David Bergeron1,2, Maria L Gorno-Tempini3, Gil D Rabinovici3, Miguel A Santos-Santos3,4,5, William Seeley3, Bruce L Miller3, Yolande Pijnenburg2, M Antoinette Keulen2, Colin Groot2, Bart N M van Berckel6, Wiesje M van der Flier2, Philip Scheltens2, Jonathan D Rohrer7, Jason D Warren7, Jonathan M Schott7, Nick C Fox7, Raquel Sanchez-Valle8, Oriol Grau-Rivera8, Ellen Gelpi8,9, Harro Seelaar10, Janne M Papma10, John C van Swieten10, John R Hodges11,12,13, Cristian E Leyton14, Olivier Piguet11,12,13, Emily J Rogalski15,16, Marsel M Mesulam16, Lejla Koric17, Kristensen Nora17, Jeéreémie Pariente18, Bradford Dickerson14, Ian R Mackenzie19, Ging-Yuek R Hsiung19, Serge Belliard19, David J Irwin20, David A Wolk21, Murray Grossman21,22, Matthew Jones23,24, Jennifer Harris24, David Mann25, Julie S Snowden24, Patricio Chrem-Mendez26, Ismael L Calandri26, Alejandra A Amengual26, Carole Miguet-Alfonsi27, Eloi Magnin27, Giuseppe Magnani28, Roberto Santangelo28, Vincent Deramecourt29, Florence Pasquier29, Niklas Mattsson30, Christer Nilsson30, Oskar Hansson30,31, Julia Keith32, Mario Masellis33,34, Sandra E Black33,34, Jordi A Matías-Guiu35, María-Nieves Cabrera-Martin35, Claire Paquet36,37, Julien Dumurgier36, Marc Teichmann38, Marie Sarazin39,40, Michel Bottlaender39,40, Bruno Dubois41, Christopher C Rowe42,43, Victor L Villemagne42,43, Rik Vandenberghe44, Elias Granadillo45,46, Edmond Teng47, Mario Mendez48, Philipp T Meyer49, Lars Frings49, Alberto Lleó50,51,52, Rafael Blesa50,51, Juan Fortea50,51, Sang Won Seo53, Janine Diehl-Schmid54, Timo Grimmer54, Kristian Steen Frederiksen55, Pascual Sánchez-Juan56, Gaël Chételat57, Willemijn Jansen58,59, Rémi W Bouchard1, Robert Jr Laforce1,60, Pieter Jelle Visser5,58, Rik Ossenkoppele2,30. 1. Interdisciplinary Clinic of Memory of the Child Jesus, Laval University, Quebec City, Quebec, Canada. 2. Alzheimer center Amsterdam, Amsterdam UMC, Amsterdam Neuroscience, VU University, Amsterdam, the Netherlands. 3. Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA. 4. Cognition and Brain Plasticity Group, Bellvitge Biomedical Research Institute, Llobregat Hospital, Barcelona, Spain. 5. Llobregat Hospital, ACE Foundation, Catalan Institute of Applied Neurosciences, UIC Barcelona, Barcelona, Spain. 6. Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands. 7. Dementia Research Centre, UCL Institute of Neurology, University College London, London, United Kingdom. 8. Alzheimer's Disease and Other Cognitive Disorders Unit, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain. 9. Institute of Neurology, Medical University of Vienna, Vienna, Austria. 10. Alzheimer Center, Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands. 11. Brain and Mind Centre, School of Medical Sciences, University of Sydney, Sydney, New South Wales, Australia. 12. Neuroscience Research Australia and School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia. 13. Australian Research Council Centre of Excellence in Cognition and its Disorders, Sydney, New South Wales, Australia. 14. Frontotemporal Dementia Unit, Department of Neurology, Massachusetts Alzheimer's Disease Research Center, Harvard Medical School, Boston, MA. 15. Neurological Sciences, Rush University, Chicago, IL. 16. Cognitive Neurology and Alzheimer Disease Center, Northwestern University Medical School, Chicago, IL. 17. Department of Neurology and Neuropsychology, La Timone Hospital, Marseille, France. 18. University of Toulouse, INSERM, Toulouse Neuroimaging Center, Toulouse, France. 19. Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. 20. Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA. 21. Department of Neurology, University of Pennsylvania, Philadelphia, PA. 22. Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, PA. 23. Cerebral Function Unit, Greater Manchester Neurosciences Centre, Manchester, United Kingdom. 24. School of Community-Based Medicine, University of Manchester, Manchester, United Kingdom. 25. Division of Neuroscience and Experimental Psychology, School of Biological Sciences, University of Manchester, Manchester, United Kingdom. 26. Center of Aging and Memory, Neurological Research Institute, Buenos Aires, Argentina. 27. Department of Neurology, CHRU Besançon and Integrative and Clinical Neurosciences Laboratory, Regional Memory Center, University of Bourgogne Franche-Comté, Besançon, France. 28. Department of Neurology, Vita Salute University and IRCCS San Raffaele Hospital, INSPE, Milan, Italy. 29. University of Lille Nord de France, INSERM U1171, DISTALZ, Lille, France. 30. Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden. 31. Neuropsychiatric Clinic, Skåne University Hospital, Malmö, Sweden. 32. Anatomical Pathology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada. 33. Department of Medicine (Neurology), Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada. 34. Hurvitz Brain Sciences Research Program, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada. 35. Department of Neurology and Nuclear Medicine, San Carlos Clinical Hospital, San Carlos Health Research Institute, Complutense University of Madrid, Madrid, Spain. 36. Memory Center, Department of Neurology, Lariboisière-Fernand-Widal Hospital, Paris, France. 37. Department of Pathology, Lariboisière-Fernand-Widal Hospital, Paris, France. 38. Department of Neurology, National Reference Center for PPA and rare dementias, Pitié Salpêtriére Hospital, AP-HP, Paris, France. 39. Frederic Joliot Hospital Service, ERL 9218 CNRS, CEA, Orsay, Île-de-France, France. 40. University of Paris-Sud, IMIV, UMR 1023 INSERM, CEA, Orsay, Île-de-France, France. 41. Center for Cognitive and Behavioral Diseases, Pitié Salpêtrière University Hospital, Paris, France. 42. Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Victoria, Australia. 43. Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia. 44. Department of Neurology, University Hospital Leuven, Leuven, Belgium. 45. Department of Neurology, University of California, Los Angeles, Los Angeles, CA. 46. VA Greater Los Angeles Healthcare System, Los Angeles, CA. 47. Neurobehavior Service, Department of Neurology, University of California, Los Angeles, Los Angeles, CA. 48. Neurobehavior Unit, West Los Angeles VA Medical Center, Los Angeles, CA. 49. Department of Nuclear Medicine, Faculty of Medicine, University Hospital of Freiburg, Freiburg, Germany. 50. Memory Unit, Department of Neurology, Santa Cruz and Saint Paul Hospital, Barcelona, Spain. 51. Saint Paul Biomedical Research Institute, Autonomous University of Barcelona, Barcelona, Spain. 52. Center for Biomedical Network Research on Neurodegenerative Diseases, Madrid, Spain. 53. Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 54. Department of Psychiatry and Psychotherapy, Technical University of Munich, Munich, Germany. 55. Department of Neurology, Danish Dementia Research Center, Copenhagen, Denmark. 56. Neurology Service, Marqués de Valdecilla University Hospital, Santander, Spain. 57. INSERM UMR-S U1237, University of Caen Normandy, Caen, France. 58. Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands. 59. Banner Alzheimer's Institute, Phoenix, AZ. 60. Clinique Interdisciplinaire de Mémoire de l'Enfant-Jésus, CHU de Québec, Université Laval, Québec, Canada.
Abstract
OBJECTIVE: To estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants. METHODS: We conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-β pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models. RESULTS: Amyloid-β positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p < 0.001). Prevalence of amyloid-β positivity increased with age in nfvPPA (from 10% at age 50 years to 27% at age 80 years, p < 0.01) and svPPA (from 6% at age 50 years to 32% at age 80 years, p < 0.001), but not in lvPPA (p = 0.94). Across PPA variants, ApoE ε4 carriers were more often amyloid-β positive (58.0%) than noncarriers (35.0%, p < 0.001). Autopsy data revealed Alzheimer disease pathology as the most common pathologic diagnosis in lvPPA (76%), frontotemporal lobar degeneration-TDP-43 in svPPA (80%), and frontotemporal lobar degeneration-TDP-43/tau in nfvPPA (64%). INTERPRETATION: This study shows that the current PPA classification system helps to predict underlying pathology across different cohorts and clinical settings, and suggests that age and ApoE genotype should be considered when interpreting amyloid-β biomarkers in PPA patients. Ann Neurol 2018;84:737-748.
OBJECTIVE: To estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants. METHODS: We conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-β pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models. RESULTS: Amyloid-β positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p < 0.001). Prevalence of amyloid-β positivity increased with age in nfvPPA (from 10% at age 50 years to 27% at age 80 years, p < 0.01) and svPPA (from 6% at age 50 years to 32% at age 80 years, p < 0.001), but not in lvPPA (p = 0.94). Across PPA variants, ApoE ε4 carriers were more often amyloid-β positive (58.0%) than noncarriers (35.0%, p < 0.001). Autopsy data revealed Alzheimer disease pathology as the most common pathologic diagnosis in lvPPA (76%), frontotemporal lobar degeneration-TDP-43 in svPPA (80%), and frontotemporal lobar degeneration-TDP-43/tau in nfvPPA (64%). INTERPRETATION: This study shows that the current PPA classification system helps to predict underlying pathology across different cohorts and clinical settings, and suggests that age and ApoE genotype should be considered when interpreting amyloid-β biomarkers in PPA patients. Ann Neurol 2018;84:737-748.
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