title: Early astrocytosis in autosomal dominant Alzheimer's disease measured in vivo by multi-tracer positron emission tomography.
abstract: Studying autosomal dominant Alzheimer's disease (ADAD), caused by gene mutations yielding nearly complete penetrance and a distinct age of symptom onset, allows investigation of presymptomatic pathological processes that can identify a therapeutic window for disease-modifying therapies. Astrocyte activation may occur in presymptomatic Alzheimer's disease (AD) because reactive astrocytes surround β-amyloid (Aβ) plaques in autopsy brain tissue. Positron emission tomography was performed to investigate fibrillar Aβ, astrocytosis and cerebral glucose metabolism with the radiotracers (11)C-Pittsburgh compound-B (PIB), (11)C-deuterium-L-deprenyl (DED) and (18)F-fluorodeoxyglucose (FDG) respectively in presymptomatic and symptomatic ADAD participants (n = 21), patients with mild cognitive impairment (n = 11) and sporadic AD (n = 7). Multivariate analysis using the combined data from all radiotracers clearly separated the different groups along the first and second principal components according to increased PIB retention/decreased FDG uptake (component 1) and increased DED binding (component 2). Presymptomatic ADAD mutation carriers showed significantly higher PIB retention than non-carriers in all brain regions except the hippocampus. DED binding was highest in presymptomatic ADAD mutation carriers. This suggests that non-fibrillar Aβ or early stage plaque depostion might interact with inflammatory responses indicating astrocytosis as an early contributory driving force in AD pathology. The novelty of this finding will be investigated in longitudinal follow-up studies.
authors.affiliation: Department NVS, Center for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, 141 57 Huddinge, Sweden.|MedTech West and the Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, 413 45 Gothenburg, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Schöll
authors.affiliation: Department NVS, Center for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, 141 57 Huddinge, Sweden.|Wolfson Molecular Imaging Centre, University of Manchester, Manchester, M20 3LJ, UK.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Carter
authors.affiliation: Department NVS, Center for Alzheimer Research, Division of Clinical Geriatrics, Karolinska Institutet, 141 57 Huddinge, Sweden.
authors.forename: Eric
authors.initials: E
authors.lastname: Westman
authors.affiliation: Department NVS, Center for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, 141 57 Huddinge, Sweden.
authors.forename: Elena
authors.initials: E
authors.lastname: Rodriguez-Vieitez
authors.affiliation: Department NVS, Center for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, 141 57 Huddinge, Sweden.|Department of Geriatric Medicine, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.|Department of Psychology, Stockholm University, 106 91 Stockholm, Sweden.
authors.forename: Ove
authors.initials: O
authors.lastname: Almkvist
authors.affiliation: Department of Geriatric Medicine, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.|Department NVS, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, 141 57 Huddinge, Sweden.
authors.forename: Steinunn
authors.initials: S
authors.lastname: Thordardottir
authors.affiliation: Department of Surgical Sciences, Section of Nuclear Medicine &PET, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Wall
authors.affiliation: Department of Geriatric Medicine, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.|Department NVS, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, 141 57 Huddinge, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Graff
authors.affiliation: Department of Chemistry, Uppsala University, 701 05 Uppsala, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Långström
authors.affiliation: Department NVS, Center for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, 141 57 Huddinge, Sweden.|Department of Geriatric Medicine, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordberg
mesh_terms: D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D060825:Cognitive Dysfunction; D005260:Female; D019788:Fluorodeoxyglucose F18; D005799:Genes, Dominant; D005838:Genotype; D005911:Gliosis / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D008297:Male; D061212:Memory, Episodic; D008875:Middle Aged; D009154:Mutation; D009483:Neuropsychological Tests; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods*; D025341:Principal Component Analysis
chemical_list: D016229:Amyloid beta-Peptides; D019788:Fluorodeoxyglucose F18