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1. Open-label study of the short-term effects of memantine on FDG-PET in frontotemporal dementia

Author

Chow TW, Graff-Guerrero A, Verhoeff NP, Binns MA, Tang-Wai DF, Freedman M, Masellis M, Black SE, Wilson AA, Houle S, and Pollock BG

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Tiffany W Chow1–6, Ariel Graff-Guerrero4,6, Nicolaas PLG Verhoeff2–4,7, Malcolm A Binns3,8, David F Tang-Wai5,9, Morris Freedman1,3,5, Mario Masellis5,10, Sandra E Black3,5,10, Alan A Wilson4,6, Sylvain Houle4,6, Bruce G Pollock4,61Division of Neurology, 2Department of Psychiatry, 3Rotman Research Institute, Baycrest; 4Departments of Psychiatry, 5Medicine, Division of Neurology, University of Toronto; 6Centre for Addiction and Mental Health PET Centre; 7Kunin-Lunenfeld Applied Research Unit, Baycrest; 8Dalla Lana School of Public Health, University of Toronto; 9University Health Network Memory Clinic; 10LC Campbell Cognitive Neurology Research Unit, Department of Medicine (Neurology), Sunnybrook Health Sciences Centre, Toronto, ON, CanadaBackground: Memantine has shown effects on cortical metabolism in Alzheimer's disease (AD), and the mechanism of action may not be specific to AD alone. We hypothesized that participants with frontotemporal dementia taking memantine would show an increased cortical metabolic activity in frontal regions, temporal regions, or in salience network hubs.Methods: Sixteen participants with behavioral or language variant frontotemporal dementia syndromes (FTD) were recruited from tertiary FTD clinics and treated with memantine hydrochloride 10 mg twice daily in this fixed-dose, open-label pilot study. The primary endpoint was enhancement of cortical metabolic activity after 7–8 weeks of treatment. Secondary endpoints were measures of mood and behavior disturbance, frontal executive function, and motor disturbance.Results: Voxel-wise parametric image analysis of positron emission tomography (PET) data from seven behavioral variant FTD patients, eight semantic dementia patients, and one progressive nonfluent aphasia patient, of mean age 64.3 years, mean duration of illness 4.25 years, and baseline mean sum of boxes Clinical Dementia Rating score 6.59, revealed an increase in [18F]-fluorodeoxyglucose (FDG) normalized metabolic activity in bilateral insulae and the left orbitofrontal cortex (P < 0.01). The increase on FDG-PET did not correlate with changes on behavioral inventories. Post hoc analysis indicated that semantic dementia participants drove this finding.Conclusion: This open-label clinical PET study suggests that memantine induces an increase in metabolism in the salience network in FTD. A placebo-controlled follow-up study is warranted.Keywords: Alzheimer's disease, frontotemporal dementia, metabolism, PET scan, semantic dementia

Published
2011

5. Entanglement of Sections, Examples Looking for a Theory

Author

Freedman, M. H. and Hastings, M. B.

Subjects
Quantum Physics, FOS: Mathematics, Algebraic Topology (math.AT), FOS: Physical sciences, Mathematical Physics (math-ph), Mathematics - Algebraic Topology, Quantum Physics (quant-ph), Mathematical Physics
Abstract

Quantum information is about the entanglement of states. To this starting point we add parameters whereby a single state becomes a non-vanishing section of a bundle. We consider through examples the possible entanglement patterns of sections., 15 pages, 0 figures; v2, typo corrections

Published
2023

6. Longitudinal changes in connected speech over a one-year span in the nonfluent/agrammatic variant of Primary Progressive Aphasia.

Author

Lavoie, M., Black, S. E., Tang-Wai, D. F., Graham, N. L., Stewart, S, Freedman, M., Leonard, C., and Rochon, E.

Subjects
STUTTERING, RESEARCH methodology, SPEECH evaluation, INTERVIEWING, APHASIA, COMPARATIVE studies, AGRAMMATISM, RESEARCH funding, SPEECH, LONGITUDINAL method
Abstract

Connected speech assessment is essential to characterize the language features in primary progressive aphasia (PPA). This is especially true for the non-fluent/agrammatic variant (nfvPPA) in which one of the core features is agrammatism. Identification of agrammatism typically involves the analysis of sentence production, as in connected speech, in order to detect syntactic deficits. However, little is known about the longitudinal changes occurring in connected speech of individuals with non-fluent PPA. The aim of this study was to assess changes in connected speech over a one-year span in participants with nfvPPA using semi-structured interviews. We conducted a prospective group study including participants with nfvPPA (n=9) and age- and education-matched healthy controls (n=9). For each individual, connected speech was obtained using topic-directed interviews at two testing rounds, each approximately one year apart. Production on each task was recorded, transcribed and analyzed according to the Quantitative Production Analysis (QPA) protocol, a tool developed by Berndt and colleagues (2000) for the analysis of sentence production in aphasia. For each group, the probability of deterioration between the two testing rounds was estimated using Bayesian analysis. For individuals with nfvPPA, statistical evidence of deterioration from the first testing round to the second was found for five variables, namely the proportion of pronouns, the proportion of verbs, the proportion of closed class words, the inflection index and the proportion of well-formed sentences. Results from the present study suggest that variables relating to word-finding and morphology are more vulnerable to time and therefore may be relevant potential targets for intervention. [ABSTRACT FROM AUTHOR]

Published
2023
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7. Comparative effectiveness of autologous haematopoietic stem cell transplantation vs. fingolimod, ocrelizumab and natalizumab in relapsing-remitting MS

Author

Atkins, H., Burman, J., Massey, J., Sutton, I., Withers, B., Macdonell, R., Grigg, A., Torkildsen, O., Bo, L., Lehmann, A., Horakova, D., Havrdova, E., Krasulova, E., Trneny, M., Kozak, T., van der Walt, A., Butzkueven, H., McCombe, P., Van Wijmeersch, B., Buzzard, K., Skibina, O., Lechner-Scott, J., Willekens, B., Barnett, M., Cartechini, E., Ozakbas, S., Alroughani, R., Izquierdo, G., Boz, C., Kalincik, T., Sharman, S., Roos, I., Freedman, M., Eichau, S., Snowden, J., Sharrack, B., Turkoglu, R., Prevost, J., Slee, M., Soysal, A., Khoury, S., Lugaresi, A., Onofrj, M., Grammond, P., Duquette, P., Girard, M., Prat, A., Terzi, M., Patti, F., and Kuhle, J.

Published
2022

12. Correspondence

Author

Granath, F., Ehrenberg, L., Paulsson, B., Törnqvist, M., Marsh, G. M., Youk, A. O., Lucas, L. J., Schall, L. C., Schulz, M. R., Hertz-Picciotto, I., Van Wijngaarden, E., Hernandez, J. C., Ball, L. M., Freedman, M., Burns, C. J., Koh, T. S., and Koh, T. H. H. G.

Published
2001

27. Peripheral Oxidative Stress Markers Are Related To Vascular Risk Factors And Subcortical Small Vessel Disease

Author

Warrick, N., Seitz, D., Prorok, J., Shawcross, D., Mahootchi, T., Esensoy, A., Yu, D., Danieli, E., Pushpakumar, D., Tony, J., Jacob, K., Dong, J., Javed, F., D’Souza, A., Mollayeva, T., Colantonio, A., Schulz, M., Burhan, A., Naidu, A. Srinivasan, Sarquis-Adamson, Y., Montero-Odasso, M., Cooper, N., Sekhon, H., Launay, C., Allali, G., Chabot, J., Beauchet, O., Watson, B., Lin, T., Korczak, A., Bartha, C., Best, S., Truemner, J., Borrie, M., Cammer, A., Whiting, S., Morgan, D., Newman, K., Duong, J. A., Mok, A., Wang, A. H., Lavoie, M., Bier, N., Macoir, J., Adlimoghaddam, A., Turner, R. S., Cadonic, C., Albensi, B. C., Davis, J., Lewis, V.-L., Pacione, J., Skanes, C., Feltz, N., Loncar, A., Naglie, G., Sanford, S., Stasiulis, E., Rapoport, M., Vrkljan, B., Tuokko, H., Porter, M., Polgar, J., Moorhouse, P., Mazer, B., Marshall, S., Gelinas, I, Crizzle, A, Belchior, P., Bedard, M, Kokorelias, K., Cameron, J., Gignac, M., Bechard, L., Beaton, D., McGilton, K.A., Tartaglia, M. C., Black, S., Mirza, S., Mutsaerts, H.-J., Cash, D., Bocchetta, M., Thomas, D., Dick, K., van Swieten, J., Borroni, B., Galimberti, D., Rowe, J., Bethell, J., Pringle, D., Commisso, E., Chambers, L., Cohen, C., Cowan, K., Fehr, P., Szeto, P., McGilton, K., Shaw, C., Okamura, H., Otani, M., Shimoyama, N., Fujii, T., Lusk, J., Punzalan, M., Dove, E., Cotnam, K., Astell, A., Chow, A. Froehlich, Bayly, M., Kosteniuk, J., Elliot, V., O’Connell, M. E., Kirk, A., Stewart, N., Holroyd-Leduc, J., Daku, J., Kennett-Russill, D., Hack, T., Dilara, A., Astell, A. J., Hernandez, A., Divine, A., Hunter, S., Jacova, C., Alexander, C., Joseph, J. T., Alvarez, A., Smith, E., Woo, S. M. S., Chan, P., Wilkins-Ho, M., Blackburn, P., Fernando, N., Mehra, A., Vasser, E., Musacchio, M., Waxman, R., Fischler, I., Ghaffar, O., DeBay, D. R., Macdonald, I. R., Reid, G. A., Pottie, I. R., Maxwell, S. P., Cash, M. K., Martin, E., Bowen, C. V., Darvesh, S., MacPhee, J., Jorgensen, M., Fogarty, J., Phillips, N., Diprospero, C., Parent, A., Whitehead, V., Campbell, T., Mohades, Z., Chertkow, H., Wong, S., Wilchesky, M., McCusker, J., Champoux, N., Vu, T.T. M., Ciampi, A., Monette, J., Lungu, O., Ballard, S. A., Belzile, E., Carmichael, P.-H., Voyer, P., Cetin-Sahin, D., Gore, B., Peretti, M., Gore, G., Landry, V., Yetman, L., MacDonald, E., McGibbon, C., MacNeil, D., Jarrett, P., Iaboni, A., Andrews, J., Hafezi, S., Marshall, C., Tsokas, M., Martin, L. Schindel, Van Ooteghem, K., Mansfield, A., Marcil, M., Gold, D., Musselman, K., Flint, A., Finger, E., Feldman, H., Cummings, J., Coleman, K., Boxer, A., Berry, S., Hsiung, R., Curtis, A., Zhang, K., Davidson, H. R., Boccone, G., Camicioli, R., Masellis, M., Tierney, M., Dolatabadi, E., Taati, B., Jonas-Simpson, C., Donovan, L., Cross, N., Keren, R., Shan, R., Holley, J., Waisman, Z., Katchaluba, J., Wimhurst, C., Steele, M., Loganathan, P., Gural, P., Shearer, T., Reardon, J., Pilgrim, J., Pitawanakwat, K., Jones, L., Piriano, E., Blind, M., Otowadjiwan, J., Makela, R., Spicer, B., Bretzlaff, M., Jacklin, K., McKay, Kristy, Graham, N., Tang-Wai, D., Leonard, C., Mitchell, S., Laird, L., Rochon, E., Maclagan, L., Maxwell, C., Guan, J., Campitelli, M., Herrmann, N., Lapane, K., Hogan, D., Amuah, J., Gill, S., Bronskill, S., Ebert, P., Kwok, J., Watt, A., Garrett, S., Hoefling, L., Ellery, C., Leggieri, M., Fornazzari, L., Thaut, M., Munoz, D., Barfett, J., Fischer, C., Schweizer, T., Yogaparan, T., Dallaire-Théroux, C., Potvin, O., Dieumegarde, L., Duchesne, Simon, Amini, A.E. Ebrahim, Amini, A.Z. Ebrahim, Dao, E., Barha, C. K., Best, J. R., Hsiung, G.-Y. R., Tam, R., Liu-Ambrose, T., Sztramko, R., Wurster, A., Papaiouannou, A., Cowan, D., St. Onge, J., Allaby, C., Harrison, L., Cimino, C., Marr, S., Patterson, C., Woo, T., Levinson, A., Fisher, S., Mojaverian, N., Hsu, A., Taljaard, M., Manuel, D., Tanuseputro, P., Park, E., Liu, L., VanderPloeg, K., Black, A., Bartha, R., Rabin, J., Yang, H.-S., Schultz, A., Hanseeuw, B., Marshall, G., Hedden, T., Rentz, D., Johnson, K., Sperling, R., Chhatwal, J., Desmarais, P., Miville, C., Keith, J., Lanctôt, K., Thomas, N., Mattek, N., Riley, T., Witter, P., Reynolds, C., Austin, J., Sharma, N., Kaye, J., Bechard, L. E., Mitchell, C. M., Regan, K., Bergelt, M. D., Middleton, L.E., Hewston, P., Kennedy, C., Merom, D., Trainor, L., Grenier, A., Ioannidis, G., Lee, J., Papaioannou, A., Qian, W., Churchill, N., Kumar, S., Rajji, T., Ojeda-López, C., Milán-Tomás, Á., Lam, B., Gao, F. Q., Cumberbatch, S., Gies, S., Tomas, A. Milan, Ojeda-Lopez, C., Lim, A. S., Black, S. E., Sharma, M. J., Ramirez, J., Holmes, M. F., Gao, F., Varatharajah, B., Yhap, V., Appel, L., Bogler, O., Appel, E., Wiseman, M., Cohen, L., Hill, D., Abrams, H., Campos, J., Sapkota, S., Adamo, S., Stuss, D. T., Martinez, M., Multani, N., Anor, C. J., Fox, S., Lang, A. E., Marras, C., Compagnone, J., Li, J., Freedman, M., Kleiner-Fisman, G., Kennedy, J., Chen, R., Lang, A., Sévigny-Dupont, P., Bocti, C., Joannette, M., Lavallée, M. M., Joubert, S., Knoefel, F., Goubran, R., Baker, A., Fraser, S., Allard, B., Wallace, B., Stroulia, E., Guana, V., Masson, P., Alli, S., Kolla, N., De Luca, V., Bouvier, L., Monetta, L., Vitali, P., Laforce, R., Martel-Sauvageau, V., Talebzadeh, A., Ashourinia, K., Moy, S., Lake, A., Cockburn, A., Krisman, D., Sadasivan, B., Sit, W., Stoops, S., McCurbin, S., Cullen, S., Carroll, S., Tasmim, S., Kapoor, E., Callahan, B., Sharma, M., Bierstone, D., Stuss, D., Kapadia, M., Mian, F., Ma, D., Rosa, E., Michalski, B., Zovkic, I., Forsythe, P., Sakic, B., Fahnestock, M., Baxter, J., Peloso, S., Tung, J., Cox, L., Benjamin, S., An, H., Ho, J., Turcotte, V., Parent, C., Gauthier-Beaupré, A., Biss, R., Sultana, A., Chu, C. H., Sun, W., Bartfay, E., Smye, V., Newton, D., Pepin, M., Biswas, S., Madahey, H., Crawford, S. J., Gutmanis, I., Blake, C., Duchesne, S., Hudon, C., Mah, L., Ali, A., Shorey, C., Szabuniewicz, C. M., Anderson, N. D., Verhoeff, N. P. L. G., Cheers, S., Penko, M., Gevaert, V., Yang, Y., Law, J., Modarresi, S., Grahn, J., Overend, T., Amini, D., Thiruparanathan, T., Cheung, T., Iskandar, S., Arone, Y., Young, C., Berezuk, C., and Zakzanis, K.

Subjects
Abstracts
Published
2018

35. 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
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36. 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

37. Recommended adult immunization schedule, United States, 2020

Author

Freedman, M., Talbot, H.K., Matanock, A., Marin, M., Robinson, C., Atmar, R.L., Schaffner, W., Koppaka, R., Sperling, R., Advisory Committee on Immunization Practices, Rittle, C., Strikas, R.A., Peterson, D., Romero, J.R., Redmon, G., Hunter, P., Dooling, K., Kroger, A., McNally, V.V., Oliver, S., Byrd, K., Cohn, A., Fryhofer, S., Leger, M.-M., Mbaeyi, S., Harriman, K., Lanzi, M.C., Desai, M., Hopkins, R.H., Jr., Aleshire, N., Woods, L., Schillie, S., Arvay, M., Lee, G.M., Frey, S.E., Szilagyi, P., Weinbaum, C., Howell, M., Schmader, K., Poehling, K.A., Fiebelkorn, A.P., Bridges, C., Patel, P., Epling, J., Weber, D., Bahta, L., Pilishvili, T., Koenigs, L.P., Lett, S.M., Bernstein, H., Sánchez, P.J., Liang, J., Bell, B.P., Tan, L., Grohskopf, L., Markowitz, L., MacNeil, J., Havers, F., Ault, K.A., Patel, M., and Williams, W.W.

Subjects
natural sciences, health care economics and organizations
Abstract

In October 2019, the Advisory Committee on Immunization Practices (ACIP) voted to approve the Recommended Adult Immunization Schedule for Ages 19 Years or Older, United States, 2020. The 2020 adult immunization schedule, available at www.cdc.gov/vaccines /schedules/hcp/imz/adult.html, summarizes ACIP recommendations in 2 tables and accompanying notes (Figure). The full ACIP recommendations for each vaccine are available at www.cdc.gov/vaccines/hcp/acip-recs/index.html. The 2020 schedule has also been approved by the director of the Centers for Disease Control and Prevention (CDC) and by the American College of Physicians (www .acponline.org), American Academy of Family Physicians (www.aafp.org), American College of Obstetricians and Gynecologists (www.acog.org), and American College of Nurse-Midwives (www.midwife.org).

Published
2020
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