Munich, Germany.

Background: Studies have previously shown evidence for presymptomatic cortical atrophy in genetic FTD. Whilst initial investigations have also identified early deep grey matter volume loss, little is known about the extent of subcortical involvement, particularly within subregions, and how this differs between genetic groups.

Methods: 480 mutation carriers from the Genetic FTD Initiative (GENFI) were included (198 GRN, 202 C9orf72, 80 MAPT), together with 298 non-carrier cognitively normal controls. Cortical and subcortical volumes of interest were generated using automated parcellation methods on volumetric 3 T T1-weighted MRI scans. Mutation carriers were divided into three disease stages based on their global CDR® plus NACC FTLD score: asymptomatic (0), possibly or mildly symptomatic (0.5) and fully symptomatic (1 or more).

Results: In all three groups, subcortical involvement was seen at the CDR 0.5 stage prior to phenoconversion, whereas in the C9orf72 and MAPT mutation carriers there was also involvement at the CDR 0 stage. In the C9orf72 expansion carriers the earliest volume changes were in thalamic subnuclei (particularly pulvinar and lateral geniculate, 9-10%) cerebellum (lobules VIIa-Crus II and VIIIb, 2-3%), hippocampus (particularly presubiculum and CA1, 2-3%), amygdala (all subregions, 2-6%) and hypothalamus (superior tuberal region, 1%). In MAPT mutation carriers changes were seen at CDR 0 in the hippocampus (subiculum, presubiculum and tail, 3-4%) and amygdala (accessory basal and superficial nuclei, 2-4%). GRN mutation carriers showed subcortical differences at CDR 0.5 in the presubiculum of the hippocampus (8%).

Conclusions: C9orf72 expansion carriers show the earliest and most widespread changes including the thalamus, basal ganglia and medial temporal lobe. By investigating individual subregions, changes can also be seen at CDR 0 in MAPT mutation carriers within the limbic system. Our results suggest that subcortical brain volumes may be used as markers of neurodegeneration even prior to the onset of prodromal symptoms.
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http://dx.doi.org/10.1016/j.nicl.2021.102646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099608PMC
July 2021

Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia.

Brain 2021 06;144(5):1467-1481

Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

Peroxiredoxin 3 (PRDX3) belongs to a superfamily of peroxidases that function as protective antioxidant enzymes. Among the six isoforms (PRDX1-PRDX6), PRDX3 is the only protein exclusively localized to the mitochondria, which are the main source of reactive oxygen species. Excessive levels of reactive oxygen species are harmful to cells, inducing mitochondrial dysfunction, DNA damage, lipid and protein oxidation and ultimately apoptosis. Neuronal cell damage induced by oxidative stress has been associated with numerous neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Leveraging the large aggregation of genomic ataxia datasets from the PREPARE (Preparing for Therapies in Autosomal Recessive Ataxias) network, we identified recessive mutations in PRDX3 as the genetic cause of cerebellar ataxia in five unrelated families, providing further evidence for oxidative stress in the pathogenesis of neurodegeneration. The clinical presentation of individuals with PRDX3 mutations consists of mild-to-moderate progressive cerebellar ataxia with concomitant hyper- and hypokinetic movement disorders, severe early-onset cerebellar atrophy, and in part olivary and brainstem degeneration. Patient fibroblasts showed a lack of PRDX3 protein, resulting in decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity. Moreover, PRDX3 knockdown in cerebellar medulloblastoma cells resulted in significantly decreased cell viability, increased H2O2 levels and increased susceptibility to apoptosis triggered by reactive oxygen species. Pan-neuronal and pan-glial in vivo models of Drosophila revealed aberrant locomotor phenotypes and reduced survival times upon exposure to oxidative stress. Our findings reveal a central role for mitochondria and the implication of oxidative stress in PRDX3 disease pathogenesis and cerebellar vulnerability and suggest targets for future therapeutic approaches.
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http://dx.doi.org/10.1093/brain/awab071DOI Listing
June 2021

Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration.

Neurology 2021 05 7;96(18):e2296-e2312. Epub 2021 Apr 7.

From the University of California, San Francisco (J.C.R., P.W., A.M.S., Y.C., A.W., S.-Y.M.G., P.A.L., H.W.H., J.C.F., J.B.T., A.M.K., L.L.M., J.K., J.H.K., B.L.M., H.J.S., A.L.B.); UK Dementia Research Centre (C.H., D.M.C., R.S.C., M.B., M.F., C.V.G., G.P., L.R., I.S., E.T., J.D.R.), UCL Institute of Neurology, Queen Square, London; Quanterix Corp (E.V., L.S., A.J., D.H.), Lexington; Novartis Institutes for Biomedical Research Inc (L.Y., A. Khinikar, R.S.), Cambridge, MA; Novartis Pharma AG (A. Kieloch, M.-A.V.), Basel, Switzerland; Bluefield Project to Cure Frontotemporal Dementia (L.L.M., R.P.), San Francisco, CA; Mayo Clinic (K.K., D.S.K., B.F.B.), Rochester, MN; Mayo Clinic (N.G.-R., L.P., R.R.), Jacksonville, FL; University of Pennsylvania (D.J.I., M.G.), Philadelphia; University of California, Los Angeles (E.M.R., G.C., M.F.M., Y.B.); Harvard University/Massachusetts General Hospital (B.D.C.), Boston, MA; Washington University (N.G.), St. Louis, MO; Columbia University (E.D.H.), New York, NY; University of British Columbia (I.R.M., G.-Y.R.H.), Vancouver, Canada; Case Western Reserve University (B.S.A.), Cleveland, OH; University of Washington (K.D.-R.), Seattle; Laboratory of Neuroimaging (A.W.T.), University of Southern California, Los Angeles; Northwestern University (S.W.), Chicago, IL; University of North Carolina (D.I.K.), Chapel Hill; Texas Health Presbyterian Hospital Dallas (D.K.); University of California, San Diego (I.L.); Johns Hopkins Hospital (C.U.O., A.P.), Baltimore, MD; University of Alabama at Birmingham (E.D.R.); University of Toronto (M.C.T., M.M.), Ontario, Canada; Indiana University School of Medicine (T.F.), Indianapolis; Biogen Inc (W.C., J.C., D.L.G.), Cambridge, MA; Erasmus Medical Centre (J.C.v.S.), Rotterdam, the Netherlands; University of Brescia (B.B.), Italy; University of Barcelona (R.S.-V.); Donostia University Hospital (F.M.), San Sebastian, Gipuzkoa, Spain; Clinique Interdisciplinaire de Mémoire (R.L.), Département des Sciences Neurologiques, CHU de Québec; Faculté de Médecine (R.L.), Université Laval, Quebec, Canada; Center for Alzheimer Research (C.G.), Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet; Unit for Hereditary Dementias (C.G.), Theme Aging, Karolinska University Hospital, Solna, Sweden; University of Tübingen (M.S.); Center for Neurodegenerative Diseases (DZNE) (M.S.), Tübingen, Germany; Fondazione IRCCS Ospedale Policlinico (D.G.); University of Milan (D.G.), Centro Dino Ferrari, Italy; Department of Clinical Neurosciences and Cambridge University Hospital (J.B.R.), University of Cambridge, UK; University of Western Ontario (E.F.), London, Canada; KU Leuven (R.V.), Belgium; Neurology Service (R.V.), University Hospitals Leuven, Belgium; University of Lisbon (A.d.M.), Portugal; Fondazione IRCCS Istituto Neurologico Carlo Besta (F.T.), Milan, Italy; University of Coimbra (I.S.), Portugal; McGill University (S.D.), Montreal, Québec, Canada; University of Oxford (C.R.B.); Wolfson Molecular Imaging Centre (A.G.), University of Manchester, UK; University of Duisburg-Essen (A.G.), Duisberg; Ludwig-Maximilians-Universität München (J.L., A.D.); German Center for Neurodegenerative Diseases (J.L.), Munich Cluster for Systems Neurology (SyNergy); University of Ulm (M.O.), Germany; and Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence, and IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.

Objective: We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression.

Methods: Baseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. , , and mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables.

Results: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers.

Conclusions: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials.

Trial Registration Information: ClinicalTrials.gov Identifier: NCT02372773 and NCT02365922.

Classification Of Evidence: This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.
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http://dx.doi.org/10.1212/WNL.0000000000011848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166434PMC
May 2021
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