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1. Severity dependent distribution of impairments in PSP and CBS: Interactive visualizations

Author

Brittain, Claire, McCarthy, Andrew, Irizarry, Michael C, McDermott, Dana, Biglan, Kevin, Höglinger, Günter U, Lorenzl, Stefan, del Ser, Teodoro, Boxer, Adam L, Group, The AL-108-231 Study, Williams, David, Lafontaine, Anne Louise, Marras, Connie, Jog, Mandar, Panisset, Michael, Lang, Anthony, Parker, Lesley, Stewart, Alistair J, Corvol, Jean-Christophe, Azulay, Jean-Philippe, Couratier, Philippe, Mollenhauer, Brit, Ludolph, Albert, Benecke, Reiner, Hoglinger, Gunter, Lipp, Axel, Reichmann, Heinz, Woitalla, Dirk, Chan, Dennis, Zermansky, Adam, Burn, David, Lees, Andrew, Gozes, Illana, Boxer, Adam, Miller, Bruce L, Lobach, Iryna V, Roberson, Erik, Honig, Lawrence, Zamrini, Edward, Pahwa, Rajesh, Bordelon, Yvette, Driver-Dunkley, Erika, Lessig, Stephanie, Lew, Mark, Womack, Kyle, Boeve, Brad, Ferrara, Joseph, Hillis, Argyle, Kaufer, Daniel, Kumar, Rajeev, Xie, Tao, Gunzler, Steven, Zesiewicz, Theresa, Dayalu, Praveen, Golbe, Lawrence, Grossman, Murray, Jankovic, Joseph, McGinnis, Scott, Santiago, Anthony, Tuite, Paul, Isaacson, Stuart, Leegwater-Kim, Julie, Litvan, Irene, Knopman, David S, Schneider, Lon S, Doody, Rachelle S, Golbe, Lawrence I, Roberson, Erik D, Koestler, Mary, Jack, Clifford R, Van Deerlin, Viviana, Randolph, Christopher, Whitaker, Steve, Hirman, Joe, Gold, Michael, Morimoto, Bruce H, investigators, The PROPSPERA, G, Georg Nuebling, Hensler, Mira, Paul, Sabine, Zwergal, Andreas, 4RNTI-1authors, Heuer, Hilary W, Tartaglia, Maria C, McGinnis, Scott M, Dickerson, Bradford C, Kornak, John, Schuff, Norbert, Rabinovici, Gil D, Rosen, Howard J, Investigators, Tau Restoration on PSP, Gómez, JC, Tijero, B, Berganzo, K, de Yebenes, J Garc'ıa, Sendón, JL Lopez, and Garcia, G

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Health Disparities, Dementia, Frontotemporal Dementia (FTD), Brain Disorders, Rare Diseases, Alzheimer's Disease Related Dementias (ADRD), Neurodegenerative, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Research, Aging, Clinical Trials and Supportive Activities, 4.2 Evaluation of markers and technologies, Neurological, Aged, Aged, 80 and over, Basal Ganglia Diseases, Data Visualization, Disease Progression, Female, Humans, Male, Middle Aged, Models, Neurological, Neurodegenerative Diseases, Prognosis, Severity of Illness Index, Supranuclear Palsy, Progressive, Syndrome, Corticobasal syndrome, Progressive supranuclear palsy, PSP rating scale, Interactive visualizations, Predictive models, AL-108-231 Study Group, PROPSPERA investigators, 4RNTI-1authors, Tau Restoration on PSP (TAUROS) Investigators, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences, Biological psychology
Abstract

BackgroundProgressive supranuclear palsy (PSP) -Richardson's Syndrome and Corticobasal Syndrome (CBS) are the two classic clinical syndromes associated with underlying four repeat (4R) tau pathology. The PSP Rating Scale is a commonly used assessment in PSP clinical trials; there is an increasing interest in designing combined 4R tauopathy clinical trials involving both CBS and PSP.ObjectivesTo determine contributions of each domain of the PSP Rating Scale to overall severity and characterize the probable sequence of clinical progression of PSP as compared to CBS.MethodsMulticenter clinical trial and natural history study data were analyzed from 545 patients with PSP and 49 with CBS. Proportional odds models were applied to model normalized cross-sectional PSP Rating Scale, estimating the probability that a patient would experience impairment in each domain using the PSP Rating Scale total score as the index of overall disease severity.ResultsThe earliest symptom domain to demonstrate impairment in PSP patients was most likely to be Ocular Motor, followed jointly by Gait/Midline and Daily Activities, then Limb Motor and Mentation, and finally Bulbar. For CBS, Limb Motor manifested first and ocular showed less probability of impairment throughout the disease spectrum. An online tool to visualize predicted disease progression was developed to predict relative disability on each subscale per overall disease severity.ConclusionThe PSP Rating Scale captures disease severity in both PSP and CBS. Modelling how domains change in relation to one other at varying disease severities may facilitate detection of therapeutic effects in future clinical trials.

Published
2019

2. CSF neurofilament light chain and phosphorylated tau 181 predict disease progression in PSP

Author

Rojas, Julio C, Bang, Jee, Lobach, Iryna V, Tsai, Richard M, Rabinovici, Gil D, Miller, Bruce L, Boxer, Adam L, Williams, David, Lafontaine, Anne Louise, Marras, Connie, Jog, Mandar, Panisset, Michael, Lang, Anthony, Parker, Lesley, Stewart, Alistair J, Corvol, Jean-Christophe, Azulay, Jean-Philippe, Couratier, Philippe, Mollenhauer, Brit, Lorenzl, Stefan, Ludolph, Albert, Benecke, Reiner, Hoglinger, Gunter, Lipp, Axel, Reichmann, Heinz, Woitalla, Dirk, Chan, Dennis, Zermansky, Adam, Burn, David, Lees, Andrew, Gozes, Illana, Boxer, Adam, Roberson, Erik, Honig, Lawrence, Zamrini, Edward, Pahwa, Rajesh, Bordelon, Yvette, Driver-Dunkley, Erika, Lessig, Stephanie, Lew, Mark, Womack, Kyle, Boeve, Brad, Ferrara, Joseph, Hillis, Argyle, Kaufer, Daniel, Kumar, Rajeev, Xie, Tao, Gunzler, Steven, Zesiewicz, Theresa, Dayalu, Praveen, Golbe, Lawrence, Grossman, Murray, Jankovic, Joseph, McGinnis, Scott, Santiago, Anthony, Tuite, Paul, Isaacson, Stuart, Leegwater-Kim, Julie, Litvan, Irene, Knopman, David S, Schneider, Lon S, Doody, Rachelle S, Koestler, Mary, Jack, Clifford R, Van Deerlin, Viviana, Randolph, Christopher, Whitaker, Steve, Hirman, Joe, Gold, Michael, and Morimoto, Bruce H

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Clinical Research, Neurodegenerative, Alzheimer's Disease, Brain Disorders, Dementia, Frontotemporal Dementia (FTD), Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease Related Dementias (ADRD), Rare Diseases, Aging, 4.1 Discovery and preclinical testing of markers and technologies, 2.1 Biological and endogenous factors, Neurological, Aged, Amyloid beta-Peptides, Biomarkers, Brain, Central Nervous System Agents, Disease Progression, Double-Blind Method, Female, Humans, Longitudinal Studies, Male, Neurofilament Proteins, Oligopeptides, Peptide Fragments, Phosphorylation, Prognosis, Severity of Illness Index, Supranuclear Palsy, Progressive, tau Proteins, AL-108-231 Investigators, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo determine the ability of CSF biomarkers to predict disease progression in progressive supranuclear palsy (PSP).MethodsWe compared the ability of baseline CSF β-amyloid1-42, tau, phosphorylated tau 181 (p-tau), and neurofilament light chain (NfL) concentrations, measured by INNO-BIA AlzBio3 or ELISA, to predict 52-week changes in clinical (PSP Rating Scale [PSPRS] and Schwab and England Activities of Daily Living [SEADL]), neuropsychological, and regional brain volumes on MRI using linear mixed effects models controlled for age, sex, and baseline disease severity, and Fisher F density curves to compare effect sizes in 50 patients with PSP. Similar analyses were done using plasma NfL measured by single molecule arrays in 141 patients.ResultsHigher CSF NfL concentration predicted more rapid decline (biomarker × time interaction) over 52 weeks in PSPRS (p = 0.004, false discovery rate-corrected) and SEADL (p = 0.008), whereas lower baseline CSF p-tau predicted faster decline on PSPRS (p = 0.004). Higher CSF tau concentrations predicted faster decline by SEADL (p = 0.004). The CSF NfL/p-tau ratio was superior for predicting change in PSPRS, compared to p-tau (p = 0.003) or NfL (p = 0.001) alone. Higher NfL concentrations in CSF or blood were associated with greater superior cerebellar peduncle atrophy (fixed effect, p ≤ 0.029 and 0.008, respectively).ConclusionsBoth CSF p-tau and NfL correlate with disease severity and rate of disease progression in PSP. The inverse correlation of p-tau with disease severity suggests a potentially different mechanism of tau pathology in PSP as compared to Alzheimer disease.

Published
2018

3. Progression of brain atrophy in PSP and CBS over 6 months and 1 year

Author

Dutt, Shubir, Binney, Richard J, Heuer, Hilary W, Luong, Phi, Attygalle, Suneth, Bhatt, Priyanka, Marx, Gabe A, Elofson, Jonathan, Tartaglia, Maria C, Litvan, Irene, McGinnis, Scott M, Dickerson, Bradford C, Kornak, John, Waltzman, Dana, Voltarelli, Lisa, Schuff, Norbert, Rabinovici, Gil D, Kramer, Joel H, Jack, Clifford R, Miller, Bruce L, Rosen, Howard J, Boxer, Adam L, Williams, David, Lafontaine, Anne Louise, Marras, Connie, Jog, Mandar, Panisset, Michael, Lang, Anthony, Parker, Lesley, Stewart, Alistair J, Corvol, Jean-Christophe, Azulay, Jean-Philippe, Couratier, Philippe, Mollenhauer, Brit, Lorenzl, Stefan, Ludolph, Albert, Benecke, Reiner, Hoglinger, Gunter, Lipp, Axel, Reichmann, Heinz, Woitalla, Dirk, Chan, Dennis, Zermansky, Adam, Burn, David, Lees, Andrew, Gozes, Illana, Boxer, Adam, Lobach, Iryna V, Roberson, Erik, Honig, Lawrence, Zamrini, Edward, Pahwa, Rajesh, Bordelon, Yvette, Driver-Dunkley, Erika, Lessig, Stephanie, Lew, Mark, Womack, Kyle, Boeve, Brad, Ferrara, Joseph, Hillis, Argyle, Kaufer, Daniel, Kumar, Rajeev, Xie, Tao, Gunzler, Steven, Zesiewicz, Theresa, Dayalu, Praveen, Golbe, Lawrence, Grossman, Murray, Jankovic, Joseph, McGinnis, Scott, Santiago, Anthony, Tuite, Paul, Isaacson, Stuart, Leegwater-Kim, Julie, Knopman, David S, Schneider, Lon S, Doody, Rachelle S, Koestler, Mary, Van Deerlin, Viviana, Randolph, Christopher, Whitaker, Steve, Hirman, Joe, Gold, Michael, Morimoto, and , Bruce H

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Frontotemporal Dementia (FTD), Clinical Research, Acquired Cognitive Impairment, Alzheimer's Disease Related Dementias (ADRD), Neurosciences, Brain Disorders, Alzheimer's Disease, Clinical Trials and Supportive Activities, Rare Diseases, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Neurodegenerative, Biomedical Imaging, 2.1 Biological and endogenous factors, Neurological, Aged, Atrophy, Basal Ganglia, Cerebral Cortex, Disease Progression, Female, Follow-Up Studies, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Middle Aged, Statistics, Nonparametric, Supranuclear Palsy, Progressive, AL-108-231 investigators, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo examine the utility and reliability of volumetric MRI in measuring disease progression in the 4 repeat tauopathies, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), to support clinical development of new tau-directed therapeutic agents.MethodsSix- and 12-month changes in regional MRI volumes and PSP Rating Scale scores were examined in 55 patients with PSP and 33 patients with CBS (78% amyloid PET negative) compared to 30 normal controls from a multicenter natural history study. Longitudinal voxel-based morphometric analyses identified patterns of volume loss, and region-of-interest analyses examined rates of volume loss in brainstem (midbrain, pons, superior cerebellar peduncle), cortical, and subcortical regions based on previously validated atlases. Results were compared to those in a replication cohort of 226 patients with PSP with MRI data from the AL-108-231 clinical trial.ResultsPatients with CBS exhibited greater baseline atrophy and greater longitudinal atrophy rates in cortical and basal ganglia regions than patients with PSP; however, midbrain and pontine atrophy rates were similar. Voxel-wise analyses showed distinct patterns of regional longitudinal atrophy in each group as compared to normal controls. The midbrain/pons volumetric ratio differed between diagnoses but remained stable over time. In both patient groups, brainstem atrophy rates were correlated with disease progression measured using the PSP Rating Scale.ConclusionsVolume loss is quantifiable over a period of 6 months in CBS and PSP. Future clinical trials may be able to combine CBS and PSP to measure therapeutic effects.

Published
2016

4. Severity dependent distribution of impairments in PSP and CBS: Interactive visualizations

Author

Williams, David, Lafontaine, Anne Louise, Marras, Connie, Jog, Mandar, Panisset, Michael, Lang, Anthony, Parker, Lesley, Stewart, Alistair J., Corvol, Jean-Christophe, Azulay, Jean-Philippe, Couratier, Philippe, Mollenhauer, Brit, Lorenzl, Stefan, Ludolph, Albert, Benecke, Reiner, Hoglinger, Gunter, Lipp, Axel, Reichmann, Heinz, Woitalla, Dirk, Chan, Dennis, Zermansky, Adam, Burn, David, Lees, Andrew, Gozes, Illana, Boxer, Adam, Miller, Bruce L., Lobach, Iryna V., Roberson, Erik, Honig, Lawrence, Zamrini, Edward, Pahwa, Rajesh, Bordelon, Yvette, Driver-Dunkley, Erika, Lessig, Stephanie, Lew, Mark, Womack, Kyle, Boeve, Brad, Ferrara, Joseph, Hillis, Argyle, Kaufer, Daniel, Kumar, Rajeev, Xie, Tao, Gunzler, Steven, Zesiewicz, Theresa, Dayalu, Praveen, Golbe, Lawrence, Grossman, Murray, Jankovic, Joseph, McGinnis, Scott, Santiago, Anthony, Tuite, Paul, Isaacson, Stuart, Leegwater-Kim, Julie, Litvan, Irene, Knopman, David S., Schneider, Lon S., Doody, Rachelle S., Golbe, Lawrence I., Roberson, Erik D., Koestler, Mary, Jack, Clifford R., Jr., Van Deerlin, Viviana, Randolph, Christopher, Whitaker, Steve, Hirman, Joe, Gold, Michael, Morimoto, Bruce H., Nuebling G, Georg, Hensler, Mira, Paul, Sabine, Zwergal, Andreas, Heuer, Hilary W., Tartaglia, Maria C., McGinnis, Scott M., Dickerson, Bradford C., Kornak, John, Schuff, Norbert, Rabinovici, Gil D., Rosen, Howard J., Boxer, Adam L., Gómez, J.C., Tijero, B., Berganzo, K., Garc'ıa de Yebenes, J., Lopez Sendón, J.L., Garcia, G., Tolosa, E., Buongiorno, M.T., Bargalló, N., Burguera, J.A., Martinez, I., Ruiz-Mart'ınez, J., Narrativel, I., Vivancos, F., Ybot, I., Aguilar, M., Quilez, P., Boada, M., Lafuente, A., Hernandez, I., López-Lozano, J.J., Mata, M., Kupsch, A., Lipp, A., Ebersbach, G., Schmidt, T., Hahn, K., Höglinger, G., Höllerhage, M., Oertel, W.H., Respondek, G., Stamelou, M., Reichmann, H., Wolz, M., Schneider, C., Klingelhöfer, L., Berg, D., Maetzler, W., Srulijes, K.K., Ludolph, A., Kassubek, J., Steiger, M., Tyler, K., Burn, D.J., Morris, L., Lees, A., Ling, H., Hauser, R., McClain, T., Truong, D., Jenkins, S., Litvan, I., Houghton, D., Ferrara, J., Bordelon, Y., Gratiano, A., Golbe, L., Mark, M., Uitti, R., Ven Gerpen, J., Brittain, Claire, McCarthy, Andrew, Irizarry, Michael C., McDermott, Dana, Biglan, Kevin, Höglinger, Günter U., and del Ser, Teodoro

Published
2019
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5. Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial

Author

Boxer, Adam L, Lang, Anthony E, Grossman, Murray, Knopman, David S, Miller, Bruce L, Schneider, Lon S, Doody, Rachelle S, Lees, Andrew, Golbe, Lawrence I, Williams, David R, Corvol, Jean-Cristophe, Ludolph, Albert, Burn, David, Lorenzl, Stefan, Litvan, Irene, Roberson, Erik D, Höglinger, Günter U, Koestler, Mary, Jack, Clifford R, Van Deerlin, Viviana, Randolph, Christopher, Lobach, Iryna V, Heuer, Hilary W, Gozes, Illana, Parker, Lesley, Whitaker, Steve, Hirman, Joe, Stewart, Alistair J, Gold, Michael, Morimoto, Bruce H, and Investigators, for the AL-108-231

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Rare Diseases, Clinical Research, Clinical Trials and Supportive Activities, Brain Disorders, Neurosciences, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Aged, Double-Blind Method, Female, Humans, Male, Oligopeptides, Supranuclear Palsy, Progressive, Treatment Outcome, AL-108-231 Investigators, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundIn preclinical studies, davunetide promoted microtubule stability and reduced tau phosphorylation. Because progressive supranuclear palsy (PSP) is linked to tau pathology, davunetide could be a treatment for PSP. We assessed the safety and efficacy of davunetide in patients with PSP.MethodsIn a double-blind, parallel group, phase 2/3 trial, participants were randomly assigned with permuted blocks in a 1:1 ratio to davunetide (30 mg twice daily, intranasally) or placebo for 52 weeks at 48 centres in Australia, Canada, France, Germany, the UK, and the USA. Participants met the modified Neuroprotection and Natural History in Parkinson Plus Syndrome study criteria for PSP. Primary endpoints were the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England Activities of Daily Living (SEADL) scale at up to 52 weeks. All participants and study personnel were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with Clinicaltrials.gov, number NCT01110720.Findings313 participants were randomly assigned to davunetide (n=157) or to placebo (n=156), and 241 (77%) completed the study (118 and 156 in the davunetide and placebo groups, respectively). There were no differences in the davunetide and placebo groups in the baseline PSPRS and SEADL. The davunetide and placebo groups did not differ in the change from baseline in PSPRS (median 11·8 [95% CI 10·5 to 13·0] vs 11·8 [10·5 to 13·0], respectively, p=0·41) or SEADL (-0·20 [-0·20 to -0·17] vs -0·20 [-0·22 to -0·17], respectively, p=0·92). 54 serious adverse events were reported in each of the treatment groups, including 11 deaths in the davunetide group and ten in the placebo group. The frequency of nasal adverse events was greater in the davunetide group than in the placebo group (epistaxis 18 [12%] of 156 vs 13 [8%] of 156, rhinorrhoea 15 [10%] vs eight [5%], and nasal discomfort 15 [10%] vs one [

Published
2014

6. SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration

Author

Barbier, Mathieu, Camuzat, Agnès, Hachimi, Khalid El, Guegan, Justine, Rinaldi, Daisy, Lattante, Serena, Houot, Marion, Sánchez-Valle, Raquel, Sabatelli, Mario, Antonell, Anna, Molina-Porcel, Laura, Clot, Fabienne, Couratier, Philippe, van der Ende, Emma, van der Zee, Julie, Manzoni, Claudia, Camu, William, Cazeneuve, Cécile, Sellal, François, Didic, Mira, Golfier, Véronique, Pasquier, Florence, Duyckaerts, Charles, Rossi, Giacomina, Bruni, Amalia C, Alvarez, Victoria, Gómez-Tortosa, Estrella, de Mendonça, Alexandre, Graff, Caroline, Masellis, Mario, Nacmias, Benedetta, Oumoussa, Badreddine Mohand, Jornea, Ludmila, Forlani, Sylvie, Van Deerlin, Viviana, Rohrer, Jonathan D, Gelpi, Ellen, Rademakers, Rosa, Van Swieten, John, Le Guern, Eric, Van Broeckhoven, Christine, Ferrari, Raffaele, Génin, Emmanuelle, Brice, Alexis, Ber, Le, Isabelle Alexis Brice, Sophie, Auriacombe, Serge, Belliard, Anne, Bertrand, Anne, Bissery, Fre ́ de, ́ ric Blanc, Marie-Paule, Boncoeur, Ste, ́ phanie Bombois, Claire Boutoleau-Bretonnie` re, Agne`, s Camuzat, Mathieu, Ceccaldi, Marie, Chupin, Philippe, Couratier, Olivier, Colliot, Vincent, Deramecourt, Mira, Didic, Bruno, Dubois, Charles, Duyckaerts, Fre ́ de, ́ rique Etcharry-Bouyx, Aure, ́ lie Guignebert-Funkiewiez, Maı ̈te, ́ Formaglio, ́ ronique Golfier, Ve, Marie-Odile, Habert, Didier, Hannequin, Lucette, Lacomblez, Julien, Lagarde, ́ raldine Lautrette, Ge, Isabelle Le Ber, Benjamin Le Toullec, Richard, Levy, Marie-Anne, Mackowiak, Bernard-Franc ̧ois Michel, Florence, Pasquier, Thibaud, Lebouvier, Carole Roue, ́ -Jagot, Christel Thauvin- Robinet, Catherine, Thomas-Anterion, Je ́ re, ́ mie Pariente, Franc ̧ois Salachas, Sabrina, Sayah, Franc ̧ois Sellal, Assi-Herve, ́ Oya, Daisy, Rinaldi, Adeline, Rollin-Sillaire, Martine, Vercelletto, David, Wallon, Armelle, Rametti-Lacroux, Raffaele, Ferrari, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Adaikalavan, Ramasamy, Kwok, John B. J., Carol Dobson- Stone, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Olivier, Piguet, Lauren, Bartley, Elizabeth, Thompson, Isabel Herna, ́ ndez, Agustı ́n Ruiz, Merce`, Boada, Barbara, Borroni, Alessandro, Padovani, Carlos, Cruchaga, Cairns, Nigel J., Luisa, Benussi, Giuliano, Binetti, Roberta, Ghidoni, Gianluigi, Forloni, Diego, Albani, Daniela, Galimberti, Chiara, Fenoglio, Maria, Serpente, Elio, Scarpini, ́ n, Jordi Clarimo, Alberto Lleo, ́, Rafael, Blesa, Maria Landqvist Waldo, ̈, Karin, Nilsson, Christer, Nilsson, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Jordan, Grafman, Morris, Christopher M., Johannes, Attems, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Pietro, Pietrini, Edward, Uey, Wassermann, Eric M., Atik, Baborie, Evelyn, Jaros, Tierney, Michael C., Pau, Pastor, Cristina, Razquin, Sara, Ortega-Cubero, Elena, Alonso, Robert, Perneczky, Janine, Diehl-Schmid, Panagiotis, Alexopoulos, Alexander, Kurz, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Ekaterina, Rogaeva, Peter St George-Hyslop, Giacomina, Rossi, Fabrizio, Tagliavini, Giorgio, Giaccone, Rowe, James B., Schlachetzki, Johannes C. M., James, Uphill, John, Collinge, Simon, Mead, Adrian, Danek, Van Deerlin, Vivianna M., Murray, Grossman, Trojanowski, John Q., Julie van der Zee, Christine Van Broeckhoven, Cappa, Stefano F., Isabelle, Leber, Alexis, Brice, Benedetta, Nacmias, Sandro, Sorbi, Silvia, Bagnoli, Irene, Piaceri, Nielsen, Jørgen E., Hjermind, Lena E., Matthias, Riemenschneider, Manuel, Mayhaus, Bernd, Ibach, Gilles, Gasparoni, Sabrina, Pichler, Wei, Gu, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Maria Grazia Spillantini, Morris, Huw R., Patrizia, Rizzu, Peter, Heutink, Snowden, Julie S., Sara, Rollinson, Anna, Richardson, Alexander, Gerhard, Bruni, Amalia C., Raffaele, Maletta, Francesca, Frangipane, Chiara, Cupidi, Livia, Bernardi, Maria, Anfossi, Maura, Gallo, Maria Elena Conidi, Nicoletta, Smirne, Rosa, Rademakers, Matt, Baker, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., David, Knopman, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Howard, Rosen, van Swieten, John C., Dopper, Elise G. P., Harro, Seelaar, Pijnenburg, Yolande A. L., Philip, Scheltens, Giancarlo, Logroscino, Rosa, Capozzo, Valeria, Novelli, Puca, Annibale A., Massimo, Franceschi, Alfredo, Postiglione, Graziella, Milan, Paolo, Sorrentino, Mark, Kristiansen, Huei-Hsin, Chiang, Caroline, Graff, Adeline, Rollin, Dimitrios, Kapogiannis, Luigi, Ferrucci, Stuart, Pickering-Brown, Singleton, Andrew B., John, Hardy, Parastoo, Momeni., Neurology, Amsterdam Neuroscience - Neurodegeneration, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Dupuytren [CHU Limoges], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Center for Molecular Neurology (VIB-UAntwerp), University of Antwerp (UA), University College of London [London] (UCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Yves le Foll, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Hospital Central de Asturias, Institute of Health Research of Principado de Asturias (ISPA), Fundación Jiménez Díaz, Fundacion Jimenez Diaz [Madrid] (FJD), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), Karolinska University Hospital [Stockholm], Sunnybrook Research Institute [Toronto] (SRI), Sunnybrook Health Sciences Centre, Università degli Studi di Firenze = University of Florence (UniFI), Fondazione Don Carlo Gnocchi, Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), The French clinical and genetic Research network on FTLD/FTLD-ALS and PREVDEMALS, The International Frontotemporal Dementia Genomics Consortium, The European Early Onset Dementia (EU -EOD) Consortium, Brainbank Neuro-CEB Neuropathology Network, and Neurological Tissue Bank of the Biobank Hospital Clinic-IDIBAPS

Subjects
Adult, Male, TDP-43, C9orf72, SLITRK2, amyotrophic lateral sclerosis, frontotemporal dementia, Nerve Tissue Proteins, Settore MED/03 - GENETICA MEDICA, Polymorphism, Single Nucleotide, Cohort Studies, Genes, X-Linked, 80 and over, Medicine, Dementia, Humans, Allele, Age of Onset, Polymorphism, Aged, Aged, 80 and over, biology, C9orf72 Protein, business.industry, Membrane Proteins, MESH: Frontotemporal Lobar Degeneration / epidemiology, Frontotemporal Lobar, Degeneration / genetics, Genes, X-Linked / genetics, Genome-Wide Association Study / methods, Frontotemporal lobar degeneration, Single Nucleotide, Middle Aged, X-Linked, medicine.disease, Amyotrophic lateral sclerosis, Minor allele frequency, Genes, Immunology, Synaptophysin, biology.protein, Female, MESH: Adult, C9orf72 Protein / genetics, Frontotemporal Lobar Degeneration / diagnosis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, Neurology (clinical), MESH: Humans, Membrane Proteins / genetics, Nerve Tissue Proteins / genetics, Polymorphism, Single Nucleotide / genetics, Age of onset, Frontotemporal Lobar Degeneration, business, Frontotemporal dementia, Genome-Wide Association Study
Abstract

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

Published
2021
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8. Severity dependent distribution of impairments in PSP and CBS: Interactive Visualizations

Author

Brittain, Claire, McCarthy, Andrew, investigators, PROPSPERA, Tolosa, E., Buongiorno, M. T., Bargalló, N., Burguera, J. A., Martinez, I., Ruiz-Mart'ınez, J., Narrativel, I., Vivancos, F., Ybot, I., Aguilar, M., 4RNTI-1authors, Quilez, P., Boada, M., Lafuente, A., Hernandez, I., López-Lozano, J. J., Mata, M., Kupsch, A., Lipp, A., Ebersbach, G., Schmidt, T., PSP, Tau Restoration on, Hahn, K., Höllerhage, M., Oertel, W. H., Respondek, G., Stamelou, M., Reichmann, H., Wolz, M., Schneider, C., Klingelhöfer, L., Berg, D., Williams, David, Maetzler, W., Srulijes, K. K., Ludolph, A., Kassubek, J., Steiger, M., Tyler, K., Burn, D. J., Morris, L., Lees, A., Ling, H., Lafontaine, Anne Louise, Hauser, R., McClain, T., Truong, D., Jenkins, S., Litvan, I., Houghton, D., Ferrara, J., Bordelon, Y., Gratiano, A., Golbe, L., Marras, Connie, Mark, M., Uitti, R., Ven Gerpen, J., Jog, Mandar, Panisset, Michael, Lang, Anthony, Parker, Lesley, Irizarry, Michael C, Stewart, Alistair J, Corvol, Jean-Christophe, Azulay, Jean-Philippe, Couratier, Philippe, Mollenhauer, Brit, Lorenzl, Stefan, Ludolph, Albert, Benecke, Reiner, Lipp, Axel, Reichmann, Heinz, McDermott, Dana, Woitalla, Dirk, Chan, Dennis, Zermansky, Adam, Burn, David, Lees, Andrew, Gozes, Illana, Boxer, Adam, Miller, Bruce L, Lobach, Iryna V, Roberson, Erik, Biglan, Kevin, Honig, Lawrence, Zamrini, Edward, Pahwa, Rajesh, Bordelon, Yvette, Driver-Dunkley, Erika, Lessig, Stephanie, Lew, Mark, Womack, Kyle, Boeve, Brad, Ferrara, Joseph, Höglinger, Günter U, Hillis, Argyle, Kaufer, Daniel, Kumar, Rajeev, Xie, Tao, Gunzler, Steven, Zesiewicz, Theresa, Dayalu, Praveen, Golbe, Lawrence, Grossman, Murray, Jankovic, Joseph, McGinnis, Scott, Santiago, Anthony, Tuite, Paul, Isaacson, Stuart, Leegwater-Kim, Julie, Litvan, Irene, Knopman, David S, Schneider, Lon S, Doody, Rachelle S, Del Ser, Teodoro, Golbe, Lawrence I, Roberson, Erik D, Koestler, Mary, Jack, Clifford R, Van Deerlin, Viviana, Randolph, Christopher, Whitaker, Steve, Hirman, Joe, Gold, Michael, Morimoto, Bruce H, Boxer, Adam L, Nuebling G, Georg, Hensler, Mira, Paul, Sabine, Zwergal, Andreas, Heuer, Hilary W, Tartaglia, Maria C, McGinnis, Scott M, Dickerson, Bradford C, Kornak, John, Group, AL-108-231 Study, Schuff, Norbert, Rabinovici, Gil D, Rosen, Howard J, Gómez, J. C., Tijero, B., Berganzo, K., Garc'ıa de Yebenes, J., Lopez Sendón, J. L., and Garcia, G.

Subjects
0301 basic medicine, Male, Activities of daily living, physiopathology [Supranuclear Palsy, Progressive], Disease, Severity of Illness Index, diagnosis [Supranuclear Palsy, Progressive], Predictive models, 0302 clinical medicine, diagnosis [Basal Ganglia Diseases], Aged, 80 and over, Neurodegenerative Diseases, Syndrome, Middle Aged, Corticobasal syndrome, Prognosis, Neurology, Disease Progression, Female, Tauopathy, Supranuclear Palsy, Progressive, Natural history study, PSP rating scale, medicine.medical_specialty, physiopathology [Basal Ganglia Diseases], diagnosis [Neurodegenerative Diseases], Models, Neurological, Article, Progressive supranuclear palsy, 03 medical and health sciences, Physical medicine and rehabilitation, Basal Ganglia Diseases, Rating scale, medicine, Humans, ddc:610, Aged, Interactive visualizations, business.industry, physiopathology [Neurodegenerative Diseases], Data Visualization, medicine.disease, Gait, eye diseases, Clinical trial, 030104 developmental biology, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery
Abstract

Background: Progressive supranuclear palsy (PSP)-Richardson's Syndrome and Corticobasal Syndrome (CBS) are the two classic clinical syndromes associated with underlying four repeat (4R) tau pathology. The PSP Rating Scale is a commonly used assessment in PSP clinical trials; there is an increasing interest in designing combined 4R tauopathy clinical trials involving both CBS and PSP. Objectives: To determine contributions of each domain of the PSP Rating Scale to overall severity and characterize the probable sequence of clinical progression of PSP as compared to CBS. Methods: Multicenter clinical trial and natural history study data were analyzed from 545 patients with PSP and 49 with CBS. Proportional odds models were applied to model normalized cross-sectional PSP Rating Scale, estimating the probability that a patient would experience impairment in each domain using the PSP Rating Scale total score as the index of overall disease severity. Results: The earliest symptom domain to demonstrate impairment in PSP patients was most likely to be Ocular Motor, followed jointly by Gait/Midline and Daily Activities, then Limb Motor and Mentation, and finally Bulbar. For CBS, Limb Motor manifested first and ocular showed less probability of impairment throughout the disease spectrum. An online tool to visualize predicted disease progression was developed to predict relative disability on each subscale per overall disease severity. Conclusion: The PSP Rating Scale captures disease severity in both PSP and CBS. Modelling how domains change in relation to one other at varying disease severities may facilitate detection of therapeutic effects in future clinical trials.

Published
2018
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9. Severity dependent distribution of impairments in PSP and CBS: Interactive visualizations

Author

Brittain, Claire, primary, McCarthy, Andrew, additional, Irizarry, Michael C., additional, McDermott, Dana, additional, Biglan, Kevin, additional, Höglinger, Günter U., additional, Lorenzl, Stefan, additional, del Ser, Teodoro, additional, Boxer, Adam L., additional, Williams, David, additional, Lafontaine, Anne Louise, additional, Marras, Connie, additional, Jog, Mandar, additional, Panisset, Michael, additional, Lang, Anthony, additional, Parker, Lesley, additional, Stewart, Alistair J., additional, Corvol, Jean-Christophe, additional, Azulay, Jean-Philippe, additional, Couratier, Philippe, additional, Mollenhauer, Brit, additional, Ludolph, Albert, additional, Benecke, Reiner, additional, Hoglinger, Gunter, additional, Lipp, Axel, additional, Reichmann, Heinz, additional, Woitalla, Dirk, additional, Chan, Dennis, additional, Zermansky, Adam, additional, Burn, David, additional, Lees, Andrew, additional, Gozes, Illana, additional, Boxer, Adam, additional, Miller, Bruce L., additional, Lobach, Iryna V., additional, Roberson, Erik, additional, Honig, Lawrence, additional, Zamrini, Edward, additional, Pahwa, Rajesh, additional, Bordelon, Yvette, additional, Driver-Dunkley, Erika, additional, Lessig, Stephanie, additional, Lew, Mark, additional, Womack, Kyle, additional, Boeve, Brad, additional, Ferrara, Joseph, additional, Hillis, Argyle, additional, Kaufer, Daniel, additional, Kumar, Rajeev, additional, Xie, Tao, additional, Gunzler, Steven, additional, Zesiewicz, Theresa, additional, Dayalu, Praveen, additional, Golbe, Lawrence, additional, Grossman, Murray, additional, Jankovic, Joseph, additional, McGinnis, Scott, additional, Santiago, Anthony, additional, Tuite, Paul, additional, Isaacson, Stuart, additional, Leegwater-Kim, Julie, additional, Litvan, Irene, additional, Knopman, David S., additional, Schneider, Lon S., additional, Doody, Rachelle S., additional, Golbe, Lawrence I., additional, Roberson, Erik D., additional, Koestler, Mary, additional, Jack, Clifford R., additional, Van Deerlin, Viviana, additional, Randolph, Christopher, additional, Whitaker, Steve, additional, Hirman, Joe, additional, Gold, Michael, additional, Morimoto, Bruce H., additional, Nuebling G, Georg, additional, Hensler, Mira, additional, Paul, Sabine, additional, Zwergal, Andreas, additional, Heuer, Hilary W., additional, Tartaglia, Maria C., additional, McGinnis, Scott M., additional, Dickerson, Bradford C., additional, Kornak, John, additional, Schuff, Norbert, additional, Rabinovici, Gil D., additional, Rosen, Howard J., additional, Gómez, J.C., additional, Tijero, B., additional, Berganzo, K., additional, Garc'ıa de Yebenes, J., additional, Lopez Sendón, J.L., additional, Garcia, G., additional, Tolosa, E., additional, Buongiorno, M.T., additional, Bargalló, N., additional, Burguera, J.A., additional, Martinez, I., additional, Ruiz-Mart'ınez, J., additional, Narrativel, I., additional, Vivancos, F., additional, Ybot, I., additional, Aguilar, M., additional, Quilez, P., additional, Boada, M., additional, Lafuente, A., additional, Hernandez, I., additional, López-Lozano, J.J., additional, Mata, M., additional, Kupsch, A., additional, Lipp, A., additional, Ebersbach, G., additional, Schmidt, T., additional, Hahn, K., additional, Höglinger, G., additional, Höllerhage, M., additional, Oertel, W.H., additional, Respondek, G., additional, Stamelou, M., additional, Reichmann, H., additional, Wolz, M., additional, Schneider, C., additional, Klingelhöfer, L., additional, Berg, D., additional, Maetzler, W., additional, Srulijes, K.K., additional, Ludolph, A., additional, Kassubek, J., additional, Steiger, M., additional, Tyler, K., additional, Burn, D.J., additional, Morris, L., additional, Lees, A., additional, Ling, H., additional, Hauser, R., additional, McClain, T., additional, Truong, D., additional, Jenkins, S., additional, Litvan, I., additional, Houghton, D., additional, Ferrara, J., additional, Bordelon, Y., additional, Gratiano, A., additional, Golbe, L., additional, Mark, M., additional, Uitti, R., additional, and Ven Gerpen, J., additional

Published
2019
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10. Recommended principles and practices for validating clinical molecular pathology tests

Author

Jennings, Lawrence, Van Deerlin, Viviana M., and Gulley, Margaret L.

Subjects
United States. Food and Drug Administration -- Powers and duties, International Organization for Standardization -- Powers and duties, Pathology, Molecular -- Standards, Pathology, Molecular -- Practice, Clinical pathology -- Practice, Clinical pathology -- Standards, Examinations -- Validity, Examinations -- Usage
Abstract

* Context. -- The use of DNA- and RNA-based tests continues to grow for applications as varied as inherited disease, infectious disease, cancer, identity testing, human leukocyte antigen typing, and pharmacogenetics. Progress is driven in part by the huge growth in knowledge about the molecular basis of disease coupled with advancements in technologic capabilities. In addition to requirements for clinical utility, every molecular test also may have limitations that must be carefully considered before clinical implementation. Analytic and clinical performance characteristics as well as test limitations are established and documented through the process of test validation. Objective. -- To describe the established principles of test validation, along with relevant regulations in the United States, in order to provide a rational approach to introducing molecular tests into the clinical laboratory. Data Sources. -- PubMed review of published literature, published guidelines, and online information from national and international professional organizations. Conclusions. -- These resources and recommendations provide a framework for validating clinical tests., The steps involved in test validation are meant to answer one main question--is a given test ready to be implemented in the clinical laboratory? In order to answer this question, [...]

Published
2009

12. A NovelGRNMutation (GRNc.708+6_+9delTGAG) in Frontotemporal Lobar Degeneration With TDP-43–Positive Inclusions

Author

Bit-Ivan, Esther N., primary, Suh, Eunran, additional, Shim, Hyung-Sub, additional, Weintraub, Sandra, additional, Hyman, Bradley T., additional, Arnold, Steven E., additional, McCarty-Wood, Elisabeth, additional, Van Deerlin, Viviana M., additional, Schneider, Julie A., additional, Trojanowski, John Q., additional, Frosch, Matthew P., additional, Baker, Matt C., additional, Rademakers, Rosa, additional, Mesulam, Marsel, additional, and Bigio, Eileen H., additional

Published
2014
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13. SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration.

Author

Barbier M, Camuzat A, Hachimi KE, Guegan J, Rinaldi D, Lattante S, Houot M, Sánchez-Valle R, Sabatelli M, Antonell A, Molina-Porcel L, Clot F, Couratier P, van der Ende E, van der Zee J, Manzoni C, Camu W, Cazeneuve C, Sellal F, Didic M, Golfier V, Pasquier F, Duyckaerts C, Rossi G, Bruni AC, Alvarez V, Gómez-Tortosa E, de Mendonça A, Graff C, Masellis M, Nacmias B, Oumoussa BM, Jornea L, Forlani S, Van Deerlin V, Rohrer JD, Gelpi E, Rademakers R, Van Swieten J, Le Guern E, Van Broeckhoven C, Ferrari R, Génin E, Brice A, and Le Ber I

Subjects
Adult, Age of Onset, Aged, Aged, 80 and over, Cohort Studies, Female, Frontotemporal Lobar Degeneration epidemiology, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide genetics, C9orf72 Protein genetics, Frontotemporal Lobar Degeneration diagnosis, Frontotemporal Lobar Degeneration genetics, Genes, X-Linked genetics, Genome-Wide Association Study methods, Membrane Proteins genetics, Nerve Tissue Proteins genetics
Abstract

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10-5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Published
2021
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