title: Cerebrospinal Fluid Levels of Amyloid Beta 1-43 Mirror 1-42 in Relation to Imaging Biomarkers of Alzheimer's Disease.
abstract: Introduction:Amyloid beta 1-43 (Aβ43), with its additional C-terminal threonine residue, is hypothesized to play a role in early Alzheimer's disease pathology possibly different from that of amyloid beta 1-42 (Aβ42). Cerebrospinal fluid (CSF) Aβ43 has been suggested as a potential novel biomarker for predicting conversion from mild cognitive impairment (MCI) to dementia in Alzheimer's disease. However, the relationship between CSF Aβ43 and established imaging biomarkers of Alzheimer's disease has never been assessed.Materials and Methods:In this observational study, CSF Aβ43 was measured with ELISA in 89 subjects; 34 with subjective cognitive decline (SCD), 51 with MCI, and four with resolution of previous cognitive complaints. All subjects underwent structural MRI; 40 subjects on a 3T and 50 on a 1.5T scanner. Forty subjects, including 24 with SCD and 12 with MCI, underwent18F-Flutemetamol PET. Seventy-eight subjects were assessed with18F-fluorodeoxyglucose PET (21 SCD/7 MCI and 11 SCD/39 MCI on two different scanners). Ten subjects with SCD and 39 with MCI also underwent diffusion tensor imaging.Results:Cerebrospinal fluid Aβ43 was both alone and together with p-tau a significant predictor of the distinction between SCD and MCI. There was a marked difference in CSF Aβ43 between subjects with18F-Flutemetamol PET scans visually interpreted as negative (37 pg/ml,n= 27) and positive (15 pg/ml,n= 9), p < 0.001. Both CSF Aβ43 and Aβ42 were negatively correlated with standardized uptake value ratios for all analyzed regions; CSF Aβ43 averagerho-0.73, Aβ42 -0.74. Both CSF Aβ peptides correlated significantly with hippocampal volume, inferior parietal and frontal cortical thickness and axial diffusivity in the corticospinal tract. There was a trend toward CSF Aβ42 being better correlated with cortical glucose metabolism. None of the studied correlations between CSF Aβ43/42 and imaging biomarkers were significantly different for the two Aβ peptides when controlling for multiple testing.Conclusion:Cerebrospinal fluid Aβ43 appears to be strongly correlated with cerebral amyloid deposits in the same way as Aβ42, even in non-demented patients with only subjective cognitive complaints. Regarding imaging biomarkers, there is no evidence from the present study that CSF Aβ43 performs better than the classical CSF biomarker Aβ42 for distinguishing SCD and MCI.
authors.affiliation: Division of Medicine and Laboratory Sciences, Institute of Clinical Medicine, Faculty of Medicine, University of OsloOslo, Norway; Department of Neurology, Akershus University HospitalLørenskog, Norway.
authors.forename: Ina S
authors.initials: IS
authors.lastname: Almdahl
authors.affiliation: Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology Trondheim, Norway.
authors.forename: Camilla
authors.initials: C
authors.lastname: Lauridsen
authors.affiliation: Division of Medicine and Laboratory Sciences, Institute of Clinical Medicine, Faculty of Medicine, University of OsloOslo, Norway; Department of Neurology, Akershus University HospitalLørenskog, Norway.
authors.forename: Per
authors.initials: P
authors.lastname: Selnes
authors.affiliation: Division of Medicine and Laboratory Sciences, Institute of Clinical Medicine, Faculty of Medicine, University of OsloOslo, Norway; Department of Neurology, Akershus University HospitalLørenskog, Norway.
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Kalheim
authors.affiliation: Preclinical PET/CT, Institute of Basic Medical Sciences, University of Oslo Oslo, Norway.
authors.forename: Christopher
authors.initials: C
authors.lastname: Coello
authors.affiliation: Aleris Oslo, Norway.
authors.forename: Beata
authors.initials: B
authors.lastname: Gajdzik
authors.affiliation: Department of Neurology and Clinical Neurophysiology, University Hospital of Trondheim Trondheim, Norway.
authors.forename: Ina
authors.initials: I
authors.lastname: Møller
authors.affiliation: Department of Neurology, Akershus University HospitalLørenskog, Norway; Department of Clinical Molecular Biology (EpiGen), Institute of Clinical Medicine, University of Oslo - Akershus University HospitalLørenskog, Norway.
authors.forename: Marianne
authors.initials: M
authors.lastname: Wettergreen
authors.affiliation: Department of Neurology, Akershus University Hospital Lørenskog, Norway.
authors.forename: Ramune
authors.initials: R
authors.lastname: Grambaite
authors.affiliation: The Intervention Centre, Oslo University Hospital Oslo, Norway.
authors.forename: Atle
authors.initials: A
authors.lastname: Bjørnerud
authors.affiliation: Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and TechnologyTrondheim, Norway; Department of Neurology and Clinical Neurophysiology, University Hospital of TrondheimTrondheim, Norway.
authors.forename: Geir
authors.initials: G
authors.lastname: Bråthen
authors.affiliation: Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and TechnologyTrondheim, Norway; Department of Neurology and Clinical Neurophysiology, University Hospital of TrondheimTrondheim, Norway.
authors.forename: Sigrid B
authors.initials: SB
authors.lastname: Sando
authors.affiliation: Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and TechnologyTrondheim, Norway; Department of Neurology and Clinical Neurophysiology, University Hospital of TrondheimTrondheim, Norway.
authors.forename: Linda R
authors.initials: LR
authors.lastname: White
authors.affiliation: Division of Medicine and Laboratory Sciences, Institute of Clinical Medicine, Faculty of Medicine, University of OsloOslo, Norway; Department of Neurology, Akershus University HospitalLørenskog, Norway.
authors.forename: Tormod
authors.initials: T
authors.lastname: Fladby
keywords: Alzheimer’s disease; amyloid beta 1-43; cerebrospinal fluid; magnetic resonance imaging; mild cognitive impairment; positron emission tomography