title: Atrophy, hypometabolism and clinical trajectories in patients with amyloid-negative Alzheimer's disease.
abstract: See O'Sullivan and Vann (doi:10.1093/aww166) for a scientific commentary on this article.About 15% of patients clinically diagnosed with Alzheimer's disease do not show high tracer retention on amyloid positon emission tomography imaging. The present study investigates clinical and demographic features, patterns of brain atrophy and hypometabolism and longitudinal clinical trajectories of these patients. Forty amyloid-negative patients carrying a pre-scan diagnosis of Alzheimer's disease dementia from four centres were included (11/29 females/males; mean age = 67 ± 9). Detailed clinical histories, including the clinical diagnoses before and after the amyloid scan and at follow-up, were collected. Patients were classified according to their pre-scan clinical phenotype as amnestic (memory predominant), non-amnestic (predominant language, visuospatial or frontal symptoms), or non-specific (diffuse cognitive deficits). Demographic, clinical, neuropsychological, magnetic resonance imaging and (18)F-fluorodeoxyglucose positon emission tomography data were compared to 27 amyloid-positive typical Alzheimer's disease cases (14/13 females/males; mean age = 71 ± 10) and 29 amyloid-negative controls (15/14 females/males; mean age = 69 ± 12) matched for age, gender and education. There were 21 amnestic, 12 non-amnestic, and seven non-specific amyloid-negative Alzheimer's disease cases. Amyloid-negative subgroups did not differ in age, gender or education. After the amyloid scan, clinicians altered the diagnosis in 68% of amyloid-negative patients including 48% of amnestic versus 94% of non-amnestic and non-specific cases. Amnestic amyloid-negative cases were most often reclassified as frontotemporal dementia, non-amnestic as frontotemporal dementia or corticobasal degeneration, and non-specific as dementia with Lewy bodies or unknown diagnosis. The longer-term clinical follow-up was consistent with the post-scan diagnosis in most cases (90%), including in amnestic amyloid-negative cases whose post-positon emission tomography diagnosis remained Alzheimer's disease. While the non-amnestic and non-specific amyloid-negative cases usually showed patterns of atrophy and hypometabolism suggestive of another degenerative disorder, the amnestic amyloid-negative cases had subtle atrophy and hypometabolism, restricted to the retrosplenial/posterior cingulate cortex. Patients with a negative amyloid positon emission tomography scan following an initial clinical diagnosis of Alzheimer's disease have heterogeneous clinical presentations and neuroimaging profiles; a majority showed a clinical progression that was consistent with a neurodegenerative condition. In contrast, in the subgroup of amnestic amyloid-negative cases, the clinical presentation and follow-up usually remained consistent with Alzheimer's disease. An alternative diagnosis was not made in about half of the amnestic amyloid-negative cases, highlighting the need for a clinical framework and terminology to define these patients, who may have underlying limbic-predominant, non-amyloid-related pathologies.
authors.affiliation: 1 INSERM, U1077, 14074 Caen, France 2 Université de Caen Basse-Normandie UMR-S1077, 14074 Caen, France 3 Ecole Pratique des Hautes Etudes, UMR-S1077, 14074 Caen, France 4 CHU de Caen, U1077, 14000 Caen, France chetelat@cyceron.fr.
authors.forename: Gaël
authors.initials: G
authors.lastname: Chételat
authors.affiliation: 5 VU University Medical Centre, Neuroscience Campus Amsterdam, Department of Neurology and Alzheimer Centre, 1081 HZ Amsterdam, The Netherlands 6 VU University Medical Centre, Department of Radiology and Nuclear Medicine, 1081 HZ Amsterdam, The Netherlands 7 University of California San Francisco, Memory and Aging Centre, Department of Neurology, San Francisco, CA 94720, USA.
authors.forename: Rik
authors.initials: R
authors.lastname: Ossenkoppele
authors.affiliation: 8 Department of Nuclear Medicine and Centre for PET, Austin Health, Melbourne, VIC 3084, Australia.
authors.forename: Victor L
authors.initials: VL
authors.lastname: Villemagne
authors.affiliation: 1 INSERM, U1077, 14074 Caen, France 2 Université de Caen Basse-Normandie UMR-S1077, 14074 Caen, France 3 Ecole Pratique des Hautes Etudes, UMR-S1077, 14074 Caen, France 4 CHU de Caen, U1077, 14000 Caen, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Perrotin
authors.affiliation: 1 INSERM, U1077, 14074 Caen, France 2 Université de Caen Basse-Normandie UMR-S1077, 14074 Caen, France 3 Ecole Pratique des Hautes Etudes, UMR-S1077, 14074 Caen, France 4 CHU de Caen, U1077, 14000 Caen, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Landeau
authors.affiliation: 1 INSERM, U1077, 14074 Caen, France 2 Université de Caen Basse-Normandie UMR-S1077, 14074 Caen, France 3 Ecole Pratique des Hautes Etudes, UMR-S1077, 14074 Caen, France 4 CHU de Caen, U1077, 14000 Caen, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Mézenge
authors.affiliation: 9 Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley CA 94720, USA; Lawrence Berkeley National Laboratory, Berkeley, California, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Jagust
authors.affiliation: 8 Department of Nuclear Medicine and Centre for PET, Austin Health, Melbourne, VIC 3084, Australia 10 Commonwealth Scientific Industrial Research Organization Health and Biosecurity Flagship, Brisbane, QLD 4006, Australia.
authors.forename: Vincent
authors.initials: V
authors.lastname: Dore
authors.affiliation: 7 University of California San Francisco, Memory and Aging Centre, Department of Neurology, San Francisco, CA 94720, USA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: 1 INSERM, U1077, 14074 Caen, France 2 Université de Caen Basse-Normandie UMR-S1077, 14074 Caen, France 3 Ecole Pratique des Hautes Etudes, UMR-S1077, 14074 Caen, France 4 CHU de Caen, U1077, 14000 Caen, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Egret
authors.affiliation: 7 University of California San Francisco, Memory and Aging Centre, Department of Neurology, San Francisco, CA 94720, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.affiliation: 6 VU University Medical Centre, Department of Radiology and Nuclear Medicine, 1081 HZ Amsterdam, The Netherlands 11 VU University Medical Centre, Department of Epidemiology and Biostatistics, 1081 HZ Amsterdam, The Netherlands.
authors.forename: Wiesje M
authors.initials: WM
authors.lastname: van der Flier
authors.affiliation: 1 INSERM, U1077, 14074 Caen, France 2 Université de Caen Basse-Normandie UMR-S1077, 14074 Caen, France 3 Ecole Pratique des Hautes Etudes, UMR-S1077, 14074 Caen, France 4 CHU de Caen, U1077, 14000 Caen, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: La Joie
authors.affiliation: 12 Academic Unit for Psychiatry of Old Age, St. Vincent's Health, Department of Psychiatry, The University of Melbourne, Kew, VIC 3101, Australia 13 National Ageing Research Institute, Parkville, VIC 3052, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Ames
authors.affiliation: 6 VU University Medical Centre, Department of Radiology and Nuclear Medicine, 1081 HZ Amsterdam, The Netherlands.
authors.forename: Bart N M
authors.initials: BN
authors.lastname: van Berckel
authors.affiliation: 5 VU University Medical Centre, Neuroscience Campus Amsterdam, Department of Neurology and Alzheimer Centre, 1081 HZ Amsterdam, The Netherlands.
authors.forename: Philip
authors.initials: P
authors.lastname: Scheltens
authors.affiliation: 6 VU University Medical Centre, Department of Radiology and Nuclear Medicine, 1081 HZ Amsterdam, The Netherlands.
authors.forename: Frederik
authors.initials: F
authors.lastname: Barkhof
authors.affiliation: 8 Department of Nuclear Medicine and Centre for PET, Austin Health, Melbourne, VIC 3084, Australia.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Rowe
authors.affiliation: 14 The Florey Institute of Neuroscience and Mental Health, Mental Health, Melbourne, VIC 3010, Australia.
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.affiliation: 1 INSERM, U1077, 14074 Caen, France 2 Université de Caen Basse-Normandie UMR-S1077, 14074 Caen, France 3 Ecole Pratique des Hautes Etudes, UMR-S1077, 14074 Caen, France 4 CHU de Caen, U1077, 14000 Caen, France 15 CHU de Caen, Service de Neurologie, 14000 Caen, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: de La Sayette
authors.affiliation: 5 VU University Medical Centre, Neuroscience Campus Amsterdam, Department of Neurology and Alzheimer Centre, 1081 HZ Amsterdam, The Netherlands.
authors.forename: Femke
authors.initials: F
authors.lastname: Bouwman
authors.affiliation: 7 University of California San Francisco, Memory and Aging Centre, Department of Neurology, San Francisco, CA 94720, USA 9 Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley CA 94720, USA; Lawrence Berkeley National Laboratory, Berkeley, California, USA.
authors.forename: Gil D
authors.initials: GD
authors.lastname: Rabinovici
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000150:complications / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D000647:Amnesia / Q000000981:diagnostic imaging / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D001284:Atrophy / Q000000981:diagnostic imaging; D005260:Female; D005500:Follow-Up Studies; D006179:Gyrus Cinguli / Q000000981:diagnostic imaging*; D006624:Hippocampus / Q000000981:diagnostic imaging*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography
keywords: Alzheimer’s disease; MRI; PET; amyloid; retrosplenial posterior cingulate