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16. 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, Brain Disorders, Frontotemporal Dementia (FTD), Clinical Research, Aging, Alzheimer's Disease Related Dementias (ADRD), Health Disparities, Clinical Trials and Supportive Activities, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Neurodegenerative, Rare Diseases, Dementia, 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

17. ADNP dysregulates methylation and mitochondrial gene expression in the cerebellum of a Helsmoortel–Van der Aa syndrome autopsy case.

Author

D'Incal, Claudio, Van Dijck, Anke, Ibrahim, Joe, De Man, Kevin, Bastini, Lina, Konings, Anthony, Elinck, Ellen, Theys, Claudia, Gozes, Illana, Marusic, Zlatko, Anicic, Mirna, Vukovic, Jurica, Van der Aa, Nathalie, Mateiu, Ligia, Vanden Berghe, Wim, and Kooy, R. Frank

Subjects
TRANSCRIPTION factors, GENE expression, CARRIER proteins, MULTIPLE organ failure, MITOCHONDRIAL proteins
Abstract

Background: Helsmoortel–Van der Aa syndrome is a neurodevelopmental disorder in which patients present with autism, intellectual disability, and frequent extra-neurological features such as feeding and gastrointestinal problems, visual impairments, and cardiac abnormalities. All patients exhibit heterozygous de novo nonsense or frameshift stop mutations in the Activity-Dependent Neuroprotective Protein (ADNP) gene, accounting for a prevalence of 0.2% of all autism cases worldwide. ADNP fulfills an essential chromatin remodeling function during brain development. In this study, we investigated the cerebellum of a died 6-year-old male patient with the c.1676dupA/p.His559Glnfs*3 ADNP mutation. Results: The clinical presentation of the patient was representative of the Helsmoortel–Van der Aa syndrome. During his lifespan, he underwent two liver transplantations after which the child died because of multiple organ failure. An autopsy was performed, and various tissue samples were taken for further analysis. We performed a molecular characterization of the cerebellum, a brain region involved in motor coordination, known for its highest ADNP expression and compared it to an age-matched control subject. Importantly, epigenome-wide analysis of the ADNP cerebellum identified CpG methylation differences and expression of multiple pathways causing neurodevelopmental delay. Interestingly, transcription factor motif enrichment analysis of differentially methylated genes showed that the ADNP binding motif was the most significantly enriched. RNA sequencing of the autopsy brain further identified downregulation of the WNT signaling pathway and autophagy defects as possible causes of neurodevelopmental delay. Ultimately, label-free quantification mass spectrometry identified differentially expressed proteins involved in mitochondrial stress and sirtuin signaling pathways amongst others. Protein–protein interaction analysis further revealed a network including chromatin remodelers (ADNP, SMARCC2, HDAC2 and YY1), autophagy-related proteins (LAMP1, BECN1 and LC3) as well as a key histone deacetylating enzyme SIRT1, involved in mitochondrial energy metabolism. The protein interaction of ADNP with SIRT1 was further biochemically validated through the microtubule-end binding proteins EB1/EB3 by direct co-immunoprecipitation in mouse cerebellum, suggesting important mito-epigenetic crosstalk between chromatin remodeling and mitochondrial energy metabolism linked to autophagy stress responses. This is further supported by mitochondrial activity assays and stainings in patient-derived fibroblasts which suggest mitochondrial dysfunctions in the ADNP deficient human brain. Conclusion: This study forms the baseline clinical and molecular characterization of an ADNP autopsy cerebellum, providing novel insights in the disease mechanisms of the Helsmoortel–Van der Aa syndrome. By combining multi-omic and biochemical approaches, we identified a novel SIRT1-EB1/EB3-ADNP protein complex which may contribute to autophagic flux alterations and impaired mitochondrial metabolism in the Helsmoortel–Van der Aa syndrome and holds promise as a new therapeutic target. Highlights: The ADNP patient mutation affects genome-wide methylation and leads to neurodevelopmental abnormalities. The ADNP brain transcriptome reveals impaired neuronal differentiation and cellular homeostasis by aberrant signaling of the WNT pathway and autophagy process. ADNP forms a complex with SIRT1 through the microtubule end-binding proteins EB1 and EB3. Mitochondrial gene expression is impaired in the ADNP brain and patient-derived cellular models. [ABSTRACT FROM AUTHOR]

Published
2024
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19. 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, Brain Disorders, Aging, Alzheimer's Disease, Neurodegenerative, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Dementia, 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

25. 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, Biomedical Imaging, Aging, Rare Diseases, Alzheimer's Disease, Clinical Research, Neurosciences, Brain Disorders, Acquired Cognitive Impairment, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, 2.1 Biological and endogenous factors, Aetiology, 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

30. The National Autism Database of Israel: a Resource for Studying Autism Risk Factors, Biomarkers, Outcome Measures, and Treatment Efficacy

Author

Dinstein, Ilan, Arazi, Ayelet, Golan, Hava M., Koller, Judah, Elliott, Evan, Gozes, Illana, Shulman, Cory, Shifman, Sagiv, Raz, Raanan, Davidovitch, Nadav, Gev, Tali, Aran, Adi, Stolar, Orit, Ben-Itzchak, Esther, Snir, Irit Mor, Israel-Yaacov, Sandra, Bauminger-Zviely, Nirit, Bonneh, Yoram S., Gal, Eynat, Shamay-Tsoory, Simone, Zait, Anat Zaidman, Hadad, Bat Sheva, Gross, Raz, Faroy, Michal, Bachmat, Eitan, Eran, Alal, Uzefovsky, Florina, Flusser, Hagit, Michaelovski, Analya, Levine, Stephen Z., Kodesh, Arad, Gothelf, Doron, Marom, Daphna, Feldman, Hagit Baris, Yosef, Dalit Ben, Bloch, Aviva Mimouni, Sadaka, Yair, Schtaierman, Chen, Davidovitch, Michael, Begin, Michal, Gabis, Lidia V., Zachor, Ditza, Menashe, Idan, Golan, Ofer, and Meiri, Gal

Published
2020
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37. 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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38. Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP

Author

Bakshi, Madhura, Wilson, Meredith, Berman, Yemina, Dickson, Rebecca, Fransen, Erik, Helsmoortel, Céline, Van den Ende, Jenneke, Van der Aa, Nathalie, van de Wijdeven, Marina J., Rosenblum, Jessica, Monteiro, Fabíola, Kok, Fernando, Quercia, Nada, Bowdin, Sarah, Dyment, David, Chitayat, David, Alkhunaizi, Ebba, Boonen, Susanne E., Keren, Boris, Jacquette, Aurelia, Faivre, Laurence, Bezieau, Stephane, Isidor, Bertrand, Rieß, Angelika, Moog, Ute, Lynch, Sally Ann, McVeigh, Terri, Elpeleg, Orly, Smeland, Marie Falkenberg, Fannemel, Madeleine, van Haeringen, Arie, Maas, Saskia M., Veenstra-Knol, H.E., Schouten, Meyke, Willemsen, Marjolein H., Marcelis, Carlo L., Ockeloen, Charlotte, van der Burgt, Ineke, Feenstra, Ilse, van der Smagt, Jasper, Jezela-Stanek, Aleksandra, Krajewska-Walasek, Malgorzata, González-Lamuño, Domingo, Anderlid, Britt-Marie, Malmgren, Helena, Nordenskjöld, Magnus, Clement, Emma, Hurst, Jane, Metcalfe, Kay, Mansour, Sahar, Lachlan, Katherine, Clayton-Smith, Jill, Hendon, Laura G., Abdulrahman, Omar A., Morrow, Eric, McMillan, Clare, Gerdts, Jennifer, Peeden, Joseph, Schrier Vergano, Samantha A., Valentino, Caitlin, Chung, Wendy K., Ozmore, Jillian R., Bedrosian-Sermone, Sandra, Dennis, Anna, Treat, Kayla, Hughes, Susan Starling, Safina, Nicole, Le Pichon, Jean-Baptiste, McGuire, Marianne, Infante, Elena, Madan-Khetarpal, Suneeta, Desai, Sonal, Benke, Paul, Krokosky, Alyson, Cristian, Ingrid, Baker, Laura, Gripp, Karen, Stessman, Holly A., Eichenberger, Jacob, Jayakar, Parul, Pizzino, Amy, Manning, Melanie Ann, Slattery, Leah, Van Dijck, Anke, Vulto-van Silfhout, Anneke T., Cappuyns, Elisa, van der Werf, Ilse M., Mancini, Grazia M., Tzschach, Andreas, Bernier, Raphael, Gozes, Illana, Eichler, Evan E., Romano, Corrado, Lindstrand, Anna, Nordgren, Ann, Kvarnung, Malin, Kleefstra, Tjitske, de Vries, Bert B.A., Küry, Sébastien, Rosenfeld, Jill A., Meuwissen, Marije E., Vandeweyer, Geert, and Kooy, R. Frank

Published
2019
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39. 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

40. Extended phenotypic characterization of a novel Helsmoortel‐van der Aa syndrome case series.

Author

Pascolini, Giulia, Di Zenzo, Giovanni, Panebianco, Annarita, Didona, Biagio, and Gozes, Illana

Abstract

The neurodevelopmental disorder known as Helsmoortel‐van der Aa syndrome (HVDAS, MIM#616580) or ADNP syndrome (Orphanet, ORPHA:404448) is a multiple congenital anomaly (MCA) condition, reported as a syndrome in 2014, associated with deleterious variants in the ADNP gene (activity‐dependent neuroprotective protein; MIM*611386) in several children. First reported in the turn of the century, ADNP is a protein with crucial functions for the normal development of the central nervous system and with pleiotropic effects, explaining the multisystemic character of the syndrome. Affected individuals present with striking facial dysmorphic features and variable congenital defects. Herein, we describe a novel case series of HVDAS Italian patients, illustrating their clinical findings and the related genotype–phenotype correlations. Interestingly, the cutaneous manifestations are also extensively expanded, giving an important contribution to the clinical characterization of the condition, and highlighting the relation between skin abnormalities and ADNP defects. [ABSTRACT FROM AUTHOR]

Published
2024
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45. Contributors

Author

Agam, Galila, primary, Ben-Shachar, Dorit, additional, Daniele, Cartelli, additional, Gabis, Lidia V., additional, Gozes, Illana, additional, Graziella, Cappelletti, additional, Gross, Christina, additional, Gross, Raz, additional, Ifhar, Lee S., additional, Jiang, Cheng, additional, Kooy, R. Frank, additional, Levine, Joseph, additional, Mekori-Domachevsky, Ehud, additional, Salton, Stephen R., additional, Sayas, Carmen Laura, additional, Segal-Gavish, Hadar, additional, Seroogy, Kim B., additional, van der Werf, Ilse M., additional, and Vandeweyer, Geert, additional

Published
2020
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46. Regional distribution of the prostaglandin E2 receptor EP1 in the rat brain: accumulation in Purkinje cells of the cerebellum

Author

Candelario-Jalil, Eduardo, Slawik, Helen, Ridelis, Ingrid, Waschbisch, Anne, Akundi, Ravi S., Hull, Michael, Fiebich, Bernd L., and Gozes, Illana

Subjects
Neuroscience: Neurochemistry, Neurochemistry
Abstract

Prostaglandin E2 (PGE2), is a major prostanoid produced by the activity of cyclooxygenases (COX) in response to various physiological and pathological stimuli. PGE2 exerts its effects by activating four specific E-type prostanoid receptors (EP1, EP2, EP3 and EP4). In the present study, we analyzed the expression of the PGE2 receptor EP1 (mRNA and protein) in different regions of the adult rat brain (hippocampus, hypothalamus, striatum, prefrontal cerebral cortex, parietal cortex, brain stem and cerebellum) using reverse transcription-polymerase chain reaction (RT-PCR), Western blotting and immunohistochemical methods. On a regional basis, levels of EP1 mRNA were the highest in parietal cortex and cerebellum. At the protein level, we found a very strong expression of EP1 in cerebellum as revealed by Western blotting experiments. Furthermore, the present study provides for the first time evidence that the EP1 receptor is highly expressed in the cerebellum, where the Purkinje cells displayed a very high immunolabeling of their perikaryon and dendrites as observed in the immunohistochemical analysis. Results from the present study indicate that the EP1 prostanoid receptor is expressed in specific neuronal populations, which possibly determine the region specific response to PGE2.

Published
2005

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