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

Author: Faber, J., Schaprian, T., Berkan, K., Reetz, K., França, M.C., Jr., Rezende, T.J.R. de, Hong, J., Liao, W., Warrenburg, B.P.C. van de, Gaalen, J. van, Durr, A., Mochel, F., Giunti, P., Garcia-Moreno, H., Schoels, L., Hengel, H., Synofzik, M., Bender, B., Oz, G., Joers, J., Vries, J.J.J. de, Kang, J.S., Timmann-Braun, D., Jacobi, H., Infante, J., Joules, R., Romanzetti, S., Diedrichsen, J., Schmid, M., Wolz, R., Klockgether, T., Faber, J., Schaprian, T., Berkan, K., Reetz, K., França, M.C., Jr., Rezende, T.J.R. de, Hong, J., Liao, W., Warrenburg, B.P.C. van de, Gaalen, J. van, Durr, A., Mochel, F., Giunti, P., Garcia-Moreno, H., Schoels, L., Hengel, H., Synofzik, M., Bender, B., Oz, G., Joers, J., Vries, J.J.J. de, Kang, J.S., Timmann-Braun, D., Jacobi, H., Infante, J., Joules, R., Romanzetti, S., Diedrichsen, J., Schmid, M., Wolz, R., and Klockgether, T.
Abstract: Item does not contain fulltext, 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.
Published: 2021

52. Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease

Author: Traschütz, A., Cortese, A., Reich, S., Dominik, N., Faber, J., Jacobi, H., Hartmann, A.M., Rujescu, D., Montaut, S., Echaniz-Laguna, A., Erer, S., Schütz, V.C., Tarnutzer, A.A., Sturm, M., Haack, T.B., Vaucamps-Diedhiou, N., Puccio, H., Schöls, L., Klockgether, T., Warrenburg, B.P.C. van de, Paucar, M., Timmann, D., Hilgers, R.D., Gazulla, J., Strupp, M., Moris, G., Filla, A., Houlden, H., Anheim, M., Infante, J., Basak, A.N., Synofzik, M., Traschütz, A., Cortese, A., Reich, S., Dominik, N., Faber, J., Jacobi, H., Hartmann, A.M., Rujescu, D., Montaut, S., Echaniz-Laguna, A., Erer, S., Schütz, V.C., Tarnutzer, A.A., Sturm, M., Haack, T.B., Vaucamps-Diedhiou, N., Puccio, H., Schöls, L., Klockgether, T., Warrenburg, B.P.C. van de, Paucar, M., Timmann, D., Hilgers, R.D., Gazulla, J., Strupp, M., Moris, G., Filla, A., Houlden, H., Anheim, M., Infante, J., Basak, A.N., and Synofzik, M.
Abstract: Item does not contain fulltext, OBJECTIVE: To delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of replication factor complex subunit 1 (RFC1) repeat expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). METHODS: Multimodal RFC1 repeat screening (PCR, Southern blot, whole-exome/genome sequencing-based approaches) combined with cross-sectional and longitudinal deep phenotyping in (1) cross-European cohort A (70 families) with ≥2 features of CANVAS or ataxia with chronic cough (ACC) and (2) Turkish cohort B (105 families) with unselected late-onset ataxia. RESULTS: Prevalence of RFC1 disease was 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and 100% in ACC. RFC1 disease was also identified in Western and Eastern Asian individuals and even by whole-exome sequencing. Visual compensation, sensory symptoms, and cough were strong positive discriminative predictors (>90%) against RFC1-negative patients. The phenotype across 70 RFC1-positive patients was mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia (28%) (overlap with cerebellar-type multiple system atrophy [MSA-C]), postural instability (49%), slow vertical saccades (17%), and chorea or dystonia (11%). Ataxia progression was ≈1.3 Scale for the Assessment and Rating of Ataxia points per year (32 cross-sectional, 17 longitudinal assessments, follow-up ≤9 years [mean 3.1 years]) but also included early falls, variable nonlinear phases of MSA-C-like progression (SARA points 2.5-5.5 per year), and premature death. Treatment trials require 330 (1-year trial) and 132 (2-year trial) patients in total to detect 50% reduced progression. CONCLUSIONS: RFC1 disease is frequent and occurs across continents, with CANVAS and ACC as highly diagnostic phenotypes yet as variable, overlapping clusters along a continuous multisystemic disease spectrum, including MSA-C-overlap. Our na
Published: 2021

53. Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C

Author: Pelletier, F., Perrier, S., Cayami, F.K., Mirchi, A., Saikali, S., Tran, L.T., Ulrick, N., Guerrero, K., Rampakakis, E., Spaendonk, R.M.L. van, Naidu, S., Pohl, D., Gibson, W.T., Demos, M., Goizet, C., Tejera-Martin, I., Potic, A., Fogel, B.L., Brais, B., Sylvain, M., Sébire, G., Lourenço, C.M., Bonkowsky, J.L., Catsman-Berrevoets, C., Pinto, P.S., Tirupathi, S., Strømme, P., Grauw, T. de, Gieruszczak-Bialek, D., Krägeloh-Mann, I., Mierzewska, H., Philippi, H., Rankin, J., Atik, T., Banwell, B., Benko, W.S., Blaschek, A., Bley, A., Boltshauser, E., Bratkovic, D., Brozova, K., Cimas, I., Clough, C., Corenblum, B., Dinopoulos, A., Dolan, G., Faletra, F., Fernandez, R., Fletcher, J., Garcia, M.E., Gasparini, P., Gburek-Augustat, J., Moron, D. Gonzalez, Hamati, A., Harting, I., Hertzberg, C., Hill, A., Hobson, G.M., Innes, A. Micheil, Kauffman, M., Kirwin, S.M., Kluger, G., Kolditz, P., Kotzaeridou, U., Piana, R., Liston, E., McClintock, W., McEntagart, M., McKenzie, F., Melançon, S., Misbahuddin, A., Suri, M., Monton, F.I., Moutton, S., Murphy, R.P.J., Nickel, M., Onay, H., Orcesi, S., Özkınay, F., Patzer, S., Pedro, H., Pekic, S., Marfa, M. Pineda, Pizzino, A., Plecko, B., Poll-The, B.T., Popovic, V., Rating, D., Rioux, M.F., Espinosa, N. Rodriguez, Ronan, A., Ostergaard, J.R., Rossignol, E., Sanchez-Carpintero, R., Schossig, A., Senbil, N., Roos, L.K. Sønderberg, Stevens, C.A., Synofzik, M., Sztriha, L., et al., Warrenburg, B.P.C. van de, Wolf, N.I., Bernard, G., Pelletier, F., Perrier, S., Cayami, F.K., Mirchi, A., Saikali, S., Tran, L.T., Ulrick, N., Guerrero, K., Rampakakis, E., Spaendonk, R.M.L. van, Naidu, S., Pohl, D., Gibson, W.T., Demos, M., Goizet, C., Tejera-Martin, I., Potic, A., Fogel, B.L., Brais, B., Sylvain, M., Sébire, G., Lourenço, C.M., Bonkowsky, J.L., Catsman-Berrevoets, C., Pinto, P.S., Tirupathi, S., Strømme, P., Grauw, T. de, Gieruszczak-Bialek, D., Krägeloh-Mann, I., Mierzewska, H., Philippi, H., Rankin, J., Atik, T., Banwell, B., Benko, W.S., Blaschek, A., Bley, A., Boltshauser, E., Bratkovic, D., Brozova, K., Cimas, I., Clough, C., Corenblum, B., Dinopoulos, A., Dolan, G., Faletra, F., Fernandez, R., Fletcher, J., Garcia, M.E., Gasparini, P., Gburek-Augustat, J., Moron, D. Gonzalez, Hamati, A., Harting, I., Hertzberg, C., Hill, A., Hobson, G.M., Innes, A. Micheil, Kauffman, M., Kirwin, S.M., Kluger, G., Kolditz, P., Kotzaeridou, U., Piana, R., Liston, E., McClintock, W., McEntagart, M., McKenzie, F., Melançon, S., Misbahuddin, A., Suri, M., Monton, F.I., Moutton, S., Murphy, R.P.J., Nickel, M., Onay, H., Orcesi, S., Özkınay, F., Patzer, S., Pedro, H., Pekic, S., Marfa, M. Pineda, Pizzino, A., Plecko, B., Poll-The, B.T., Popovic, V., Rating, D., Rioux, M.F., Espinosa, N. Rodriguez, Ronan, A., Ostergaard, J.R., Rossignol, E., Sanchez-Carpintero, R., Schossig, A., Senbil, N., Roos, L.K. Sønderberg, Stevens, C.A., Synofzik, M., Sztriha, L., et al., Warrenburg, B.P.C. van de, Wolf, N.I., and Bernard, G.
Abstract: Contains fulltext : 235629.pdf (Publisher’s version ) (Open Access), CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
Published: 2021

54. Solving unsolved rare neurological diseases-a Solve-RD viewpoint

Author: Schüle, R., Timmann, D., Erasmus, C.E., Reichbauer, J., Wayand, M., Warrenburg, B.P.C. van de, Schöls, L., Wilke, C., Bevot, A., Zuchner, S., Beltran, S., Laurie, S., Matalonga, L., Brunner, H.G., Scheffer, H., Hoogerbrugge, N., Hoischen, A., Hoen, P.A.C. 't, Vissers, L.E.L.M., Gilissen, C., Graessner, H., Synofzik, M., Schüle, R., Timmann, D., Erasmus, C.E., Reichbauer, J., Wayand, M., Warrenburg, B.P.C. van de, Schöls, L., Wilke, C., Bevot, A., Zuchner, S., Beltran, S., Laurie, S., Matalonga, L., Brunner, H.G., Scheffer, H., Hoogerbrugge, N., Hoischen, A., Hoen, P.A.C. 't, Vissers, L.E.L.M., Gilissen, C., Graessner, H., and Synofzik, M.
Abstract: Contains fulltext : 237907.pdf (Publisher’s version ) (Open Access)
Published: 2021

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

Author: Wiessner, M., Maroofian, R., Ni, M.Y., Pedroni, A., Müller, J.S., Stucka, R., Beetz, C., Efthymiou, S., Santorelli, F.M., Alfares, A.A., Zhu, C., Meszarosova, A. Uhrova, Alehabib, E., Bakhtiari, S., Janecke, A.R., Otero, M.G., Chen, J.Y., Peterson, J.T., Strom, T.M., Jonghe, P. De, Deconinck, T., Ridder, W. De, Winter, J., Pasquariello, R., Ricca, I., Alfadhel, M., Warrenburg, B.P.C. van de, Portier, R., Bergmann, C., Firouzabadi, S. Ghasemi, Jin, S.C., Bilguvar, K., Hamed, S., Abdelhameed, M., Haridy, N.A., Maqbool, S., Rahman, F., Anwar, N., Carmichael, J., Pagnamenta, A., Wood, N.W., Mau-Them, F. Tran, Haack, T., Rocco, M. Di, Ceccherini, I., Iacomino, M., Zara, F., Salpietro, V., Scala, M., Rusmini, M., Xu, Y., Wang, Y., Suzuki, Y., Koh, K., Nan, H., Ishiura, H., Tsuji, S., Lambert, L., Schmitt, E., Lacaze, E., Küpper, H., Dredge, D., Skraban, C., Goldstein, A., Willis, M.J.H., Grand, K., Graham, J.M., Lewis, R.A., Millan, F., Duman, Ö., Dündar, N., Uyanik, G., Schöls, L., Nürnberg, P., Nürnberg, G., Bordes, A. Catala, Seeman, P., Kuchar, M., Darvish, H., Rebelo, A., Bouçanova, F., Medard, J.J., Chrast, R., Auer-Grumbach, M., Alkuraya, F.S., Shamseldin, H., Tala, S. Al, Varaghchi, J. Rezazadeh, Najafi, Maryam, Deschner, S., Gläser, D., Hüttel, W., Kruer, M.C., Kamsteeg, E.J., Takiyama, Y., Züchner, S., Baets, J., Synofzik, M., Schüle, R., Horvath, R., Pierson, T.M., Senderek, J., Wiessner, M., Maroofian, R., Ni, M.Y., Pedroni, A., Müller, J.S., Stucka, R., Beetz, C., Efthymiou, S., Santorelli, F.M., Alfares, A.A., Zhu, C., Meszarosova, A. Uhrova, Alehabib, E., Bakhtiari, S., Janecke, A.R., Otero, M.G., Chen, J.Y., Peterson, J.T., Strom, T.M., Jonghe, P. De, Deconinck, T., Ridder, W. De, Winter, J., Pasquariello, R., Ricca, I., Alfadhel, M., Warrenburg, B.P.C. van de, Portier, R., Bergmann, C., Firouzabadi, S. Ghasemi, Jin, S.C., Bilguvar, K., Hamed, S., Abdelhameed, M., Haridy, N.A., Maqbool, S., Rahman, F., Anwar, N., Carmichael, J., Pagnamenta, A., Wood, N.W., Mau-Them, F. Tran, Haack, T., Rocco, M. Di, Ceccherini, I., Iacomino, M., Zara, F., Salpietro, V., Scala, M., Rusmini, M., Xu, Y., Wang, Y., Suzuki, Y., Koh, K., Nan, H., Ishiura, H., Tsuji, S., Lambert, L., Schmitt, E., Lacaze, E., Küpper, H., Dredge, D., Skraban, C., Goldstein, A., Willis, M.J.H., Grand, K., Graham, J.M., Lewis, R.A., Millan, F., Duman, Ö., Dündar, N., Uyanik, G., Schöls, L., Nürnberg, P., Nürnberg, G., Bordes, A. Catala, Seeman, P., Kuchar, M., Darvish, H., Rebelo, A., Bouçanova, F., Medard, J.J., Chrast, R., Auer-Grumbach, M., Alkuraya, F.S., Shamseldin, H., Tala, S. Al, Varaghchi, J. Rezazadeh, Najafi, Maryam, Deschner, S., Gläser, D., Hüttel, W., Kruer, M.C., Kamsteeg, E.J., Takiyama, Y., Züchner, S., Baets, J., Synofzik, M., Schüle, R., Horvath, R., Pierson, T.M., and Senderek, J.
Abstract: Item does not contain fulltext, 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.
Published: 2021

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

Author: Rebelo, A.P., Eidhof, I.J.M., Cintra, V.P., Guillot-Noel, L., Pereira, C.V., Timmann, D., Traschütz, A., Schöls, L., Coarelli, G., Durr, A., Anheim, M., Tranchant, C., Warrenburg, B.P.C. van de, Guissart, C., Koenig, M., Howell, J., Moraes, C.T., Schenck, A., Stevanin, G., Züchner, S., Synofzik, M., Rebelo, A.P., Eidhof, I.J.M., Cintra, V.P., Guillot-Noel, L., Pereira, C.V., Timmann, D., Traschütz, A., Schöls, L., Coarelli, G., Durr, A., Anheim, M., Tranchant, C., Warrenburg, B.P.C. van de, Guissart, C., Koenig, M., Howell, J., Moraes, C.T., Schenck, A., Stevanin, G., Züchner, S., and Synofzik, M.
Abstract: Item does not contain fulltext, 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.
Published: 2021

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

Author: Traschütz, A., Reich, S., Adarmes, A.D., Anheim, M., Ashrafi, M.R., Baets, J., Basak, A.N., Bertini, E., Brais, B., Gagnon, C., Gburek-Augustat, J., Hanagasi, H.A., Heinzmann, A., Horvath, R., Jonghe, P. De, Kamm, C., Klivenyi, P., Klopstock, T., Minnerop, M., Münchau, A., Renaud, M., Roxburgh, R.H., Santorelli, F.M., Schirinzi, T., Sival, D.A., Timmann, D., Vielhaber, S., Wallner, M., Warrenburg, B.P.C. van de, Zanni, G., Zuchner, S., Klockgether, T., Schüle, R., Schöls, L., Synofzik, M., Traschütz, A., Reich, S., Adarmes, A.D., Anheim, M., Ashrafi, M.R., Baets, J., Basak, A.N., Bertini, E., Brais, B., Gagnon, C., Gburek-Augustat, J., Hanagasi, H.A., Heinzmann, A., Horvath, R., Jonghe, P. De, Kamm, C., Klivenyi, P., Klopstock, T., Minnerop, M., Münchau, A., Renaud, M., Roxburgh, R.H., Santorelli, F.M., Schirinzi, T., Sival, D.A., Timmann, D., Vielhaber, S., Wallner, M., Warrenburg, B.P.C. van de, Zanni, G., Zuchner, S., Klockgether, T., Schüle, R., Schöls, L., and Synofzik, M.
Abstract: Contains fulltext : 238566.pdf (Publisher’s version ) (Open Access), 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 ARCA Registry, 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
Published: 2021

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

Author: Zurek, B., Ellwanger, K., Vissers, L.E.L.M., Schüle, R., Synofzik, M., Töpf, A., Voer, R.M. de, Laurie, S., Matalonga, L., Gilissen, C.F.H.A., Ossowski, S., Hoen, P.A.C. 't, Vitobello, A., Schulze-Hentrich, J.M., Riess, O., Brunner, H.G., Brookes, A.J., Rath, A., Bonne, G., Gumus, G., Verloes, A., Hoogerbrugge, N., Evangelista, T., Harmuth, T., Swertz, M., Spalding, D., Hoischen, A., Warrenburg, B.P.C. van de, Beltran, S., Graessner, H., Zurek, B., Ellwanger, K., Vissers, L.E.L.M., Schüle, R., Synofzik, M., Töpf, A., Voer, R.M. de, Laurie, S., Matalonga, L., Gilissen, C.F.H.A., Ossowski, S., Hoen, P.A.C. 't, Vitobello, A., Schulze-Hentrich, J.M., Riess, O., Brunner, H.G., Brookes, A.J., Rath, A., Bonne, G., Gumus, G., Verloes, A., Hoogerbrugge, N., Evangelista, T., Harmuth, T., Swertz, M., Spalding, D., Hoischen, A., Warrenburg, B.P.C. van de, Beltran, S., and Graessner, H.
Abstract: Contains fulltext : 237904.pdf (Publisher’s version ) (Open Access), 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.
Published: 2021

59. Natural history, phenotypic spectrum, and discriminative features of multisystemic RFC1 disease

Author: Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Traschütz, A; Cortese, A.; Reich, S.; Dominik, N.; Faber, J.; Jacobi, H.; Hartmann, A. M.; Rujescu, D.; Montaut, S.; Echaniz-Laguna, A.; Erer, S.; Schütz, V. C.; Tarnutzer, A. A.; Sturm, M.; Haack, T. B.; Vaucamps-Diedhiou, N.; Puccio, H.; Schöls, L.; Klockgether, T.; van de Warrenburg, B. P.; Paucar, M.; Timmann, D.; Hilgers, R. D.; Gazulla, J.; Strupp, M.; Moris, G.; Filla, A.; Houlden, H.; Anheim, M.; Infante, J.; Synofzik, M.; RFC1 Study Group, Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), and Traschütz, A; Cortese, A.; Reich, S.; Dominik, N.; Faber, J.; Jacobi, H.; Hartmann, A. M.; Rujescu, D.; Montaut, S.; Echaniz-Laguna, A.; Erer, S.; Schütz, V. C.; Tarnutzer, A. A.; Sturm, M.; Haack, T. B.; Vaucamps-Diedhiou, N.; Puccio, H.; Schöls, L.; Klockgether, T.; van de Warrenburg, B. P.; Paucar, M.; Timmann, D.; Hilgers, R. D.; Gazulla, J.; Strupp, M.; Moris, G.; Filla, A.; Houlden, H.; Anheim, M.; Infante, J.; Synofzik, M.; RFC1 Study Group
Abstract: Objective: to delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of replication factor complex subunit 1 (RFC1) repeat expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). Methods: multimodal RFC1 repeat screening (PCR, Southern blot, whole-exome/genome sequencing-based approaches) combined with cross-sectional and longitudinal deep phenotyping in (1) cross-European cohort A (70 families) with ≥2 features of CANVAS or ataxia with chronic cough (ACC) and (2) Turkish cohort B (105 families) with unselected late-onset ataxia. Results: prevalence of RFC1 disease was 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and 100% in ACC. RFC1 disease was also identified in Western and Eastern Asian individuals and even by whole-exome sequencing. Visual compensation, sensory symptoms, and cough were strong positive discriminative predictors (>90%) against RFC1-negative patients. The phenotype across 70 RFC1-positive patients was mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia (28%) (overlap with cerebellar-type multiple system atrophy [MSA-C]), postural instability (49%), slow vertical saccades (17%), and chorea or dystonia (11%). Ataxia progression was ≈1.3 Scale for the Assessment and Rating of Ataxia points per year (32 cross-sectional, 17 longitudinal assessments, follow-up ≤9 years [mean 3.1 years]) but also included early falls, variable nonlinear phases of MSA-C-like progression (SARA points 2.5-5.5 per year), and premature death. Treatment trials require 330 (1-year trial) and 132 (2-year trial) patients in total to detect 50% reduced progression. Conclusions: RFC1 disease is frequent and occurs across continents, with CANVAS and ACC as highly diagnostic phenotypes yet as variable, overlapping clusters along a continuous multisystemic disease spectrum, including MSA-C-overlap. Our na
Published: 2021

60. Progression of Behavioral Disturbances and Neuropsychiatric Symptoms in Patients With Genetic Frontotemporal Dementia

Author: Benussi, A. (Alberto), Premi, E. (Enrico), Gazzina, S. (Stefano), Brattini, C. (Chiara), Bonomi, E. (Elisa), Alberici, P. (Paola), Jiskoot, L.C. (Lize), Swieten, J.C. (John) van, Sánchez-Valle, R. (Raquel), Moreno, F. (Fermin), Laforce, R. (Robert), Graff, C. (Caroline), Synofzik, M. (Matthis), Galimberti, D. (Daniela), Masellis, M. (Mario), Tartaglia, C. (Carmela), Rowe, J.B. (James), Finger, E. (Elizabeth), Vandenberghe, R. (Rik), De Mendonça, A. (Alexandre), Tagliavini, F. (Fabrizio), Santana, I. (Isabel), Ducharme, S. (Simon), Butler, C.R. (Chris R.), Gerhard, A. (Alex), Levin, J. (Johannes), Danek, A. (Adrian), Otto, M. (Markus), Frisoni, G.B. (Giovanni B.), Ghidoni, R. (Roberta), Sorbi, S. (Sandro), Le Ber, I. (Isabelle), Pasquier, F. (Florence), Peakman, G. (Georgia), Todd, E. (Emily), Bocchetta, M. (Martina), Rohrer, J.D. (Jonathan), Borroni, B. (Barbara), Benussi, A. (Alberto), Premi, E. (Enrico), Gazzina, S. (Stefano), Brattini, C. (Chiara), Bonomi, E. (Elisa), Alberici, P. (Paola), Jiskoot, L.C. (Lize), Swieten, J.C. (John) van, Sánchez-Valle, R. (Raquel), Moreno, F. (Fermin), Laforce, R. (Robert), Graff, C. (Caroline), Synofzik, M. (Matthis), Galimberti, D. (Daniela), Masellis, M. (Mario), Tartaglia, C. (Carmela), Rowe, J.B. (James), Finger, E. (Elizabeth), Vandenberghe, R. (Rik), De Mendonça, A. (Alexandre), Tagliavini, F. (Fabrizio), Santana, I. (Isabel), Ducharme, S. (Simon), Butler, C.R. (Chris R.), Gerhard, A. (Alex), Levin, J. (Johannes), Danek, A. (Adrian), Otto, M. (Markus), Frisoni, G.B. (Giovanni B.), Ghidoni, R. (Roberta), Sorbi, S. (Sandro), Le Ber, I. (Isabelle), Pasquier, F. (Florence), Peakman, G. (Georgia), Todd, E. (Emily), Bocchetta, M. (Martina), Rohrer, J.D. (Jonathan), and Borroni, B. (Barbara)
Abstract: Importance: Behavioral disturbances are core features of frontotemporal dementia (FTD); however, symptom progression across the course of disease is not well characterized in genetic FTD. Objective: To investigate behavioral symptom frequency and severity and their evolution and progression in different forms of genetic FTD. Design, Setting, and Participants: This longitudinal cohort study, the international Genetic FTD Initiative (GENFI), was conducted from January 30, 2012, to May 31, 2019, at 23 multicenter specialist tertiary FTD research clinics in the United Kingdom, the Netherlands, Belgium, France, Spain, Portugal, Italy, Germany, Sweden, Finland, and Canada. Participants included a consecutive sample of 232 symptomatic FTD gene variation carriers comprising 115 with variations in C9orf72, 78 in GRN, and 39 in MAPT. A total of 101 carriers had at least 1 follow-up evaluation (for a total of 400 assessments). Gene variations were included only if considered pathogenetic. Main Outcomes and Measures: Behavioral and neuropsychiatric symptoms were assessed across disease duration and evaluated from symptom onset. Hierarchical generalized linear mixed models were used to model behavioral and neuropsychiatric measures as a function of
Published: 2021
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61. Disease-related cortical thinning in presymptomatic granulin mutation carriers

Author: Borrego-Écija, S. (Sergi), Sala-Llonch, R. (Roser), Swieten, J.C. (John) van, Borroni, B. (Barbara), Moreno, F. (Fermin), Masellis, M. (Mario), Tartaglia, C. (Carmela), Graff, C. (Caroline), Galimberti, D. (Daniela), Laforce, R. (Robert), Rowe, J.B. (James), Finger, E. (Elizabeth), Vandenberghe, R. (Rik), Tagliavini, F. (Fabrizio), De Mendonça, A. (Alexandre), Santana, I. (Isabel), Synofzik, M. (Matthis), Ducharme, S. (Simon), Levin, J. (Johannes), Danek, A. (Adrian), Gerhard, A. (Alex), Otto, M. (Markus), Butler, C. (Chris), Frisoni, G.B. (Giovanni B.), Sorbi, S. (Sandro), Heller, C. (Carolin), Bocchetta, M. (Martina), Cash, D.M. (David M), Convery, R.S. (Rhian S), Moore, K.M. (Katrina M), Rohrer, J.D. (Jonathan), Sánchez-Valle, R. (Raquel), Rossor, M.N. (Martin N.), Fox, N.C. (Nick), Woollacott, I.O.C. (Ione O.C.), Shafei, R. (Rachelle), Greaves, C. (Caroline), Neason, M. (Mollie), Guerreiro, R. (Rita), Bras, J. (Jose), Thomas, D.L. (David L), Nicholas, J. (Jennifer), Mead, S. (Simon), Meeter, L.H.H. (Lieke), Panman, J.L. (Jessica), Papma, J.M. (Janne), Thornton, A.S. (Andrew), Pijnenburg, Y.A.L. (Yolande), Indakoetxea, B. (Begoña), Gabilondo, A. (Alazne), TaintaMD, M. (Mikel), de Arriba, M. (Maria), Gorostidi, A. (Ana), Zulaica, M. (Miren), Villanua, J. (Jorge), Diaz, Z. (Zigor), Olives, J. (Jaume), Lladó, A. (Albert), Balasa, M. (Mircea), Antonell, A. (Anna), Bargallo, N. (Nuria), Premi, E. (Enrico), Cosseddu, M. (Maura), Gazzina, S. (Stefano), Padovani, A. (Alessandro), Gasparotti, R. (Roberto), Archetti, S. (Silvana), Black, S. (Sandra), Mitchell, S. (Sara), Rogaeva, E. (Ekaterina), Freedman, M. (Morris), Keren, R. (Ron), Tang-Wai, D. (David), Öijerstedt, L. (Linn), Andersson, C. (Christin), Jelic, S. (Svetislav Svetislav), Thonberg, H. (Håkan), Arighi, A. (Andrea), Fenoglio, C. (Chiara), Scarpini MD, E. (Elio), Fumagalli, G. (Giorgio), Cope, T. (Thomas), Timberlake, C. (Carolyn), Rittman, T. (Timothy), Shoesmith, C. (Christen), Bartha, R. (Robart), Rademakers, S. (Suzanne), Wilke, C. (Carlo), Bender, B. (Benjamin), Bruffaerts, R. (Rose), Vandamme, P. (Philip), Vandenbulcke, M. (Mathieu), Maruta, C. (Carolina), Ferreira, C.B. (Catarina B.), Miltenberger, G. (Gabriel), Verdelho, A. (Ana), Afonso, S. (Sónia), Taipa, R. (Ricardo), Caroppo, P. (Paola), Di Fede, G. (Giuseppe), Giaccone, G. (Giorgio), Prioni, S. (Sara), Redaelli, V. (Veronica), Rossi, G. (Giacomina), Tiraboschi, P. (Pietro), Duro, D. (Diana), Rosario Almeida, M. (Maria), Castelo-Branco, M. (Miguel), João Leitão, M. (Maria), Tabuas-Pereira, M. (Miguel), Santiago, B. (Beatriz), Gauthier, S. (Serge), Rosa-Neto, P. (Pedro), Veldsman, M. (Michele), Flanagan, T. (Toby), Prix, C. (Catharina), Hoegen, T. (Tobias), Wlasich, E. (Elisabeth), Loosli, S. (Sandra), Schonecker, S. (Sonja), Semler, E. (Elisa), Anderl-Straub, S. (Sarah), Borrego-Écija, S. (Sergi), Sala-Llonch, R. (Roser), Swieten, J.C. (John) van, Borroni, B. (Barbara), Moreno, F. (Fermin), Masellis, M. (Mario), Tartaglia, C. (Carmela), Graff, C. (Caroline), Galimberti, D. (Daniela), Laforce, R. (Robert), Rowe, J.B. (James), Finger, E. (Elizabeth), Vandenberghe, R. (Rik), Tagliavini, F. (Fabrizio), De Mendonça, A. (Alexandre), Santana, I. (Isabel), Synofzik, M. (Matthis), Ducharme, S. (Simon), Levin, J. (Johannes), Danek, A. (Adrian), Gerhard, A. (Alex), Otto, M. (Markus), Butler, C. (Chris), Frisoni, G.B. (Giovanni B.), Sorbi, S. (Sandro), Heller, C. (Carolin), Bocchetta, M. (Martina), Cash, D.M. (David M), Convery, R.S. (Rhian S), Moore, K.M. (Katrina M), Rohrer, J.D. (Jonathan), Sánchez-Valle, R. (Raquel), Rossor, M.N. (Martin N.), Fox, N.C. (Nick), Woollacott, I.O.C. (Ione O.C.), Shafei, R. (Rachelle), Greaves, C. (Caroline), Neason, M. (Mollie), Guerreiro, R. (Rita), Bras, J. (Jose), Thomas, D.L. (David L), Nicholas, J. (Jennifer), Mead, S. (Simon), Meeter, L.H.H. (Lieke), Panman, J.L. (Jessica), Papma, J.M. (Janne), Thornton, A.S. (Andrew), Pijnenburg, Y.A.L. (Yolande), Indakoetxea, B. (Begoña), Gabilondo, A. (Alazne), TaintaMD, M. (Mikel), de Arriba, M. (Maria), Gorostidi, A. (Ana), Zulaica, M. (Miren), Villanua, J. (Jorge), Diaz, Z. (Zigor), Olives, J. (Jaume), Lladó, A. (Albert), Balasa, M. (Mircea), Antonell, A. (Anna), Bargallo, N. (Nuria), Premi, E. (Enrico), Cosseddu, M. (Maura), Gazzina, S. (Stefano), Padovani, A. (Alessandro), Gasparotti, R. (Roberto), Archetti, S. (Silvana), Black, S. (Sandra), Mitchell, S. (Sara), Rogaeva, E. (Ekaterina), Freedman, M. (Morris), Keren, R. (Ron), Tang-Wai, D. (David), Öijerstedt, L. (Linn), Andersson, C. (Christin), Jelic, S. (Svetislav Svetislav), Thonberg, H. (Håkan), Arighi, A. (Andrea), Fenoglio, C. (Chiara), Scarpini MD, E. (Elio), Fumagalli, G. (Giorgio), Cope, T. (Thomas), Timberlake, C. (Carolyn), Rittman, T. (Timothy), Shoesmith, C. (Christen), Bartha, R. (Robart), Rademakers, S. (Suzanne), Wilke, C. (Carlo), Bender, B. (Benjamin), Bruffaerts, R. (Rose), Vandamme, P. (Philip), Vandenbulcke, M. (Mathieu), Maruta, C. (Carolina), Ferreira, C.B. (Catarina B.), Miltenberger, G. (Gabriel), Verdelho, A. (Ana), Afonso, S. (Sónia), Taipa, R. (Ricardo), Caroppo, P. (Paola), Di Fede, G. (Giuseppe), Giaccone, G. (Giorgio), Prioni, S. (Sara), Redaelli, V. (Veronica), Rossi, G. (Giacomina), Tiraboschi, P. (Pietro), Duro, D. (Diana), Rosario Almeida, M. (Maria), Castelo-Branco, M. (Miguel), João Leitão, M. (Maria), Tabuas-Pereira, M. (Miguel), Santiago, B. (Beatriz), Gauthier, S. (Serge), Rosa-Neto, P. (Pedro), Veldsman, M. (Michele), Flanagan, T. (Toby), Prix, C. (Catharina), Hoegen, T. (Tobias), Wlasich, E. (Elisabeth), Loosli, S. (Sandra), Schonecker, S. (Sonja), Semler, E. (Elisa), and Anderl-Straub, S. (Sarah)
Abstract: Mutations in the granulin gene (GRN) cause familial frontotemporal dementia. Understanding the structural brain changes in presymptomatic GRN carriers would enforce the use of neuroimaging biomarkers for early diagnosis and monitoring. We studied 100 presymptomatic GRN mutation carriers and 94 noncarriers from the Genetic Frontotemporal dementia initiative (GENFI), with MRI structural images. We analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject. We also perform a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables as gender, age, the estimated years to onset and education. We also explored differences according to TMEM106B genotype, a possible disease modifier. Whole brain CTh did not differ between carriers and noncarriers. Both groups showed age-related cortical thinning. The group-by-age interaction analysis showed that this age-related cortical thinning was significantly greater in GRN carriers in the left superior frontal cortex. TMEM106B did not significantly influence the age-related cortical thinning. Our results validate and expand previous findings suggesting an
Published: 2021
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62. Polyglutamine-Expanded Ataxin-3: A Target Engagement Marker for Spinocerebellar Ataxia Type 3 in Peripheral Blood

Author: Hübener-Schmid, J., Kuhlbrodt, K., Peladan, J., Faber, J., Santana, M.M., Hengel, H., Jacobi, H., Reetz, K., Garcia-Moreno, H., Raposo, M., Gaalen, J. van, Infante, J., Steiner, K.M., Vries, Jeroen de, Verbeek, M.M., Giunti, P., Almeida, L., Lima, M., Warrenburg, B.P.C. van de, Schöls, L., Klockgether, T., Synofzik, M., Riess, O., Hübener-Schmid, J., Kuhlbrodt, K., Peladan, J., Faber, J., Santana, M.M., Hengel, H., Jacobi, H., Reetz, K., Garcia-Moreno, H., Raposo, M., Gaalen, J. van, Infante, J., Steiner, K.M., Vries, Jeroen de, Verbeek, M.M., Giunti, P., Almeida, L., Lima, M., Warrenburg, B.P.C. van de, Schöls, L., Klockgether, T., Synofzik, M., and Riess, O.
Abstract: Contains fulltext : 244281.pdf (Publisher’s version ) (Open Access), 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.
Published: 2021

63. Natural History of Polymerase Gamma-Related Ataxia

Author: Bender, F., Timmann, D., Warrenburg, B.P.C. van de, Adarmes-Gómez, A.D., Bender, B., Thieme, A., Synofzik, M., Schöls, L., Bender, F., Timmann, D., Warrenburg, B.P.C. van de, Adarmes-Gómez, A.D., Bender, B., Thieme, A., Synofzik, M., and Schöls, L.
Abstract: Contains fulltext : 244268.pdf (Publisher’s version ) (Open Access), 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. ©
Published: 2021

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

Author: Matalonga, L., Hernández-Ferrer, C., Piscia, D., Schüle, R., Synofzik, M., Töpf, A., Vissers, L.E.L.M., Voer, R.M. de, Tonda, R., Laurie, S., Fernandez-Callejo, M., Picó, D., Garcia-Linares, C., Papakonstantinou, A., Corvó, A., Joshi, R., Diez, H., Gut, I., Hoischen, A., Warrenburg, B.P.C. van de, Graessner, H., Beltran, S., Matalonga, L., Hernández-Ferrer, C., Piscia, D., Schüle, R., Synofzik, M., Töpf, A., Vissers, L.E.L.M., Voer, R.M. de, Tonda, R., Laurie, S., Fernandez-Callejo, M., Picó, D., Garcia-Linares, C., Papakonstantinou, A., Corvó, A., Joshi, R., Diez, H., Gut, I., Hoischen, A., Warrenburg, B.P.C. van de, Graessner, H., and Beltran, S.
Abstract: Contains fulltext : 237905.pdf (Publisher’s version ) (Open Access), 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.
Published: 2021

65. Fluid biomarkers in frontotemporal dementia: past, present and future

Author: Swift, IJ, Sogorb-Esteve, A, Heller, C, Synofzik, M, Otto, M, Graff, C, Galimberti, D, Todd, E, Heslegrave, AJ, van der Ende, Emma, van Swieten, J.C., Zetterberg, H, Rohrer, JD, Swift, IJ, Sogorb-Esteve, A, Heller, C, Synofzik, M, Otto, M, Graff, C, Galimberti, D, Todd, E, Heslegrave, AJ, van der Ende, Emma, van Swieten, J.C., Zetterberg, H, and Rohrer, JD
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 domai
Published: 2021

66. Boucher-Neuhäuser syndrome: cerebellar degeneration, chorioretinal dystrophy and hypogonadotropic hypogonadism: two novel cases and a review of 40 cases from the literature

Author: Tarnutzer, A., Gerth-Kahlert, C., Timmann, D., Chang, D., Harmuth, F., Bauer, P., Straumann, D., Synofzik, M., Tarnutzer, A., Gerth-Kahlert, C., Timmann, D., Chang, D., Harmuth, F., Bauer, P., Straumann, D., and Synofzik, M.
Abstract: The combination of progressive cerebellar degeneration, hypogonadotropic hypogonadism and chorioretinal dystrophy defines the rare Boucher-Neuhäuser syndrome (BNS), which has recently been linked to autosomal-recessive mutations in the PNPLA6 gene in four index patients. Here we present two novel unrelated patients with BNS, where we identified four recessive PNPLA6 mutations (3 of them novel) as the genetic cause, using a targeted high-throughput approach. This finding provides the first replication from independent families that BNS is caused by PNPLA6 and, moreover, highlights PNPLA6 as the major gene leading to BNS. Given the fact that the major gene causing BNS has thus now been identified, we summarize the spectrum of clinical presentations and phenotype evolution of BNS based on a systematic in-depth review of the literature of previously published cases (n=40). Both the two cases presented here and our review of the literature propose that the clinical presentation of BNS can be variable regarding both the age (ranging from 1 to 40years) and the clinical symptoms at onset (cerebellar ataxia in 38%; vision loss in 36%; delayed puberty in 26%). A substantial fraction of BNS cases may present with relatively selective atrophy of the superior and dorsal parts of the cerebellar vermis along with atrophy of the cerebellar hemispheres on MRI, while brainstem or cortical changes on MRI seem to be present only in small fractions. Also in the literature, no other major genetic causes of BNS other than PNPLA6 mutations were identified.
Published: 2021

67. Progression of Behavioral Disturbances and Neuropsychiatric Symptoms in Patients With Genetic Frontotemporal Dementia

Author: Benussi, A, Premi, E, Gazzina, S, Brattini, C, Bonomi, E, Alberici, A, Jiskoot, Lize, van Swieten, J.C., Sanchez-Valle, R, Moreno, F, Laforce, R, Graff, C, Synofzik, M, Galimberti, D, Masellis, M, Tartaglia, C, Rowe, JB, Finger, E, Vandenberghe, R, De Mendonca, A, Tagliavini, F, Santana, I, Ducharme, S, Butler, CR, Gerhard, A, Levin, J, Danek, A, Otto, M, Frisoni, G, Ghidoni, R, Sorbi, S, Le Ber, I, Pasquier, F, Peakman, G, Todd, E, Bocchetta, M, Rohrer, JD, Borroni, B, Benussi, A, Premi, E, Gazzina, S, Brattini, C, Bonomi, E, Alberici, A, Jiskoot, Lize, van Swieten, J.C., Sanchez-Valle, R, Moreno, F, Laforce, R, Graff, C, Synofzik, M, Galimberti, D, Masellis, M, Tartaglia, C, Rowe, JB, Finger, E, Vandenberghe, R, De Mendonca, A, Tagliavini, F, Santana, I, Ducharme, S, Butler, CR, Gerhard, A, Levin, J, Danek, A, Otto, M, Frisoni, G, Ghidoni, R, Sorbi, S, Le Ber, I, Pasquier, F, Peakman, G, Todd, E, Bocchetta, M, Rohrer, JD, and Borroni, B
Abstract: Importance: Behavioral disturbances are core features of frontotemporal dementia (FTD); however, symptom progression across the course of disease is not well characterized in genetic FTD. Objective: To investigate behavioral symptom frequency and severity and their evolution and progression in different forms of genetic FTD. Design, Setting, and Participants: This longitudinal cohort study, the international Genetic FTD Initiative (GENFI), was conducted from January 30, 2012, to May 31, 2019, at 23 multicenter specialist tertiary FTD research clinics in the United Kingdom, the Netherlands, Belgium, France, Spain, Portugal, Italy, Germany, Sweden, Finland, and Canada. Participants included a consecutive sample of 232 symptomatic FTD gene variation carriers comprising 115 with variations in C9orf72, 78 in GRN, and 39 in MAPT. A total of 101 carriers had at least 1 follow-up evaluation (for a total of 400 assessments). Gene variations were included only if considered pathogenetic. Main Outcomes and Measures: Behavioral and neuropsychiatric symptoms were assessed across disease duration and evaluated from symptom onset. Hierarchical generalized linear mixed models were used to model behavioral and neuropsychiatric measures as a function of disease duration and variation. Results: Of 232 patients with FTD, 115 (49.6%) had a C9orf72 expansion (median [interquartile range (IQR)] age at evaluation, 64.3 [57.5-69.7] years; 72 men [62.6%]; 115 White patients [100%]), 78 (33.6%) had a GRN variant (median [IQR] age, 63.4 [58.3-68.8] years; 40 women [51.3%]; 77 White patients [98.7%]), and 39 (16.8%) had a MAPT variant (median [IQR] age, 56.3 [49.9-62.4] years; 25 men [64.1%]; 37 White patients [94.9%]). All core behavioral symptoms, including disinhibition, apathy, loss of empathy, perseverative behavior, and hyperorality, were highly expressed in all gene variant carriers (>50% patients), with apathy being one of the most common and severe symptoms throughout the disease
Published: 2021

68. Gangveränderungen als Frühindikator einer Demenz

Author: Jamour, M., Becker, C., Synofzik, M., and Maetzler, W.
Published: 2012
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69. Ataxia rating scales are age-dependent in healthy children

Author: Brandsma, Rick, Spits, Anne H, Kuiper, Marieke J, Lunsing, Roelinka J, Burger, Huibert, Kremer, Hubertus P, Sival, Deborah A, Barisic, N., Baxter, P., Brankovic-Sreckovic, V., Calabrò, G. E., Catsman-Berrevoets, C., de Coo, IFM, Craiu, D., Dan, B., Gburek-Augustat, J., Kammoun-Feki, F., Kennedy, C., Mancini, F., Mirabelli-Badenier, M., Nemeth, A., Newton, R., Poll-The, B. T., Steinlin, M., Synofzik, M., Topcu, M., Triki, C., and Valente, E. M.
Published: 2014
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70. PEG-Ernährung bei fortgeschrittener Demenz: Eine evidenzgestützte ethische Analyse

Author: Synofzik, M.
Published: 2007
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71. CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons

Author: Schuster, S., Heuten, E., Velic, A., Admard, J., Synofzik, M., Ossowski, S., Macek, B., Hauser, S., and Schöls, L.
Subjects: Cortical neurons, CHIP/STUB1, Proteome, Cell Survival, Ubiquitin-Protein Ligases, Induced Pluripotent Stem Cells, lcsh:Medicine, genetics [Mutation], genetics [Heat-Shock Response], chemistry [Ubiquitin-Protein Ligases], Protein Refolding, metabolism [Ubiquitin-Protein Ligases], ddc:570, lcsh:Pathology, pathology [Neurons], Humans, CRISPR/Cas9, genetics [Ubiquitin-Protein Ligases], Neurons, Heat shock response, lcsh:R, SCAR16, Ubiquitination, cytology [Induced Pluripotent Stem Cells], metabolism [Proteome], Fibroblasts, Induced pluripotent stem cells, Oxidative Stress, metabolism [Neurons], Mutation, pathology [Fibroblasts], metabolism [Fibroblasts], Biomarkers, Heat-Shock Response, lcsh:RB1-214, metabolism [Biomarkers], Research Article
Abstract: C-terminus of HSC70-interacting protein (CHIP) encoded by the gene STUB1 is a co-chaperone and E3 ligase that acts as a key regulator of cellular protein homeostasis. Mutations in STUB1 cause autosomal recessive spinocerebellar ataxia type 16 (SCAR16) with widespread neurodegeneration manifesting as spastic-ataxic gait disorder, dementia and epilepsy. CHIP−/− mice display severe cerebellar atrophy, show high perinatal lethality and impaired heat stress tolerance. To decipher the pathomechanism underlying SCAR16, we investigated the heat shock response (HSR) in primary fibroblasts of three SCAR16 patients. We found impaired HSR induction and recovery compared to healthy controls. HSPA1A/B transcript levels (coding for HSP70) were reduced upon heat shock but HSP70 remained higher upon recovery in patient- compared to control-fibroblasts. As SCAR16 primarily affects the central nervous system we next investigated the HSR in cortical neurons (CNs) derived from induced pluripotent stem cells of SCAR16 patients. We found CNs of patients and controls to be surprisingly resistant to heat stress with high basal levels of HSP70 compared to fibroblasts. Although heat stress resulted in strong transcript level increases of many HSPs, this did not translate into higher HSP70 protein levels upon heat shock, independent of STUB1 mutations. Furthermore, STUB1(−/−) neurons generated by CRISPR/Cas9-mediated genome editing from an isogenic healthy control line showed a similar HSR to patients. Proteomic analysis of CNs showed dysfunctional protein (re)folding and higher basal oxidative stress levels in patients. Our results question the role of impaired HSR in SCAR16 neuropathology and highlight the need for careful selection of proper cell types for modeling human diseases., Summary: Cell viability, expression and immunocytochemical analyses reveal that mutations in STUB1 that cause SCAR16 impair the heat-shock response in patient-derived fibroblasts, but not in iPSC-derived cortical neurons.
Published: 2020

72. Correction to:A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity (Acta Neuropathologica, (2019), 138, 2, (237-250), 10.1007/s00401-019-02026-8)

Author: van der Lee, Sven J., Conway, Olivia J., Jansen, Iris, Carrasquillo, Minerva M., Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R., Stringa, Najada, Chen, Jason A., Zettergren, Anna, Andlauer, Till F.M., Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E., Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J., Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A., Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M., Indakoetxea, Begoña, Collij, Lyduine E., Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W., van Berckel, Bart N.M., Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L., Pastor, Pau, Rodríguez Rodríguez, Eloy, Mead, S., Synofzik, M., van Swieten, J. C., Leber, I., Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B.J., Dobson-Stone, C., Schofield, P. R., Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Blesa, R., Landqvist Waldö, M., Nilsson, K., Nilsson, C., Mackenzie, I. R.A., Hsiung, G. Y.R., Mann, D. M.A., Grafman, J., Morris, C. M., Attems, J., Griffiths, T. D., McKeith, I. G., Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Razquin, C., Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C.M., Uphill, J., Collinge, J., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., van der Zee, J., Van Broeckhoven, C., Cappa, S. F., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Baker, M., Josephs, K. A., Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., Dopper, E. G.P., Seelaar, H., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H. H., Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Boeve, Bradley F., Petersen, Ronald C., Ferman, Tanis J., van Gerpen, Jay A., Reinders, Marcel J.T., Uitti, Ryan J., Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K., van Schoor, Natasja M., Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K., Ross, Owen A., Dickson, Dennis W., Graff-Radford, Neill R., Knopman, David, Rademakers, Rosa, Lemstra, Afina W., Pijnenburg, Yolande A.L., Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F., Hemmer, Bernhard, Huisman, Martijn A., Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A., Sørensen, Thorkild I.A., Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, Coppola, G., Varpetian, A., Foroud, T. M., Levey, A. I., Kukull, W. A., Mendez, M. F., Ringman, J., Chui, H., Cotman, C., DeCarli, C., Geschwind, D. H., Clarimón, Jordi, Christensen, Kaare, Ertekin-Taner, Nilüfer, Scholz, Sonja W., Ramirez, Alfredo, Ruiz, Agustín, Slagboom, Eline, van der Flier, Wiesje M., and Holstege, Henne
Abstract: The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.
Published: 2020

73. Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity (Acta Neuropathologica, (2019), 138, 2, (237-250), 10.1007/s00401-019-02026-8)

Author: van der Lee, S. J., Conway, O. J., Jansen, I., Carrasquillo, M. M., Kleineidam, L., van den Akker, E., Hernandez, I., van Eijk, K. R., Stringa, N., Chen, J. A., Zettergren, A., Andlauer, T. F. M., Diez-Fairen, M., Simon-Sanchez, J., Lleo, A., Zetterberg, H., Nygaard, M., Blauwendraat, C., Savage, J. E., Mengel-From, J., Moreno-Grau, S., Wagner, M., Fortea, J., Keogh, M. J., Blennow, K., Skoog, I., Friese, M. A., Pletnikova, O., Zulaica, M., Lage, C., de Rojas, I., Riedel-Heller, S., Illan-Gala, I., Wei, W., Jeune, B., Orellana, A., Then Bergh, F., Wang, X., Hulsman, M., Beker, N., Tesi, N., Morris, C. M., Indakoetxea, B., Collij, L. E., Scherer, M., Morenas-Rodriguez, E., Ironside, J. W., van Berckel, B. N. M., Alcolea, D., Wiendl, H., Strickland, S. L., Pastor, P., Rodriguez Rodriguez, E., Mead, S., Synofzik, M., van Swieten, J. C., Leber, I., Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Schofield, P. R., Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Blesa, R., Landqvist Waldo, M., Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G. -Y. R., Mann, D. M. A., Grafman, J., Attems, J., Griffiths, T. D., Mckeith, I. G., Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Razquin, C., Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., van der Zee, J., Van Broeckhoven, C., Cappa, S. F., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Baker, M., Josephs, K. A., Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., Dopper, E. G. P., Seelaar, H., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H. -H., Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Boeve, B. F., Petersen, R. C., Ferman, T. J., van Gerpen, J. A., Reinders, M. J. T., Uitti, R. J., Tarraga, L., Maier, W., Dols-Icardo, O., Kawalia, A., Dalmasso, M. C., Boada, M., Zettl, U. K., van Schoor, N. M., Beekman, M., Allen, M., Masliah, E., de Munain, A. L., Pantelyat, A., Wszolek, Z. K., Ross, O. A., Dickson, D. W., Graff-Radford, N. R., Knopman, D., Rademakers, R., Lemstra, A. W., Pijnenburg, Y. A. L., Scheltens, P., Gasser, T., Chinnery, P. F., Hemmer, B., Huisman, M. A., Troncoso, J., Moreno, F., Nohr, E. A., Sorensen, T. I. A., Heutink, P., Sanchez-Juan, P., Posthuma, D., Coppola, G., Varpetian, A., Foroud, T. M., Levey, A. I., Kukull, W. A., Mendez, M. F., Ringman, J., Chui, H., Cotman, C., Decarli, C., Geschwind, D. H., Clarimon, J., Christensen, K., Ertekin-Taner, N., Scholz, S. W., Ramirez, A., Ruiz, A., Slagboom, E., van der Flier, W. M., Holstege, H., Neurology, Epidemiology and Data Science, Human genetics, APH - Societal Participation & Health, APH - Aging & Later Life, Amsterdam Neuroscience - Complex Trait Genetics, APH - Personalized Medicine, and APH - Methodology
Subjects: education
Abstract: The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.
Published: 2020

74. Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice

Author: Wilke, Carlo, Haas, Eva, Reetz, K., Faber, Jennifer, Garcia-Moreno, Hector, Santana, Magda M., Warrenburg, B.P.C. van de, Huebener-Schmid, Jeannette, and Synofzik, M.
Subjects: All institutes and research themes of the Radboud University Medical Center, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3]
Abstract: Contains fulltext : 221548.pdf (Publisher’s version ) (Open Access)
Published: 2020

75. Analysis of brain atrophy and local gene expression in genetic frontotemporal dementia

Author: Altmann, A., Cash, D. M., Bocchetta, M., Heller, C., Reynolds, R., Moore, K., Convery, R. S., Thomas, D. L., Van Swieten, J. C., Moreno, F., Sanchez-Valle, R., Borroni, B., Laforce, R., Masellis, M., Tartaglia, M. C., Graff, C., Galimberti, D., Rowe, J. B., Finger, E., Synofzik, M., Vandenberghe, R., De Mendonca, A., Tagliavini, F., Santana, I., Ducharme, S., Butler, C. R., Gerhard, A., Levin, J., Danek, A., Frisoni, G., Ghidoni, R., Sorbi, S., Otto, M., Ryten, M., Rohrer, J. D., Greaves, C., Peakman, G., Shafei, R., Todd, E., Rossor, M. N., Warren, J. D., Fox, N. C., Zetterberg, H., Guerreiro, R., Bras, J., Nicholas, J., Mead, S., Jiskoot, L., Meeter, L., Panman, J., Papma, J. M., Van Minkelen, R., Pijnenburg, Y., Barandiaran, M., Indakoetxea, B., Gabilondo, A., Tainta, M., De Arriba, M., Gorostidi, A., Zulaica, M., Villanua, J., Diaz, Z., Borrego-Ecija, S., Olives, J., Llado, A., Balasa, M., Antonell, A., Bargallo, N., Premi, E., Cosseddu, M., Gazzina, S., Padovani, A., Gasparotti, R., Archetti, S., Black, S., Mitchell, S., Rogaeva, E., Freedman, M., Keren, R., Tang-Wai, D., Oijerstedt, L., Andersson, C., Jelic, V., Thonberg, H., Arighi, A., Fenoglio, C., Scarpini, E., Fumagalli, G., Cope, T., Timberlake, C., Rittman, T., Shoesmith, C., Bartha, R., Rademakers, R., Wilke, C., Karnarth, H. -O., Bender, B., Bruffaerts, R., Van Damme, P., Vandenbulcke, M., Ferreira, C. B., Miltenberger, G., Maruta, C., Verdelho, A., Afonso, S., Taipa, R., Caroppo, P., Di Fede, G., Giaccone, G., Prioni, S., Redaelli, V., Rossi, G., Tiraboschi, P., Duro, D., Almeida, M. R., Castelo-Branco, M., Leitao, M. J., Tabuas-Pereira, M., Santiago, B., Gauthier, S., Rosa-Neto, P., Veldsman, M., Thompson, P., Langheinrich, T., Prix, C., Hoegen, T., Wlasich, E., Loosli, S., Schonecker, S., Semler, E., Anderl-Straub, S., Benussi, L., Binetti, G., Pievani, M., Lombardi, G., Nacmias, B., Ferrari, C., Bessi, V., Polito, C., Rowe, James [0000-0001-7216-8679], Apollo - University of Cambridge Repository, Medical Research Council, and Genetic FTD Initiative, GENFI
Subjects: 0301 basic medicine, Cell type, Imaging genetics, Clinical Neurology, Medizin, Biology, Article, DISEASE, 03 medical and health sciences, 0302 clinical medicine, Atrophy, atrophy, C9orf72, Gene expression, medicine, Astrocytes, Frontotemporal dementia, ddc:610, 10. No inequality, Gene, 030304 developmental biology, Genetics, 0303 health sciences, Science & Technology, TREM2, AcademicSubjects/SCI01870, Neurodegeneration, General Engineering, C9orf72 Gene, Neurosciences, astrocytes, Genetic FTD Initiative, GENFI, medicine.disease, C9orf72 Protein, 030104 developmental biology, gene expression, imaging genetics, Original Article, AcademicSubjects/MED00310, Human medicine, Neurosciences & Neurology, Life Sciences & Biomedicine, 030217 neurology & neurosurgery
Abstract: Frontotemporal dementia is a heterogeneous neurodegenerative disorder characterized by neuronal loss in the frontal and temporal lobes. Despite progress in understanding which genes are associated with the aetiology of frontotemporal dementia, the biological basis of how mutations in these genes lead to cell loss in specific cortical regions remains unclear. In this work, we combined gene expression data for 16 772 genes from the Allen Institute for Brain Science atlas with brain maps of grey matter atrophy in symptomatic C9orf72, GRN and MAPT mutation carriers obtained from the Genetic Frontotemporal dementia Initiative study. No significant association was seen between C9orf72, GRN and MAPT expression and the atrophy patterns in the respective genetic groups. After adjusting for spatial autocorrelation, between 1000 and 5000 genes showed a negative or positive association with the atrophy pattern within each individual genetic group, with the most significantly associated genes being TREM2, SSBP3 and GPR158 (negative association in C9Orf72, GRN and MAPT respectively) and RELN, MXRA8 and LPA (positive association in C9Orf72, GRN and MAPT respectively). An overrepresentation analysis identified a negative association with genes involved in mitochondrial function, and a positive association with genes involved in vascular and glial cell function in each of the genetic groups. A set of 423 and 700 genes showed significant positive and negative association, respectively, with atrophy patterns in all three maps. The gene set with increased expression in spared cortical regions was enriched for neuronal and microglial genes, while the gene set with increased expression in atrophied regions was enriched for astrocyte and endothelial cell genes. Our analysis suggests that these cell types may play a more active role in the onset of neurodegeneration in frontotemporal dementia than previously assumed, and in the case of the positively associated cell marker genes, potentially through emergence of neurotoxic astrocytes and alteration in the blood–brain barrier, respectively., Altmann et al. investigated the concordance between spatial cortical gene expression in healthy subjects and atrophy patterns in genetic frontotemporal dementia. They found that elevated gene expression of endothelial cell and astrocyte-related genes in regions with atrophy, suggesting a role of these cell types in the aetiology of frontotemporal dementia., Graphical Abstract Graphical Abstract
Published: 2020

76. Spinocerebellar ataxia type 14: refining clinico-genetic diagnosis in a rare adult-onset disorder

Author: Schmitz-Hübsch, T., Lux, Silke, Synofzik, M., Giorgetti, A., Carloni, Paolo, Shah, N. J., Schöls, L., Kopp, U., Bussenius, L., Oberwahrenbrock, T., Zimmermann, H., Pfueller, C., Bauer, P., Kadas, E. M., Rönnefarth, M., Grosch, A. S., Endres, M., Amunts, Katrin, Friedemann, P., Doss, S., Minnerop, Martina, Schlapakow, E., Greschus, S., Scheel, M., Gärtner, Hanna, Kirlangic, Mehmet Eylem, Gras, Vincent, and Timmann, D.
Subjects: ddc:610
Published: 2020

77. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

Author: Moore, K.M. Nicholas, J. Grossman, M. McMillan, C.T. Irwin, D.J. Massimo, L. Van Deerlin, V.M. Warren, J.D. Fox, N.C. Rossor, M.N. Mead, S. Bocchetta, M. Boeve, B.F. Knopman, D.S. Graff-Radford, N.R. Forsberg, L.K. Rademakers, R. Wszolek, Z.K. van Swieten, J.C. Jiskoot, L.C. Meeter, L.H. Dopper, E.G. Papma, J.M. Snowden, J.S. Saxon, J. Jones, M. Pickering-Brown, S. Le Ber, I. Camuzat, A. Brice, A. Caroppo, P. Ghidoni, R. Pievani, M. Benussi, L. Binetti, G. Dickerson, B.C. Lucente, D. Krivensky, S. Graff, C. Öijerstedt, L. Fallström, M. Thonberg, H. Ghoshal, N. Morris, J.C. Borroni, B. Benussi, A. Padovani, A. Galimberti, D. Scarpini, E. Fumagalli, G.G. Mackenzie, I.R. Hsiung, G.-Y.R. Sengdy, P. Boxer, A.L. Rosen, H. Taylor, J.B. Synofzik, M. Wilke, C. Sulzer, P. Hodges, J.R. Halliday, G. Kwok, J. Sanchez-Valle, R. Lladó, A. Borrego-Ecija, S. Santana, I. Almeida, M.R. Tábuas-Pereira, M. Moreno, F. Barandiaran, M. Indakoetxea, B. Levin, J. Danek, A. Rowe, J.B. Cope, T.E. Otto, M. Anderl-Straub, S. de Mendonça, A. Maruta, C. Masellis, M. Black, S.E. Couratier, P. Lautrette, G. Huey, E.D. Sorbi, S. Nacmias, B. Laforce, R., Jr Tremblay, M.-P.L. Vandenberghe, R. Damme, P.V. Rogalski, E.J. Weintraub, S. Gerhard, A. Onyike, C.U. Ducharme, S. Papageorgiou, S.G. Ng, A.S.L. Brodtmann, A. Finger, E. Guerreiro, R. Bras, J. Rohrer, J.D. Heller, C. Convery, R.S. Woollacott, I.O. Shafei, R.M. Graff-Radford, J. Jones, D.T. Dheel, C.M. Savica, R. Lapid, M.I. Baker, M. Fields, J.A. Gavrilova, R. Domoto-Reilly, K. Poos, J.M. Van der Ende, E.L. Panman, J.L. Donker Kaat, L. Seelaar, H. Richardson, A. Frisoni, G. Mega, A. Fostinelli, S. Chiang, H.-H. Alberici, A. Arighi, A. Fenoglio, C. Heuer, H. Miller, B. Karydas, A. Fong, J. João Leitão, M. Santiago, B. Duro, D. Ferreira, C. Gabilondo, A. De Arriba, M. Tainta, M. Zulaica, M. Ferreira, C. Semler, E. Ludolph, A. Landwehrmeyer, B. Volk, A.E. Miltenberger, G. Verdelho, A. Afonso, S. Tartaglia, M.C. Freedman, M. Rogaeva, E. Ferrari, C. Piaceri, I. Bessi, V. Lombardi, G. St-Onge, F. Doré, M.-C. Bruffaerts, R. Vandenbulcke, M. Van den Stock, J. Mesulam, M.M. Bigio, E. Koros, C. Papatriantafyllou, J. Kroupis, C. Stefanis, L. Shoesmith, C. Robertson, E. Coppola, G. Da Silva Ramos, E.M. Geschwind, D.
Abstract: Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35–62, for age at onset; 61%, 47–73, for age at death), and even more by family membership (66%, 56–75, for age at onset; 74%, 65–82, for age at death). In the GRN group, only 2% (0–10) of the variability of age at onset and 9% (3–21) of that of age of death was explained by the specific mutation, whereas 14% (9–22) of the variability of age at onset and 20% (12–30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11–26) of the variability of age at onset and 19% (12–29) of that of age at death. Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates. Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society. © 2020 Elsevier Ltd
Published: 2020

78. Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients

Author: Traschütz, A., Schirinzi, T., Laugwitz, L., Murray, N.H., Bingman, C.A., Reich, S., Kern, J., Heinzmann, A., Vasco, G., Bertini, E., Zanni, G., Durr, A., Magri, S., Taroni, F., Malandrini, A., Baets, J., Jonghe, P. De, Ridder, W. De, Bereau, M., Demuth, S., Ganos, C., Basak, A.N., Hanagasi, H., Kurul, S.H., Bender, B., Schöls, L., Grasshoff, U., Klopstock, T., Horvath, R., Warrenburg, B.P.C. van de, Burglen, L., Rougeot, C., Ewenczyk, C., Koenig, M., Santorelli, F.M., Anheim, M., Munhoz, R.P., Haack, T., Distelmaier, F., Pagliarini, D.J., Puccio, H., Synofzik, M., Traschütz, A., Schirinzi, T., Laugwitz, L., Murray, N.H., Bingman, C.A., Reich, S., Kern, J., Heinzmann, A., Vasco, G., Bertini, E., Zanni, G., Durr, A., Magri, S., Taroni, F., Malandrini, A., Baets, J., Jonghe, P. De, Ridder, W. De, Bereau, M., Demuth, S., Ganos, C., Basak, A.N., Hanagasi, H., Kurul, S.H., Bender, B., Schöls, L., Grasshoff, U., Klopstock, T., Horvath, R., Warrenburg, B.P.C. van de, Burglen, L., Rougeot, C., Ewenczyk, C., Koenig, M., Santorelli, F.M., Anheim, M., Munhoz, R.P., Haack, T., Distelmaier, F., Pagliarini, D.J., Puccio, H., and Synofzik, M.
Abstract: Contains fulltext : 229734.pdf (Publisher’s version ) (Open Access), OBJECTIVE: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). METHODS: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype-phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. RESULTS: Fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82-93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: -0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. INTERPRETATION: This study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia. ANN NEUROL 2020;88:251-263.
Published: 2020

79. Apathy in presymptomatic genetic frontotemporal dementia predicts cognitive decline and is driven by structural brain changes

Author: Malpetti, M. (Maura), Jones, P.S. (P. Simon), Tsvetanov, K.A. (Kamen A.), Rittman, T. (Timothy), Swieten, J.C. (John) van, Borroni, B. (Barbara), Sánchez-Valle, R. (Raquel), Moreno, F. (Fermin), Laforce, R. (Robert), Graff, C. (Caroline), Synofzik, M. (Matthis), Galimberti, D. (Daniela), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Finger, E. (Elizabeth), Vandenberghe, R. (Rik), De Mendonça, A. (Alexandre), Tagliavini, F. (Fabrizio), Santana, I. (Isabel), Ducharme, S. (Simon), Butler, C.R. (Chris R.), Gerhard, A. (Alex), Levin, J. (Johannes), Danek, A. (Adrian), Otto, M. (Markus), Frisoni, G.B. (Giovanni B.), Ghidoni, R. (Roberta), Sorbi, S. (Sandro), Heller, C. (Carolin), Todd, E.G. (Emily G.), Bocchetta, M. (Martina), Cash, D.M. (David M.), Convery, R.S. (Rhian S.), Peakman, G. (Georgia), Moore, K.M. (Katrina M.), Rohrer, J.D. (Jonathan), Kievit, R.A. (Rogier A.), Rowe, J.B. (James), Malpetti, M. (Maura), Jones, P.S. (P. Simon), Tsvetanov, K.A. (Kamen A.), Rittman, T. (Timothy), Swieten, J.C. (John) van, Borroni, B. (Barbara), Sánchez-Valle, R. (Raquel), Moreno, F. (Fermin), Laforce, R. (Robert), Graff, C. (Caroline), Synofzik, M. (Matthis), Galimberti, D. (Daniela), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Finger, E. (Elizabeth), Vandenberghe, R. (Rik), De Mendonça, A. (Alexandre), Tagliavini, F. (Fabrizio), Santana, I. (Isabel), Ducharme, S. (Simon), Butler, C.R. (Chris R.), Gerhard, A. (Alex), Levin, J. (Johannes), Danek, A. (Adrian), Otto, M. (Markus), Frisoni, G.B. (Giovanni B.), Ghidoni, R. (Roberta), Sorbi, S. (Sandro), Heller, C. (Carolin), Todd, E.G. (Emily G.), Bocchetta, M. (Martina), Cash, D.M. (David M.), Convery, R.S. (Rhian S.), Peakman, G. (Georgia), Moore, K.M. (Katrina M.), Rohrer, J.D. (Jonathan), Kievit, R.A. (Rogier A.), and Rowe, J.B. (James)
Abstract: 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.
Published: 2020
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80. Social cognition impairment in genetic frontotemporal dementia within the GENFI cohort

Author: Russell, L.L. (Lucy L.), Greaves, C.V. (Caroline V.), Bocchetta, M. (Martina), Nicholas, J.M. (Jennifer), Convery, R.S. (Rhian S.), Moore, K. (Katrina), Cash, D.M. (David M.), Swieten, J.C. (John) van, Jiskoot, L.C. (Lize), Moreno, F. (Fermin), Sánchez-Valle, R. (Raquel), Borroni, B. (Barbara), Laforce, R. (Robert), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Graff, C. (Caroline), Rotondo, E. (Emanuela), Galimberti, D. (Daniela), Rowe, J.B. (James), Finger, E. (Elizabeth), Synofzik, M. (Matthis), Vandenberghe, R. (Rik), De Mendonça, A. (Alexandre), Tagliavini, F. (Fabrizio), Santana, I. (Isabel), Ducharme, S. (Simon), Butler, C. (Chris), Gerhard, A. (Alex), Levin, J. (Johannes), Danek, A. (Adrian), Otto, M. (Markus), Warren, J.D. (Jason), Rohrer, J.D. (Jonathan), Rossor, M. (Martin), Fox, N.C. (Nick), Woollacott, I.O.C. (Ione O.C.), Shafei, R. (Rachelle), Heller, C. (Carolin), Guerreiro, R. (Rita), Bras, J. (Jose), Thomas, D.L. (David L), Mead, S. (Simon), Meeter, L.H.H. (Lieke), Panman, J.L. (Jessica), Papma, J.M. (Janne), Poos, J.M. (Jackie), Thornton, A.S. (Andrew), Pijnenburg, Y. (Yolanda), Barandiaran, M. (Myriam), Indakoetxea, B. (Begoña), Gabilondo, A. (Alazne), Tainta, M. (Mikel), de Arriba, M. (Maria), Gorostidi, A. (Ana), Zulaica, M. (Miren), Villanua, J. (Jorge), Diaz, Z. (Zigor), Borrego-Ecija, S. (Sergi), Olives, J. (Jaume), Lladó, A. (Albert), Balasa, M. (Mircea), Antonell, A. (Anna), Bargallo, N. (Nuria), Premi, E. (Enrico), Cosseddu MPsych, M. (Maura), Gazzina, S. (Stefano), Padovani, A. (Alessandro), Gasparotti, R. (Roberto), Archetti, S. (Silvana), Black, S.E. (Sandra), Mitchell, S. (Sara), Rogaeva, E. (Ekaterina), Freedman, M. (Morris), Keren, R. (Ron), Tang-Wai, D. (Daid), Öijerstedt, L. (Linn), Andersson, C. (Christin), Jelic, S. (Svetislav Svetislav), Thonberg, H. (Håkan), Arighi, A. (Andrea), Fenoglio, C. (Chiara), Scarpini, E. (Elio), Fumagalli, G. (Giorgio), Cope, T. (Thomas), Timberlake, C. (Carolyn), Rittman, T. (Timothy), Shoesmith, C. (Christen), Bartha, R. (Robart), Rademakers, S. (Suzanne), Wilke, C. (Carlo), Karnarth, H.-O. (Hans-Otto), Bender, B. (Benjamin), Bruffaerts, R. (Rose), Vandamme, P. (Philip), Vandenbulcke, M. (Mathieu), Ferreira, C.B. (Catarina B.), Miltenberger, G. (Gabriel), Maruta MPsych, C. (Carolina), Verdelho, A. (Ana), Afonso, S. (Sónia), Taipa, R. (Ricardo), Caroppo, P. (Paola), Di Fede, G. (Giuseppe), Giaccone, G. (Giuseppe), Muscio, C. (Cristina), Prioni, S. (Sara), Redaelli, V. (Veronica), Rossi, G. (Giacomina), Tiraboschi, P. (Pietro), Duro NPsych, D. (Diana), Almeida, M.R. (Maria R.), Castelo-Branco, M. (Miguel), Leitão, M.J. (Maria J.), Tabuas-Pereira, M. (Miguel), Santiago, B. (Beatriz), Gauthier, S. (Serge), Rosa-Neto, P. (Pedro), Veldsman, M. (Michele), Thompson, P.M. (Paul), Langheinrich, T. (Tobias), Prix, C. (Catharina), Hoegen, T. (Tobias), Wlasich, E. (Elisabeth), Loosli, S. (Sandra), Schonecker, S. (Sonja), Semler, E. (Elisa), Anderl-Straub, S. (Sarah), Russell, L.L. (Lucy L.), Greaves, C.V. (Caroline V.), Bocchetta, M. (Martina), Nicholas, J.M. (Jennifer), Convery, R.S. (Rhian S.), Moore, K. (Katrina), Cash, D.M. (David M.), Swieten, J.C. (John) van, Jiskoot, L.C. (Lize), Moreno, F. (Fermin), Sánchez-Valle, R. (Raquel), Borroni, B. (Barbara), Laforce, R. (Robert), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Graff, C. (Caroline), Rotondo, E. (Emanuela), Galimberti, D. (Daniela), Rowe, J.B. (James), Finger, E. (Elizabeth), Synofzik, M. (Matthis), Vandenberghe, R. (Rik), De Mendonça, A. (Alexandre), Tagliavini, F. (Fabrizio), Santana, I. (Isabel), Ducharme, S. (Simon), Butler, C. (Chris), Gerhard, A. (Alex), Levin, J. (Johannes), Danek, A. (Adrian), Otto, M. (Markus), Warren, J.D. (Jason), Rohrer, J.D. (Jonathan), Rossor, M. (Martin), Fox, N.C. (Nick), Woollacott, I.O.C. (Ione O.C.), Shafei, R. (Rachelle), Heller, C. (Carolin), Guerreiro, R. (Rita), Bras, J. (Jose), Thomas, D.L. (David L), Mead, S. (Simon), Meeter, L.H.H. (Lieke), Panman, J.L. (Jessica), Papma, J.M. (Janne), Poos, J.M. (Jackie), Thornton, A.S. (Andrew), Pijnenburg, Y. (Yolanda), Barandiaran, M. (Myriam), Indakoetxea, B. (Begoña), Gabilondo, A. (Alazne), Tainta, M. (Mikel), de Arriba, M. (Maria), Gorostidi, A. (Ana), Zulaica, M. (Miren), Villanua, J. (Jorge), Diaz, Z. (Zigor), Borrego-Ecija, S. (Sergi), Olives, J. (Jaume), Lladó, A. (Albert), Balasa, M. (Mircea), Antonell, A. (Anna), Bargallo, N. (Nuria), Premi, E. (Enrico), Cosseddu MPsych, M. (Maura), Gazzina, S. (Stefano), Padovani, A. (Alessandro), Gasparotti, R. (Roberto), Archetti, S. (Silvana), Black, S.E. (Sandra), Mitchell, S. (Sara), Rogaeva, E. (Ekaterina), Freedman, M. (Morris), Keren, R. (Ron), Tang-Wai, D. (Daid), Öijerstedt, L. (Linn), Andersson, C. (Christin), Jelic, S. (Svetislav Svetislav), Thonberg, H. (Håkan), Arighi, A. (Andrea), Fenoglio, C. (Chiara), Scarpini, E. (Elio), Fumagalli, G. (Giorgio), Cope, T. (Thomas), Timberlake, C. (Carolyn), Rittman, T. (Timothy), Shoesmith, C. (Christen), Bartha, R. (Robart), Rademakers, S. (Suzanne), Wilke, C. (Carlo), Karnarth, H.-O. (Hans-Otto), Bender, B. (Benjamin), Bruffaerts, R. (Rose), Vandamme, P. (Philip), Vandenbulcke, M. (Mathieu), Ferreira, C.B. (Catarina B.), Miltenberger, G. (Gabriel), Maruta MPsych, C. (Carolina), Verdelho, A. (Ana), Afonso, S. (Sónia), Taipa, R. (Ricardo), Caroppo, P. (Paola), Di Fede, G. (Giuseppe), Giaccone, G. (Giuseppe), Muscio, C. (Cristina), Prioni, S. (Sara), Redaelli, V. (Veronica), Rossi, G. (Giacomina), Tiraboschi, P. (Pietro), Duro NPsych, D. (Diana), Almeida, M.R. (Maria R.), Castelo-Branco, M. (Miguel), Leitão, M.J. (Maria J.), Tabuas-Pereira, M. (Miguel), Santiago, B. (Beatriz), Gauthier, S. (Serge), Rosa-Neto, P. (Pedro), Veldsman, M. (Michele), Thompson, P.M. (Paul), Langheinrich, T. (Tobias), Prix, C. (Catharina), Hoegen, T. (Tobias), Wlasich, E. (Elisabeth), Loosli, S. (Sandra), Schonecker, S. (Sonja), Semler, E. (Elisa), and Anderl-Straub, S. (Sarah)
Abstract: A key symptom of frontotemporal dementia (FTD) is difficulty interacting socially with others. Social cognition problems in FTD include impaired emotion processing and theory of mind difficulties, and whilst these have been studied extensively in sporadic FTD, few studies have investigated them in familial FTD. Facial Emotion Recognition (FER) and Faux Pas (FP) recognition tests were used to study social cognition within the Genetic Frontotemporal Dementia Initiative (GENFI), a large familial FTD cohort of C9orf72, GRN, and MAPT mutation carriers. 627 participants undertook at least one of the tasks, and were separated into mutation-negative healthy controls, presymptomatic mutation carriers (split into early and late groups) and symptomatic mutation carriers. Groups were compared using a linear regression model with bootstrapping, adjusting for age, sex, education, and for the FP recognition test, language. Neural correlates of social cognition deficits were explored using a voxel-based morphometry (VBM) study. All three of the symptomatic genetic groups were impaired on both tasks with no significant difference between them. However, prior to onset, only the late presymptomatic C9orf72 mutation carriers on the FER test were impaired compared to the control group, with a subanalysis showing differences particularly in fear and sadness. The VBM analysis revealed that impaired social cognition was mainly associated with a left hemisphere predominant network of regions involving particularly the striatum, orbitofrontal cortex and insula, and to a lesser extent the inferomedial temporal lobe and other areas of the frontal lobe. In conclusion, theory of mind and emotion processing abilities are impaired in familial FTD, with early changes occurring prior to symptom onset in C9orf72 presymptomatic mutation carriers. Future work should investigate how performance changes over time, in order to gain a clearer insight into social cognitive impairment over the course of the
Published: 2020
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81. LifeTime and improving European healthcare through cell-based interceptive medicine

Author: Rajewsky, N. (Nikolaus), Almouzni, G. (Geneviève), Gorski, S.A. (Stanislaw A.), Aerts, S. (Stein), Amit, I. (Ido), Bertero, M.G. (Michela G.), Bock, C. (Christoph), Bredenoord, A.L. (Annelien L.), Cavalli, G. (Giacomo), Chiocca, S. (Susanna), Clevers, H.C. (Hans), Strooper, B. (Bart) de, Eggert, A. (Angelika), Ellenberg, J. (Jan), Fernández, X.M. (Xosé M.), Figlerowicz, M. (Marek), Gasser, S.M. (Susan M.), Hübner, N. (Norbert), Kjems, J. (Jørgen), Knoblich, J.A. (Jürgen A.), Krabbe, G. (Grietje), Lichter, P. (Peter), Linnarsson, S. (Sten), Marine, J.-C. (J.), Marioni, J. (John), Marti-Renom, M.A. (Marc A.), Netea, M.G. (Mihai), Nickel, D. (Dörthe), Nollmann, M. (Marcelo), Novak, H.R. (Halina R.), Parkinson, H. (Helen), Piccolo, S. (Stefano), Pinheiro, I. (Inês), Pombo, A. (Ana), Popp, C. (Christian), Reik, W. (Wolf), Roman-Roman, S. (Sergio), Rosenstiel, P. (Philip), Schultze, J.L. (Joachim), Stegle, O. (Oliver), Tanay, A. (Amos), Testa, G. (Giuseppe), Thanos, D. (Dimitris), Theis, F. (Fabian), Torres-Padilla, M.-E. (Maria-Elena), Valencia, A. (Alfonso), Vallot, C. (Céline), van Oudenaarden, A. (Alexander), Vidal, M. (Marie), Voet, T. (Thierry), Alberi, L. (Lavinia), Alexander, S. (Stephanie), Alexandrov, T. (Theodore), Arenas, E. (Ernest), Bagni, C. (Claudia), Balderas, R. (Robert), Bandelli, A. (Andrea), Becher, B. (Burkhard), Becker, M. (Matthias), Beerenwinkel, N. (Niko), Benkirame, M. (Monsef), Beyer, M. (Marc), Bickmore, W. (Wendy), Biessen, E.E.A.L. (Erik E.A.L.), Blomberg, N. (Niklas), Blumcke, I. (Ingmar), Bodenmiller, B. (Bernd), Borroni, B. (Barbara), Boumpas, D.T. (Dimitrios T.), Bourgeron, T. (Thomas), Bowers, S. (Sarion), Braeken, D. (Dries), Brooksbank, C. (Catherine), Brose, N. (Nils), Bruining, J. (Hans), Bury, J. (Jo), Caporale, N. (Nicolo), Cattoretti, G. (Giorgio), Chabane, N. (Nadia), Chneiweiss, H. (Hervé), Cook, S.A. (Stuart A.), Curatolo, P. (Paolo), Jonge, M.I. (Marien) de, Deplancke, B. (Bart), De Strooper, B. (Bart), de Witte, P. (Peter), Dimmeler, S. (Stefanie), Draganski, B. (Bogdan), Drews, A.-D. (Anna-Dorothee), Dumbrava, C. (Costica), Engelhardt, S. (Stefan), Gasser, T. (Thomas), Giamarellos-Bourboulis, E. (Evangelos), Graff, C. (Caroline), Grün, D. (Dominic), Gut, I. (Ivo), Hansson, O. (Oskar), Henshall, D.C. (David C.), Herland, A. (Anna), Heutink, P. (Peter), Heymans, S. (Stephane), Heyn, H. (Holger), Huch, M. (Meritxell), Huitinga, I. (Inge), Jackowiak, P. (Paulina), Jongsma, K.R. (Karin), Journot, L. (Laurent), Junker, J.P. (Jan Philipp), Katz, S. (Shauna), Kehren, J. (Jeanne), Kempa, S. (Stefan), Kirchhof, P. (Paulus), Klein, C. (Christoph), Koralewska, N. (Natalia), Korbel, J.O. (Jan), Kühnemund, M. (Malte), Lamond, A.I. (Angus I.), Lauwers, E. (Elsa), Le Ber, I. (Isabelle), Leinonen, V. (Ville), Tobon, A.L. (Alejandro Lopez), Lundberg, E. (Emma), Lunkes, A. (Astrid), Maatz, H. (Henrike), Mann, M. (Mathias), Marelli, L. (Luca), Matser, V. (Vera), Matthews, P.M. (P.), Mechta-Grigoriou, F. (Fatima), Menon, R. (Radhika), Nielsen, A.F. (Anne F.), Pagani, M. (Massimiliano), Pasterkamp, R.J. (Jeroen), Pitkanen, A. (Asla), Popescu, V. (Valentin), Pottier, C. (Cyril), Puisieux, A. (Alain), Rademakers, R. (Rosa), Reiling, D. (Dory), Reiner, O. (Orly), Remondini, D. (Daniel), Ritchie, C. (Craig), Rohrer, J.D. (Jonathan D.), Saliba, A.-E. (Antione-Emmanuel), Sánchez-Valle, R. (Raquel), Santosuosso, A. (Amedeo), Sauter, A. (Arnold), Scheltema, R.A. (Richard A.), Scheltens, P. (Philip), Schiller, H.B. (Herbert B.), Schneider, A. (Anja), Seibler, P. (Philip), Sheehan-Rooney, K. (Kelly), Shields, D. (David), Sleegers, K. (Kristel), Smit, G. (Guus), Smith, K.G.C. (Kenneth G. C.), Smolders, I. (Ilse), Synofzik, M. (Matthis), Tam, W.L. (Wai Long), Teichmann, S. (Sarah), Thom, M. (Maria), Turco, M.Y. (Margherita Y.), Beusekom, H.M.M. (Heleen) van, Vandenberghe, R. (Rik), den Hoecke, S.V. (Silvie Van), Van de Poel, E. (Ellen), der Ven, A. (Andre van), van der Zee, J. (Julie), van Lunzen, J. (Jan), van Minnebruggen, G. (Geert), Van Paesschen, W. (Wim), Swieten, J.C. (John) van, van Vught, R. (Remko), Verhage, M. (Matthijs), Verstreken, P. (Patrik), Villa, C.E. (Carlo Emanuele), Vogel, J. (Jörg), Kalle, C. (Christof) von, Walter, J. (Jörn), Weckhuysen, S. (Sarah), Weichert, W. (Wilko), Wood, L. (Louisa), Ziegler, A.-G. (Anette-Gabriele), Zipp, F. (Frauke), Rajewsky, N. (Nikolaus), Almouzni, G. (Geneviève), Gorski, S.A. (Stanislaw A.), Aerts, S. (Stein), Amit, I. (Ido), Bertero, M.G. (Michela G.), Bock, C. (Christoph), Bredenoord, A.L. (Annelien L.), Cavalli, G. (Giacomo), Chiocca, S. (Susanna), Clevers, H.C. (Hans), Strooper, B. (Bart) de, Eggert, A. (Angelika), Ellenberg, J. (Jan), Fernández, X.M. (Xosé M.), Figlerowicz, M. (Marek), Gasser, S.M. (Susan M.), Hübner, N. (Norbert), Kjems, J. (Jørgen), Knoblich, J.A. (Jürgen A.), Krabbe, G. (Grietje), Lichter, P. (Peter), Linnarsson, S. (Sten), Marine, J.-C. (J.), Marioni, J. (John), Marti-Renom, M.A. (Marc A.), Netea, M.G. (Mihai), Nickel, D. (Dörthe), Nollmann, M. (Marcelo), Novak, H.R. (Halina R.), Parkinson, H. (Helen), Piccolo, S. (Stefano), Pinheiro, I. (Inês), Pombo, A. (Ana), Popp, C. (Christian), Reik, W. (Wolf), Roman-Roman, S. (Sergio), Rosenstiel, P. (Philip), Schultze, J.L. (Joachim), Stegle, O. (Oliver), Tanay, A. (Amos), Testa, G. (Giuseppe), Thanos, D. (Dimitris), Theis, F. (Fabian), Torres-Padilla, M.-E. (Maria-Elena), Valencia, A. (Alfonso), Vallot, C. (Céline), van Oudenaarden, A. (Alexander), Vidal, M. (Marie), Voet, T. (Thierry), Alberi, L. (Lavinia), Alexander, S. (Stephanie), Alexandrov, T. (Theodore), Arenas, E. (Ernest), Bagni, C. (Claudia), Balderas, R. (Robert), Bandelli, A. (Andrea), Becher, B. (Burkhard), Becker, M. (Matthias), Beerenwinkel, N. (Niko), Benkirame, M. (Monsef), Beyer, M. (Marc), Bickmore, W. (Wendy), Biessen, E.E.A.L. (Erik E.A.L.), Blomberg, N. (Niklas), Blumcke, I. (Ingmar), Bodenmiller, B. (Bernd), Borroni, B. (Barbara), Boumpas, D.T. (Dimitrios T.), Bourgeron, T. (Thomas), Bowers, S. (Sarion), Braeken, D. (Dries), Brooksbank, C. (Catherine), Brose, N. (Nils), Bruining, J. (Hans), Bury, J. (Jo), Caporale, N. (Nicolo), Cattoretti, G. (Giorgio), Chabane, N. (Nadia), Chneiweiss, H. (Hervé), Cook, S.A. (Stuart A.), Curatolo, P. (Paolo), Jonge, M.I. (Marien) de, Deplancke, B. (Bart), De Strooper, B. (Bart), de Witte, P. (Peter), Dimmeler, S. (Stefanie), Draganski, B. (Bogdan), Drews, A.-D. (Anna-Dorothee), Dumbrava, C. (Costica), Engelhardt, S. (Stefan), Gasser, T. (Thomas), Giamarellos-Bourboulis, E. (Evangelos), Graff, C. (Caroline), Grün, D. (Dominic), Gut, I. (Ivo), Hansson, O. (Oskar), Henshall, D.C. (David C.), Herland, A. (Anna), Heutink, P. (Peter), Heymans, S. (Stephane), Heyn, H. (Holger), Huch, M. (Meritxell), Huitinga, I. (Inge), Jackowiak, P. (Paulina), Jongsma, K.R. (Karin), Journot, L. (Laurent), Junker, J.P. (Jan Philipp), Katz, S. (Shauna), Kehren, J. (Jeanne), Kempa, S. (Stefan), Kirchhof, P. (Paulus), Klein, C. (Christoph), Koralewska, N. (Natalia), Korbel, J.O. (Jan), Kühnemund, M. (Malte), Lamond, A.I. (Angus I.), Lauwers, E. (Elsa), Le Ber, I. (Isabelle), Leinonen, V. (Ville), Tobon, A.L. (Alejandro Lopez), Lundberg, E. (Emma), Lunkes, A. (Astrid), Maatz, H. (Henrike), Mann, M. (Mathias), Marelli, L. (Luca), Matser, V. (Vera), Matthews, P.M. (P.), Mechta-Grigoriou, F. (Fatima), Menon, R. (Radhika), Nielsen, A.F. (Anne F.), Pagani, M. (Massimiliano), Pasterkamp, R.J. (Jeroen), Pitkanen, A. (Asla), Popescu, V. (Valentin), Pottier, C. (Cyril), Puisieux, A. (Alain), Rademakers, R. (Rosa), Reiling, D. (Dory), Reiner, O. (Orly), Remondini, D. (Daniel), Ritchie, C. (Craig), Rohrer, J.D. (Jonathan D.), Saliba, A.-E. (Antione-Emmanuel), Sánchez-Valle, R. (Raquel), Santosuosso, A. (Amedeo), Sauter, A. (Arnold), Scheltema, R.A. (Richard A.), Scheltens, P. (Philip), Schiller, H.B. (Herbert B.), Schneider, A. (Anja), Seibler, P. (Philip), Sheehan-Rooney, K. (Kelly), Shields, D. (David), Sleegers, K. (Kristel), Smit, G. (Guus), Smith, K.G.C. (Kenneth G. C.), Smolders, I. (Ilse), Synofzik, M. (Matthis), Tam, W.L. (Wai Long), Teichmann, S. (Sarah), Thom, M. (Maria), Turco, M.Y. (Margherita Y.), Beusekom, H.M.M. (Heleen) van, Vandenberghe, R. (Rik), den Hoecke, S.V. (Silvie Van), Van de Poel, E. (Ellen), der Ven, A. (Andre van), van der Zee, J. (Julie), van Lunzen, J. (Jan), van Minnebruggen, G. (Geert), Van Paesschen, W. (Wim), Swieten, J.C. (John) van, van Vught, R. (Remko), Verhage, M. (Matthijs), Verstreken, P. (Patrik), Villa, C.E. (Carlo Emanuele), Vogel, J. (Jörg), Kalle, C. (Christof) von, Walter, J. (Jörn), Weckhuysen, S. (Sarah), Weichert, W. (Wilko), Wood, L. (Louisa), Ziegler, A.-G. (Anette-Gabriele), and Zipp, F. (Frauke)
Abstract: LifeTime aims to track, understand and target human cells during the onset and progression of complex diseases and their response to therapy at single-cell resolution. This mission will be implemented through the development and integration of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during progression from health to disease. Analysis of such large molecular and clinical datasets will discover molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. Timely detection and interception of disease embedded in an ethical and patient-centered vision will be achieved through interactions across academia, hospitals, patient-associations, health data management systems and industry. Applying this strategy to key medical challenges in cancer, neurological, infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade.
Published: 2020
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82. Features of speech and swallowing dysfunction in pre-ataxic spinocerebellar ataxia type 2

Author: Vogel, AP, Magee, M, Torres-Vega, R, Medrano-Montero, J, Cyngler, MP, Kruse, M, Rojas, S, Cubillos, SC, Canento, T, Maldonado, F, Vazquez-Mojena, Y, Ilg, W, Rodriguez-Labrada, R, Velazquez-Perez, L, Synofzik, M, Vogel, AP, Magee, M, Torres-Vega, R, Medrano-Montero, J, Cyngler, MP, Kruse, M, Rojas, S, Cubillos, SC, Canento, T, Maldonado, F, Vazquez-Mojena, Y, Ilg, W, Rodriguez-Labrada, R, Velazquez-Perez, L, and Synofzik, M
Abstract: OBJECTIVE: To determine whether objective and quantitative assessment of dysarthria and dysphagia in spinocerebellar ataxia type 2 (SCA2), specifically at pre-ataxic and early disease phases, can act as sensitive disease markers. METHODS: Forty-six individuals (16 with pre-ataxic SCA2, 14 with early-stage ataxic SCA2, and 16 healthy controls) were recruited in Holguin, Cuba. All participants underwent a comprehensive battery of assessments including objective acoustic analysis, clinician-derived ratings of speech function and swallowing, and quality of life assessments of swallowing. RESULTS: Reduced speech agility manifest at the pre-ataxic stage was observed during diadochokinetic tasks, with the magnitude of speech deficit augmented in the early ataxic stage. Speech rate was slower in early-stage ataxic SCA2 compared with pre-ataxic SCA2 and healthy controls. Reduced speech agility and speech rate correlated with disease severity and time to ataxia onset, verifying that speech deficits occur prior to ataxia onset and increase in severity as the disease progresses. Whereas dysphagia was observed in both pre-ataxic and ataxic SCA2, it was not associated with swallowing-related quality of life, disease severity, or time to ataxia onset. CONCLUSIONS: Speech and swallowing deficits appear sensitive to disease progression in early-stage SCA2, with syllabic rate a viable marker. Findings provide insight into mechanisms of disease progression in early-stage SCA2, signaling an opportunity for stratifying early-stage SCA2 and identifying salient markers of disease onset as well as outcome measures in future early-stage therapeutic studies.
Published: 2020

83. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

Author: Moore, KM, Nicholas, J, Grossman, M, McMillan, CT, Irwin, DJ, Massimo, L, Van Deerlin, VM, Warren, JD, Fox, NC, Rossor, MN, Mead, S, Bocchetta, M, Boeve, BF, Knopman, DS, Graff-Radford, NR, Forsberg, LK, Rademakers, R, Wszolek, ZK, van Swieten, JC, Jiskoot, LC, Meeter, LH, Dopper, EGP, Papma, JM, Snowden, JS, Saxon, J, Jones, M, Pickering-Brown, S, Le Ber, I, Camuzat, A, Brice, A, Caroppo, P, Ghidoni, R, Pievani, M, Benussi, L, Binetti, G, Dickerson, BC, Lucente, D, Krivensky, S, Graff, C, Oijerstedt, L, Fallstrom, M, Thonberg, H, Ghoshal, N, Morris, JC, Borroni, B, Benussi, A, Padovani, A, Galimberti, D, Scarpini, E, Fumagalli, GG, Mackenzie, IR, Hsiung, G-YR, Sengdy, P, Boxer, AL, Rosen, H, Taylor, JB, Synofzik, M, Wilke, C, Sulzer, P, Hodges, JR, Halliday, G, Kwok, J, Sanchez-Valle, R, Llado, A, Borrego-Ecija, S, Santana, I, Almeida, MR, Tabuas-Pereira, M, Moreno, F, Barandiaran, M, Indakoetxea, B, Levin, J, Danek, A, Rowe, JB, Cope, TE, Otto, M, Anderl-Straub, S, de Mendonca, A, Maruta, C, Masellis, M, Black, SE, Couratier, P, Lautrette, G, Huey, ED, Sorbi, S, Nacmias, B, Laforce, R, Tremblay, M-PL, Vandenberghe, R, Van Damme, P, Rogalski, EJ, Weintraub, S, Gerhard, A, Onyike, CU, Ducharme, S, Papageorgiou, SG, Ng, ASL, Brodtmann, A, Finger, E, Guerreiro, R, Bras, J, Rohrer, JD, Heller, C, Convery, R, Woollacott, IOC, Shafei, R, Graff-Radford, J, Jones, DT, Dheel, CM, Savica, R, Lapid, MI, Baker, M, Fields, JA, Gavrilova, R, Domoto-Reilly, K, Poos, JM, van der Ende, EL, Panman, JL, Kaat, LD, Seelaar, H, Richardson, A, Frisoni, G, Mega, A, Fostinelli, S, Chiang, H-H, Alberici, A, Arighi, A, Fenoglio, C, Heuer, H, Miller, B, Karydas, A, Fong, J, Leitao, MJ, Santiago, B, Duro, D, Ferreira, C, Gabilondo, A, de Arriba, M, Tainta, M, Zulaica, M, Ferreira, CB, Semler, E, Ludolph, A, Landwehrmeyer, B, Volk, AE, Miltenberger, G, Verdelho, A, Afonso, S, Tartaglia, MC, Freedman, M, Rogaeva, E, Ferrari, C, Piaceri, I, Bessi, V, Lombardi, G, St-Onge, F, Dore, M-C, Bruffaerts, R, Vandenbulcke, M, Van den Stock, J, Mesulam, MM, Bigio, E, Koros, C, Papatriantafyllou, J, Kroupis, C, Stefanis, L, Shoesmith, C, Roberson, E, Coppola, G, Ramos, EMDS, Geschwind, D, Moore, KM, Nicholas, J, Grossman, M, McMillan, CT, Irwin, DJ, Massimo, L, Van Deerlin, VM, Warren, JD, Fox, NC, Rossor, MN, Mead, S, Bocchetta, M, Boeve, BF, Knopman, DS, Graff-Radford, NR, Forsberg, LK, Rademakers, R, Wszolek, ZK, van Swieten, JC, Jiskoot, LC, Meeter, LH, Dopper, EGP, Papma, JM, Snowden, JS, Saxon, J, Jones, M, Pickering-Brown, S, Le Ber, I, Camuzat, A, Brice, A, Caroppo, P, Ghidoni, R, Pievani, M, Benussi, L, Binetti, G, Dickerson, BC, Lucente, D, Krivensky, S, Graff, C, Oijerstedt, L, Fallstrom, M, Thonberg, H, Ghoshal, N, Morris, JC, Borroni, B, Benussi, A, Padovani, A, Galimberti, D, Scarpini, E, Fumagalli, GG, Mackenzie, IR, Hsiung, G-YR, Sengdy, P, Boxer, AL, Rosen, H, Taylor, JB, Synofzik, M, Wilke, C, Sulzer, P, Hodges, JR, Halliday, G, Kwok, J, Sanchez-Valle, R, Llado, A, Borrego-Ecija, S, Santana, I, Almeida, MR, Tabuas-Pereira, M, Moreno, F, Barandiaran, M, Indakoetxea, B, Levin, J, Danek, A, Rowe, JB, Cope, TE, Otto, M, Anderl-Straub, S, de Mendonca, A, Maruta, C, Masellis, M, Black, SE, Couratier, P, Lautrette, G, Huey, ED, Sorbi, S, Nacmias, B, Laforce, R, Tremblay, M-PL, Vandenberghe, R, Van Damme, P, Rogalski, EJ, Weintraub, S, Gerhard, A, Onyike, CU, Ducharme, S, Papageorgiou, SG, Ng, ASL, Brodtmann, A, Finger, E, Guerreiro, R, Bras, J, Rohrer, JD, Heller, C, Convery, R, Woollacott, IOC, Shafei, R, Graff-Radford, J, Jones, DT, Dheel, CM, Savica, R, Lapid, MI, Baker, M, Fields, JA, Gavrilova, R, Domoto-Reilly, K, Poos, JM, van der Ende, EL, Panman, JL, Kaat, LD, Seelaar, H, Richardson, A, Frisoni, G, Mega, A, Fostinelli, S, Chiang, H-H, Alberici, A, Arighi, A, Fenoglio, C, Heuer, H, Miller, B, Karydas, A, Fong, J, Leitao, MJ, Santiago, B, Duro, D, Ferreira, C, Gabilondo, A, de Arriba, M, Tainta, M, Zulaica, M, Ferreira, CB, Semler, E, Ludolph, A, Landwehrmeyer, B, Volk, AE, Miltenberger, G, Verdelho, A, Afonso, S, Tartaglia, MC, Freedman, M, Rogaeva, E, Ferrari, C, Piaceri, I, Bessi, V, Lombardi, G, St-Onge, F, Dore, M-C, Bruffaerts, R, Vandenbulcke, M, Van den Stock, J, Mesulam, MM, Bigio, E, Koros, C, Papatriantafyllou, J, Kroupis, C, Stefanis, L, Shoesmith, C, Roberson, E, Coppola, G, Ramos, EMDS, and Geschwind, D
Abstract: BACKGROUND: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. METHODS: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. FINDINGS: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at
Published: 2020

84. Neuronal pentraxin 2: a synapse-derived CSF biomarker in genetic frontotemporal dementia

Author: van der Ende, Emma, Xiao, MF, Xu, DS, Poos, Jackie, Panman, Jessica, Jiskoot, Lize, Meeter, Lieke, Dopper, Elise, Papma, Janne, Heller, C, Convery, H, Moore, K, Bocchetta, M, Neason, M, Peakman, G, Cash, D, Teunissen, CE, Graff, C, Synofzik, M, Moreno, F, Finger, E, Sanchez-Valle, R, Vandenberghe, R, Laforce, R, Jr, Masellis, M, Carmela Tartaglia, M, Rowe, JB, Butler, CR, Ducharme, S, Gerhard, A, Danek, A, Levin, J, Pijnenburg, YAL, Otto, M, Borroni, B, Tagliavini, F, De Mendonca, A, Santana, I, Galimberti, D, Seelaar, Harro, Rohrer, JD, Worley, PF, van Swieten, J.C., van der Ende, Emma, Xiao, MF, Xu, DS, Poos, Jackie, Panman, Jessica, Jiskoot, Lize, Meeter, Lieke, Dopper, Elise, Papma, Janne, Heller, C, Convery, H, Moore, K, Bocchetta, M, Neason, M, Peakman, G, Cash, D, Teunissen, CE, Graff, C, Synofzik, M, Moreno, F, Finger, E, Sanchez-Valle, R, Vandenberghe, R, Laforce, R, Jr, Masellis, M, Carmela Tartaglia, M, Rowe, JB, Butler, CR, Ducharme, S, Gerhard, A, Danek, A, Levin, J, Pijnenburg, YAL, Otto, M, Borroni, B, Tagliavini, F, De Mendonca, A, Santana, I, Galimberti, D, Seelaar, Harro, Rohrer, JD, Worley, PF, and van Swieten, J.C.
Published: 2020

85. Social cognition impairment in genetic frontotemporal dementia within the GENFI cohort

Author: Russell, LL, Greaves, CV, Bocchetta, M, Nicholas, J, Convery, RS, Moore, K, Cash, DM, van Swieten, J.C., Jiskoot, Lize, Moreno, F, Sanchez-Valle, R, Borroni, B, Laforce, R, Jr, Masellis, M, Tartaglia, MC, Graff, C, Rotondo, E, Galimberti, D, Rowe, JB, Finger, E, Synofzik, M, Vandenberghe, R, Mendonça, A, Tagliavini, F, Santana, I, Ducharme, S, Butler, C, Gerhard, A, Levin, J, Danek, A, Otto, M, Warren, JD, Rohrer, JD, Rossor, MN, Fox, NC, Woollacott, IOC, Shafei, R, Heller, C, Guerreiro, R, Bras, J, Thomas, DL, Mead, S, Meeter, Lieke, Panman, J, Papma, J, Poos, J, van Minkelen, Rick, Al Pijnenburg, Y, Barandiaran, M, Indakoetxea, B, Gabilondo, A, Tainta, M, de Arriba, M, Gorostidi, A, Zulaica, M, Villanua, J, Diaz, Z, Borrego-Ecija, S, Olives, J, Lladó, A, Balasa, M, Antonell, A, Bargallo, N, Premi, E, Cosseddu Mpsych, M, Gazzina, S, Padovani, A, Gasparotti, R, Archetti, S, Black, S, Mitchell, S, Rogaeva, E, Freedman, M, Keren, R, Tang-Wai, D, Öijerstedt, L, Andersson, C, Jelic, V, Thonberg, H, Arighi, A, Fenoglio, C, Scarpini, E, Fumagalli, G, Cope, T, Timberlake, C, Rittman, T, Shoesmith, C, Bartha, R, Rademakers, R, Wilke, C, Karnarth, HO, Bender, B, Bruffaerts, R, Vandamme, P, Vandenbulcke, M, Ferreira, CB, Miltenberger, G, Maruta Mpsych, C, Verdelho, A, Afonso, S, Taipa, R, Caroppo, P, Di Fede, G, Giaccone, G, Muscio, C, Prioni, S, Redaelli, V, Rossi, G, Tiraboschi, P, Duro Npsych, D, Almeida, M R, Castelo-Branco, M, Leitão, MJ, Tabuas-Pereira, M, Santiago, B, Gauthier, S, Rosa-Neto, P, Veldsman, M, Thompson, P, Langheinrich, T, Prix, C, Hoegen, T, Wlasich, E, Loosli, S, Schonecker, S, Semler, E, Anderl-Straub, S, Russell, LL, Greaves, CV, Bocchetta, M, Nicholas, J, Convery, RS, Moore, K, Cash, DM, van Swieten, J.C., Jiskoot, Lize, Moreno, F, Sanchez-Valle, R, Borroni, B, Laforce, R, Jr, Masellis, M, Tartaglia, MC, Graff, C, Rotondo, E, Galimberti, D, Rowe, JB, Finger, E, Synofzik, M, Vandenberghe, R, Mendonça, A, Tagliavini, F, Santana, I, Ducharme, S, Butler, C, Gerhard, A, Levin, J, Danek, A, Otto, M, Warren, JD, Rohrer, JD, Rossor, MN, Fox, NC, Woollacott, IOC, Shafei, R, Heller, C, Guerreiro, R, Bras, J, Thomas, DL, Mead, S, Meeter, Lieke, Panman, J, Papma, J, Poos, J, van Minkelen, Rick, Al Pijnenburg, Y, Barandiaran, M, Indakoetxea, B, Gabilondo, A, Tainta, M, de Arriba, M, Gorostidi, A, Zulaica, M, Villanua, J, Diaz, Z, Borrego-Ecija, S, Olives, J, Lladó, A, Balasa, M, Antonell, A, Bargallo, N, Premi, E, Cosseddu Mpsych, M, Gazzina, S, Padovani, A, Gasparotti, R, Archetti, S, Black, S, Mitchell, S, Rogaeva, E, Freedman, M, Keren, R, Tang-Wai, D, Öijerstedt, L, Andersson, C, Jelic, V, Thonberg, H, Arighi, A, Fenoglio, C, Scarpini, E, Fumagalli, G, Cope, T, Timberlake, C, Rittman, T, Shoesmith, C, Bartha, R, Rademakers, R, Wilke, C, Karnarth, HO, Bender, B, Bruffaerts, R, Vandamme, P, Vandenbulcke, M, Ferreira, CB, Miltenberger, G, Maruta Mpsych, C, Verdelho, A, Afonso, S, Taipa, R, Caroppo, P, Di Fede, G, Giaccone, G, Muscio, C, Prioni, S, Redaelli, V, Rossi, G, Tiraboschi, P, Duro Npsych, D, Almeida, M R, Castelo-Branco, M, Leitão, MJ, Tabuas-Pereira, M, Santiago, B, Gauthier, S, Rosa-Neto, P, Veldsman, M, Thompson, P, Langheinrich, T, Prix, C, Hoegen, T, Wlasich, E, Loosli, S, Schonecker, S, Semler, E, and Anderl-Straub, S
Published: 2020

86. Philosophieren über die Rätsel des Gehirns: Übersicht zur Neurophilosophie

Author: Synofzik, M., Huber, L., and Wiesing, U.
Published: 2004
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87. Mutations in the PDYN gene (SCA23) are not a frequent cause of dominant ataxia in Central Europe

Author: Schicks, J, Synofzik, M, Beetz, C, Schiele, F, and Schöls, L
Published: 2011
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88. Amplicon-based high-throughput pooled sequencing identifies mutations in CYP7B1 and SPG7 in sporadic spastic paraplegia patients

Author: Schlipf, N A, Schüle, R, Klimpe, S, Karle, K N, Synofzik, M, Schicks, J, Riess, O, Schöls, L, and Bauer, P
Published: 2011
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89. OUTCOME MEASURES

Author: Bourcier, D., primary, Bélanger, M., additional, Côté, I., additional, Brais, B., additional, Synofzik, M., additional, Brisson, J., additional, Rodrigue, X., additional, Gagnon, M., additional, Mathieu, J., additional, and Gagnon, C., additional
Published: 2020
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90. FV2 From clinical motor assessments to ecologically valid biomarkers: Real-life gait assessment in cerebellar ataxia

Author: Seemann, J., primary, Synofzik, M., additional, and Ilg, W., additional
Published: 2020
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91. Counterregulation of cAMP-directed kinase activities controls ciliogenesis

Author: Porpora M, SAUCHELLA, SIMONA, Rinaldi L, Delle Donne R, Sepe M, Torres-Quesada O, Intartaglia D, Garbi C, Insabato L, Santoriello M, Bachmann VA, Synofzik M, Lindner HH, Conte I, Stefan E, Feliciello A., CONTE, IVAN, Porpora, M, Sauchella, Simona, Rinaldi, L, Delle Donne, R, Sepe, M, Torres-Quesada, O, Intartaglia, D, Garbi, C, Insabato, L, Santoriello, M, Bachmann, Va, Synofzik, M, Lindner, Hh, Conte, I, Stefan, E, Feliciello, A., and Conte, Ivan
Subjects: PKA, cAMP, proteasome, primary cilium, NEK10, ubiquitin
Abstract: The primary cilium emanates from the cell surface of growth-arrested cells and plays a central role in vertebrate development and tissue homeostasis. The mechanisms that control ciliogenesis have been extensively explored. However, the intersection between GPCR signaling and the ubiquitin pathway in the control of cilium stability is unknown. Here, we observe that cAMP elevation promotes cilia resorption. At centriolar satellites, we identify a multimeric complex nucleated by PCM1 that includes two kinases, NEK10 and PKA, and the E3 ubiquitin ligase CHIP. We show that NEK10 is essential for ciliogenesis in mammals and for the development of medaka fish. PKA phosphorylation primes NEK10 for CHIP-mediated ubiquitination and proteolysis resulting in cilia resorption. Dearangement of this control mechanism occurs in proliferative and genetic disorders. These findings unveil a pericentriolar kinase signalosome that efficiently links the cAMP cascade with the ubiquitin-proteasome system, controlling essential aspects of ciliogenesis.
Published: 2018

92. Frequency and phenotype of SPG11 and SPG15 in complicated hereditary spastic paraplegia

Author: Schüle, R, Schlipf, N, Synofzik, M, Klebe, S, Klimpe, S, Hehr, U, Winner, B, Lindig, T, Dotzer, A, Rie, O, Winkler, J, Schöls, L, and Bauer, P
Published: 2009
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93. Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients

Author: Anheim, M, Monga, B, Fleury, M, Charles, P, Barbot, C, Salih, M, Delaunoy, J P, Fritsch, M, Arning, L, Synofzik, M, Schöls, L, Sequeiros, J, Goizet, C, Marelli, C, Le Ber, I, Koht, J, Gazulla, J, De Bleecker, J, Mukhtar, M, Drouot, N, Ali-Pacha, L, Benhassine, T, Chbicheb, M, M’Zahem, A, Hamri, A, Chabrol, B, Pouget, J, Murphy, R, Watanabe, M, Coutinho, P, Tazir, M, Durr, A, Brice, A, Tranchant, C, and Koenig, M
Published: 2009

94. Prion mutation D178N with highly variable disease onset and phenotype

Author: Synofzik, M, Bauer, P, and Schöls, L
Published: 2009
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95. Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

Author: van der Lee, Sven J, Conway, Olivia J, Zettergren, Anna, Christensen, Kaare, Ertekin-Taner, Nilüfer, Scholz, Sonja W, Ramirez, Alfredo, Ruiz, Agustín, Slagboom, Eline, van der Flier, Wiesje M, Holstege, Henne, Mead, S., Synofzik, M., Andlauer, Till F M, van Swieten, J. C., Leber, I., Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Schofield, P. R., Diez-Fairen, Monica, Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Simon-Sanchez, Javier, Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Blesa, R., Landqvist Waldö, M., Lleó, Alberto, Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G-Y R, Mann, D. M. A., Grafman, J., Morris, C. M., Attems, J., Griffiths, T. D., McKeith, I. G., Zetterberg, Henrik, Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Razquin, C., Ortega-Cubero, S., Alonso, E., Nygaard, Marianne, Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Blauwendraat, Cornelis, Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., Savage, Jeanne E, van der Zee, J., Van Broeckhoven, C., Cappa, S. F., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Mengel-From, Jonas, Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Jansen, Iris, Moreno-Grau, Sonia, Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Wagner, Michael, Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Baker, M., Josephs, K. A., Fortea, Juan, Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., Dopper, E. G. P., Seelaar, H., Logroscino, G., Capozzo, R., Novelli, V., Keogh, Michael J, Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H-H, Graff, C., Pasquier, F., Rollin, A., Blennow, Kaj, Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Coppola, G., Skoog, Ingmar, Varpetian, A., Foroud, T. M., Levey, A. I., Kukull, W. A., Mendez, M. F., Ringman, J., Chui, H., Cotman, C., DeCarli, C., Friese, Manuel A, Geschwind, D. H., Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, Carrasquillo, Minerva M, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Kleineidam, Luca, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart N M, Alcolea, Daniel, Wiendl, Heinz, van den Akker, Erik, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO, EADB, IFGC, IPDGC, RiMod-FTD, Bank, Netherlands Brain, Boeve, Bradley F, Hernández, Isabel, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel J T, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, van Eijk, Kristel R, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Stringa, Najada, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande A L, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Chen, Jason A, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild I A, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT, and Clarimón, Jordi
Subjects: 0301 basic medicine, Dementia with Lewy bodies, Disease, Bioinformatics, Neurodegenerative disease, 0302 clinical medicine, Missense mutation, media_common, 2. Zero hunger, Longevity, Brain, Parkinson Disease, Phospholipase C Gamma 2, Biobank, 3. Good health, ddc, Frontotemporal Dementia, Microglia, Alzheimer's disease, Alzheimer’s disease, Amyotrophic lateral sclerosis, Frontotemporal dementia, Multiple sclerosis, PLCG2, Parkinson’s disease, Progressive supranuclear palsy, Lewy Body Disease, Risk, Multiple Sclerosis, media_common.quotation_subject, education, Neuroimaging, Genomics, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Alzheimer Disease, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Alleles, Phospholipase C gamma, business.industry, Amyotrophic Lateral Sclerosis, Correction, medicine.disease, 030104 developmental biology, Mutation, Dementia, Neurology (clinical), business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target. The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.
Published: 2019

96. Deformation-based morphometry in a german multicenter SCA14 cohort reveals structural changes in cerebellum and forebrain

Author: Pieperhoff, Peter, Schmitz-Hübsch, T., Shah, N. J., Schöls, L., Kopp, U., Klockgether, T., Amunts, Katrin, Doss, S., Minnerop, Martina, Schlapakow, E., Gärtner, Hanna, Lux, Silke, Bauer, P., Kirlangic, Mehmet Eylem, Gras, V., Timmann-Braun, D., and Synofzik, M.
Published: 2019

97. Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7

Author: Coarelli, G., Schule, R., Warrenburg, B.P.C. van de, Jonghe, P. De, Ewenczyk, C., Martinuzzi, A., Synofzik, M., Hamer, E.G., Baets, J., Anheim, M., Schols, L., Deconinck, T., Masrori, P., Fontaine, B., Klockgether, T., D'Angelo, M.G., Monin, M.L., Bleecker, J. De, Migeotte, I., Charles, P., Bassi, M.T., Klopstock, T., Mochel, F., Ollagnon-Roman, E., D'Hooghe, M., Kamm, C., Kurzwelly, D., Papin, M., Davoine, C.S., Banneau, G., Montcel, S. Tezenas du, Seilhean, D., Brice, A., Duyckaerts, C., Stevanin, G., Durr, A., Coarelli, G., Schule, R., Warrenburg, B.P.C. van de, Jonghe, P. De, Ewenczyk, C., Martinuzzi, A., Synofzik, M., Hamer, E.G., Baets, J., Anheim, M., Schols, L., Deconinck, T., Masrori, P., Fontaine, B., Klockgether, T., D'Angelo, M.G., Monin, M.L., Bleecker, J. De, Migeotte, I., Charles, P., Bassi, M.T., Klopstock, T., Mochel, F., Ollagnon-Roman, E., D'Hooghe, M., Kamm, C., Kurzwelly, D., Papin, M., Davoine, C.S., Banneau, G., Montcel, S. Tezenas du, Seilhean, D., Brice, A., Duyckaerts, C., Stevanin, G., and Durr, A.
Abstract: Item does not contain fulltext, OBJECTIVE: We took advantage of a large multinational recruitment to delineate genotype-phenotype correlations in a large, trans-European multicenter cohort of patients with spastic paraplegia gene 7 (SPG7). METHODS: We analyzed clinical and genetic data from 241 patients with SPG7, integrating neurologic follow-up data. One case was examined neuropathologically. RESULTS: Patients with SPG7 had a mean age of 35.5 +/- 14.3 years (n = 233) at onset and presented with spasticity (n = 89), ataxia (n = 74), or both (n = 45). At the first visit, patients with a longer disease duration (>20 years, n = 62) showed more cerebellar dysarthria (p < 0.05), deep sensory loss (p < 0.01), muscle wasting (p < 0.01), ophthalmoplegia (p < 0.05), and sphincter dysfunction (p < 0.05) than those with a shorter duration (<10 years, n = 93). Progression, measured by Scale for the Assessment and Rating of Ataxia evaluations, showed a mean annual increase of 1.0 +/- 1.4 points in a subgroup of 30 patients. Patients homozygous for loss of function (LOF) variants (n = 65) presented significantly more often with pyramidal signs (p < 0.05), diminished visual acuity due to optic atrophy (p < 0.0001), and deep sensory loss (p < 0.0001) than those with at least 1 missense variant (n = 176). Patients with at least 1 Ala510Val variant (58%) were older (age 37.6 +/- 13.7 vs 32.8 +/- 14.6 years, p < 0.05) and showed ataxia at onset (p < 0.05). Neuropathologic examination revealed reduction of the pyramidal tract in the medulla oblongata and moderate loss of Purkinje cells and substantia nigra neurons. CONCLUSIONS: This is the largest SPG7 cohort study to date and shows a spasticity-predominant phenotype of LOF variants and more frequent cerebellar ataxia and later onset in patients carrying at least 1 Ala510Val variant.
Published: 2019

98. The movement disorder spectrum of SCA21 (ATX-TMEM240): 3 novel families and systematic review of the literature

Author: Traschutz, A., Gaalen, J. van, Oosterloo, M., Vreeburg, M., Kamsteeg, E.J., Deininger, N., Riess, O., Reimold, M., Haack, T., Schols, L., Warrenburg, B.P.C. van de, Synofzik, M., Traschutz, A., Gaalen, J. van, Oosterloo, M., Vreeburg, M., Kamsteeg, E.J., Deininger, N., Riess, O., Reimold, M., Haack, T., Schols, L., Warrenburg, B.P.C. van de, and Synofzik, M.
Abstract: Contains fulltext : 208431.pdf (publisher's version ) (Closed access), Spinocerebellar ataxia type 21 (SCA21/ATX-TMEM240) was recently found to be caused by mutations in TMEM240, with still limited knowledge on the phenotypic spectrum and disease course. Here we present five subjects from three novel SCA21 families from different parts of the world (including a novel c.196G>A, p.G66R TMEM240 variant from Colombia), demonstrating that, in addition to cerebellar ataxia, not only hypokinetic features (hypomimia, bradykinesia), but also hyperkinetic movement disorders (poly-mini-myoclonus, proximal myoclonus) are a recurrent part of the phenotypic spectrum of SCA21. Presenting first prospective longitudinal data, our results provide examples of two different disease trajectories: while it was inherently progressive in adult-onset cases, a dramatically improving trajectory was observed in an infantile-onset case. A systematic review of all previously reported SCA21 patients (n=42) demonstrates that SCA21 is a relatively early-onset SCA (median onset age 18 years; range 1-61 years) with frequent non-cerebellar involvement, including hyporeflexia (69%), bradykinesia (65%), slow saccades (38%) and pyramidal signs (17%). Our results characterize SCA21 as a multisystem disorder with substantial extra-cerebellar involvement, including a wide spectrum of hypo- as well as hyperkinetic movement disorders as well as damage to the midbrain, corticospinal tract and peripheral nerves. However, in contrast to the current perspective on SCA21 disease, cognitive impairment is not an obligatory feature of the disease. The disease course is inherently progressive in adult-onset subjects, but might also be characterized by improvement in infantile-onset cases. These findings have important consequences of the work-up and counseling of SCA21/ATX-TMEM240 patients.
Published: 2019

99. White matter hyperintensities in progranulin-associated frontotemporal dementia: A longitudinal GENFI study

Author: Sudre, C.H. (Carole H.), Bocchetta, M. (Martina), Heller, C. (Carolin), Convery, R. (Rhian), Neason, M. (Mollie), Moore, K.M. (Katrina M.), Cash, D.M. (David M.), Thomas, D.L. (David L), Woollacott, I.O.C. (Ione O.C.), Foiani, M. (Martha), Heslegrave, A. (Amanda), Shafei, R. (Rachelle), Greaves, C. (Caroline), Swieten, J.C. (John) van, Moreno, F. (Fermin), Sánchez-Valle, R. (Raquel), Borroni, B. (Barbara), Laforce, R. (Robert), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Graff, C. (Caroline), Galimberti, D. (Daniela), Rowe, J.B. (James), Finger, E. (Elizabeth), Synofzik, M. (Matthis), Vandenberghe, R. (Rik), De Mendonça, A. (Alexandre), Tagliavini, F. (Fabrizio), Santana, I. (Isabel), Ducharme, S. (Simon), Butler, C. (Chris), Gerhard, A. (Alex), Levin, J. (Johannes), Danek, A. (Adrian), Frisoni, G.B. (Giovanni B.), Sorbi, S. (Sandro), Otto, M. (Markus), Zetterberg, H. (Henrik), Ourselin, S. (Sebastien), Cardoso, M.J. (M. Jorge), Rohrer, J.D. (Jonathan), Sudre, C.H. (Carole H.), Bocchetta, M. (Martina), Heller, C. (Carolin), Convery, R. (Rhian), Neason, M. (Mollie), Moore, K.M. (Katrina M.), Cash, D.M. (David M.), Thomas, D.L. (David L), Woollacott, I.O.C. (Ione O.C.), Foiani, M. (Martha), Heslegrave, A. (Amanda), Shafei, R. (Rachelle), Greaves, C. (Caroline), Swieten, J.C. (John) van, Moreno, F. (Fermin), Sánchez-Valle, R. (Raquel), Borroni, B. (Barbara), Laforce, R. (Robert), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Graff, C. (Caroline), Galimberti, D. (Daniela), Rowe, J.B. (James), Finger, E. (Elizabeth), Synofzik, M. (Matthis), Vandenberghe, R. (Rik), De Mendonça, A. (Alexandre), Tagliavini, F. (Fabrizio), Santana, I. (Isabel), Ducharme, S. (Simon), Butler, C. (Chris), Gerhard, A. (Alex), Levin, J. (Johannes), Danek, A. (Adrian), Frisoni, G.B. (Giovanni B.), Sorbi, S. (Sandro), Otto, M. (Markus), Zetterberg, H. (Henrik), Ourselin, S. (Sebastien), Cardoso, M.J. (M. Jorge), and Rohrer, J.D. (Jonathan)
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 di
Published: 2019
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100. Clinical value of cerebrospinal fluid neurofilament light chain in semantic dementia

Author: Meeter, L.H.H. (Lieke), Steketee, R.M.E., Salkovic, D., Vos, M.E., Grossman, M. (Murray), McMillan, C.T., Irwin, D.J., Boxer, AL, Rojas, J.C., Olney, N.T., Karydas, A., Miller, BL, Pijnenburg, YA, Barkhof, F. (Frederik), Sánchez-Valle, R. (Raquel), Lladó, A. (Albert), Borrego-Ecija, S., Diehl-Schmid, J, Grimmer, T., Goldhardt, O., Santillo, A.F., Hansson, O. (Ola), Vestberg, S., Borroni, B. (Barbara), Padovani, A. (Alessandro), Galimberti, D. (Daniela), Scarpini, E. (Elio), Rohrer, JD, Woollacott, I.O.C., Synofzik, M., Wilke, C., Mendonça, A., Vandenberghe, R. (Rik), Benussi, L, Ghidoni, R, Binetti, G, Niessen, W.J. (Wiro), Papma, J.M. (Janne), Seelaar, H. (Harro), Jiskoot, L.C. (Lize), Jong, F.J. (Fransina) de, Kaat, L.D., Del Campo, M, Teunissen, C.E. (Charlotte), Bron, E.E. (Esther), Berg, E. (Esther) van den, Swieten, J.C. (John) van, Meeter, L.H.H. (Lieke), Steketee, R.M.E., Salkovic, D., Vos, M.E., Grossman, M. (Murray), McMillan, C.T., Irwin, D.J., Boxer, AL, Rojas, J.C., Olney, N.T., Karydas, A., Miller, BL, Pijnenburg, YA, Barkhof, F. (Frederik), Sánchez-Valle, R. (Raquel), Lladó, A. (Albert), Borrego-Ecija, S., Diehl-Schmid, J, Grimmer, T., Goldhardt, O., Santillo, A.F., Hansson, O. (Ola), Vestberg, S., Borroni, B. (Barbara), Padovani, A. (Alessandro), Galimberti, D. (Daniela), Scarpini, E. (Elio), Rohrer, JD, Woollacott, I.O.C., Synofzik, M., Wilke, C., Mendonça, A., Vandenberghe, R. (Rik), Benussi, L, Ghidoni, R, Binetti, G, Niessen, W.J. (Wiro), Papma, J.M. (Janne), Seelaar, H. (Harro), Jiskoot, L.C. (Lize), Jong, F.J. (Fransina) de, Kaat, L.D., Del Campo, M, Teunissen, C.E. (Charlotte), Bron, E.E. (Esther), Berg, E. (Esther) van den, and Swieten, J.C. (John) van
Abstract: Background Semantic dementia (SD) is a neurodegenerative disorder characterised by progressive language problems falling within the clinicopathological spectrum of frontotemporal lobar degeneration (FTLD). The development of diseasemodifying agents may be facilitated by the relative clinical and pathological homogeneity of SD, but we need robust monitoring biomarkers to measure their efficacy. In different FTLD subtypes, neurofilament light chain (NfL) is a promising marker, therefore we investigated the utility of cerebrospinal fluid (CSF) NfL in SD. Methods This large retrospective multicentre study compared cross-sectional CSF NfL levels of 162 patients with SD with 65 controls. CSF NfL levels of patients were correlated with clinical parameters (including survival), neuropsychological test scores and regional grey matter atrophy (including longitudinal data in a subset). Results CSF NfL levels were significantly higher in patients with SD (median: 2326 pg/mL, IQR: 1628– 3593) than in controls (577 (446–766), p<0.001). Higher CSF NfL levels were moderately associated with naming impairment as measured by the Boston Naming Test (r s =−0.32, p=0.002) and with smaller grey matter volume of the parahippocampal gyri (r s =−0.31, p=0.004). However, cross-sectional CSF NfL levels were not associated with progression of grey matter atrophy and did not predict survival. Conclusion CSF NfL is a promising biomarker in the diagnostic process of SD, although it has limited crosssectional monitoring or prognostic abilities.
Published: 2019
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