Daniel Ferreira1, Scott A Przybelski1, Timothy G Lesnick1, Afina W Lemstra1, Elisabet Londos1, Frederic Blanc1, Zuzana Nedelska1, Christopher G Schwarz1, Jonathan Graff-Radford1, Matthew L Senjem1, Julie A Fields1, David S Knopman1, Rodolfo Savica1, Tanis J Ferman1, Neill R Graff-Radford1, Val J Lowe1, Clifford R Jack1, Ronald C Petersen1, Brit Mollenhauer1, Sara Garcia-Ptacek1, Carla Abdelnour1, Jakub Hort1, Laura Bonanni1, Ketil Oppedal1, Milica G Kramberger1, Bradley F Boeve1, Dag Aarsland1, Eric Westman1, Kejal Kantarci2. 1. From the Division of Clinical Geriatrics (D.F., S.G.-P., E.W.), Center for Alzheimer's Research, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Stockholm, Sweden; Departments of Radiology (D.F., Z.N., C.G.S., M.L.S., V.J.L., C.R.J., K.K.), Health Sciences (S.A.P., T.G.L.), Neurology (J.G.-R., D.S.K., R.S., R.C.P., B.F.B.), Information Technology (M.L.S.), and Psychiatry and Psychology (J.A.F.), Mayo Clinic, Rochester, MN; Department of Neurology and Alzheimer Center (A.W.L.), VU University Medical Center, Amsterdam, the Netherlands; Clinical Memory Research Unit (E.L.), Department of Clinical Sciences, Lund University, Malmö, Sweden; Day Hospital of Geriatrics (F.B.), Memory Resource and Research Centre (CM2R) of Strasbourg; Department of Geriatrics (F.B.), Hopitaux Universitaires de Strasbourg; University of Strasbourg and French National Centre for Scientific Research (CNRS) (F.B.), ICube Laboratory and Federation de Medecine Translationnelle de Strasbourg (FMTS), Team Imagerie Multimodale Integrative en Sante (IMIS)/ICONE, Strasbourg, France; Department of Neurology (Z.N., J.H.), Charles University, 2nd Faculty of Medicine, Motol University Hospital, Prague, Czech Republic; Departments of Psychiatry and Psychology (T.J.F.) and Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL; Paracelsus-Elena-Klinik (B.M.), Kassel; and University Medical Center (B.M.), Department of Neurosurgery and Institute of Neuropathology, Göttingen, Germany; Fundació ACE (C.A.), Alzheimer Research Center and Memory Clinic, Institut Català de Neurociències Aplicades, Barcelona, Spain; International Clinical Research Center (J.H.), St. Anne's University Hospital Brno, Czech Republic; Department of Neuroscience Imaging and Clinical Sciences and CESI (L.B.), University G d'Annunzio of Chieti-Pescara, Chieti, Italy; Centre for Age-Related Medicine (K.O., D.A.), Stavanger University Hospital; Stavanger Medical Imaging Laboratory (SMIL) (K.O.), Department of Radiology, Stavanger University Hospital; Department of Electrical Engineering and Computer Science (K.O.), University of Stavanger, Norway; Department of Neurology (M.G.K.), University Medical Centre Ljubljana, Medical Faculty, University of Ljubljana, Slovenia; Institute of Psychiatry, Psychology and Neuroscience (D.A.) and Department of Neuroimaging (E.W.), Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK. 2. From the Division of Clinical Geriatrics (D.F., S.G.-P., E.W.), Center for Alzheimer's Research, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Stockholm, Sweden; Departments of Radiology (D.F., Z.N., C.G.S., M.L.S., V.J.L., C.R.J., K.K.), Health Sciences (S.A.P., T.G.L.), Neurology (J.G.-R., D.S.K., R.S., R.C.P., B.F.B.), Information Technology (M.L.S.), and Psychiatry and Psychology (J.A.F.), Mayo Clinic, Rochester, MN; Department of Neurology and Alzheimer Center (A.W.L.), VU University Medical Center, Amsterdam, the Netherlands; Clinical Memory Research Unit (E.L.), Department of Clinical Sciences, Lund University, Malmö, Sweden; Day Hospital of Geriatrics (F.B.), Memory Resource and Research Centre (CM2R) of Strasbourg; Department of Geriatrics (F.B.), Hopitaux Universitaires de Strasbourg; University of Strasbourg and French National Centre for Scientific Research (CNRS) (F.B.), ICube Laboratory and Federation de Medecine Translationnelle de Strasbourg (FMTS), Team Imagerie Multimodale Integrative en Sante (IMIS)/ICONE, Strasbourg, France; Department of Neurology (Z.N., J.H.), Charles University, 2nd Faculty of Medicine, Motol University Hospital, Prague, Czech Republic; Departments of Psychiatry and Psychology (T.J.F.) and Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL; Paracelsus-Elena-Klinik (B.M.), Kassel; and University Medical Center (B.M.), Department of Neurosurgery and Institute of Neuropathology, Göttingen, Germany; Fundació ACE (C.A.), Alzheimer Research Center and Memory Clinic, Institut Català de Neurociències Aplicades, Barcelona, Spain; International Clinical Research Center (J.H.), St. Anne's University Hospital Brno, Czech Republic; Department of Neuroscience Imaging and Clinical Sciences and CESI (L.B.), University G d'Annunzio of Chieti-Pescara, Chieti, Italy; Centre for Age-Related Medicine (K.O., D.A.), Stavanger University Hospital; Stavanger Medical Imaging Laboratory (SMIL) (K.O.), Department of Radiology, Stavanger University Hospital; Department of Electrical Engineering and Computer Science (K.O.), University of Stavanger, Norway; Department of Neurology (M.G.K.), University Medical Centre Ljubljana, Medical Faculty, University of Ljubljana, Slovenia; Institute of Psychiatry, Psychology and Neuroscience (D.A.) and Department of Neuroimaging (E.W.), Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK. kantarci.kejal@mayo.edu.
Abstract
OBJECTIVE: In a multicenter cohort of probable dementia with Lewy bodies (DLB), we tested the hypothesis that β-amyloid and tau biomarker positivity increases with age, which is modified by APOE genotype and sex, and that there are isolated and synergistic associations with the clinical phenotype. METHODS: We included 417 patients with DLB (age 45-93 years, 31% women). Positivity on β-amyloid (A+) and tau (T+) biomarkers was determined by CSF β-amyloid1-42 and phosphorylated tau in the European cohort and by Pittsburgh compound B and AV-1451 PET in the Mayo Clinic cohort. Patients were stratified into 4 groups: A-T-, A+T-, A-T+, and A+T+. RESULTS: A-T- was the largest group (39%), followed by A+T- (32%), A+T+ (15%), and A-T+ (13%). The percentage of A-T- decreased with age, and A+ and T+ increased with age in both women and men. A+ increased more in APOE ε4 carriers with age than in noncarriers. A+ was the main predictor of lower cognitive performance when considered together with T+. T+ was associated with a lower frequency of parkinsonism and probable REM sleep behavior disorder. There were no significant interactions between A+ and T+ in relation to the clinical phenotype. CONCLUSIONS: Alzheimer disease pathologic changes are common in DLB and are associated with the clinical phenotype. β-Amyloid is associated with cognitive impairment, and tau pathology is associated with lower frequency of clinical features of DLB. These findings have important implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with probable DLB, β-amyloid is associated with lower cognitive performance and tau pathology is associated with lower frequency of clinical features of DLB.
OBJECTIVE: In a multicenter cohort of probable dementia with Lewy bodies (DLB), we tested the hypothesis that β-amyloid and tau biomarker positivity increases with age, which is modified by APOE genotype and sex, and that there are isolated and synergistic associations with the clinical phenotype. METHODS: We included 417 patients with DLB (age 45-93 years, 31% women). Positivity on β-amyloid (A+) and tau (T+) biomarkers was determined by CSF β-amyloid1-42 and phosphorylated tau in the European cohort and by Pittsburgh compound B and AV-1451 PET in the Mayo Clinic cohort. Patients were stratified into 4 groups: A-T-, A+T-, A-T+, and A+T+. RESULTS: A-T- was the largest group (39%), followed by A+T- (32%), A+T+ (15%), and A-T+ (13%). The percentage of A-T- decreased with age, and A+ and T+ increased with age in both women and men. A+ increased more in APOE ε4 carriers with age than in noncarriers. A+ was the main predictor of lower cognitive performance when considered together with T+. T+ was associated with a lower frequency of parkinsonism and probable REM sleep behavior disorder. There were no significant interactions between A+ and T+ in relation to the clinical phenotype. CONCLUSIONS: Alzheimer disease pathologic changes are common in DLB and are associated with the clinical phenotype. β-Amyloid is associated with cognitive impairment, and tau pathology is associated with lower frequency of clinical features of DLB. These findings have important implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with probable DLB, β-amyloid is associated with lower cognitive performance and tau pathology is associated with lower frequency of clinical features of DLB.
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