TY - JOUR
T1 - Astrocyte reactivity with late-onset cognitive impairment assessed in vivo using 11C-BU99008 PET and its relationship with amyloid load
AU - Calsolaro, Valeria
AU - Matthews, Paul M.
AU - Donat, Cornelius K.
AU - Livingston, Nicholas R.
AU - Femminella, Grazia D.
AU - Guedes, Sandra Silva
AU - Myers, Jim
AU - Fan, Zhen
AU - Tyacke, Robin J.
AU - Venkataraman, Ashwin V.
AU - Perneczky, Robert
AU - Gunn, Roger
AU - Rabiner, Eugenii A.
AU - Gentleman, Steve
AU - Parker, Christine A.
AU - Murphy, Philip S.
AU - Wren, Paul B.
AU - Hinz, Rainer
AU - Sastre, Magdalena
AU - Nutt, David J.
AU - Edison, Paul
N1 - Funding Information:
gratefully acknowledges generous support from Edmond J Safra Foundation and Lily Safra, the NIHR Investigator programme and the UK Dementia Research Institute.
Funding Information:
The authors thank Invicro Centre for Imaging Sciences for the provision of 11C-BU99008, scanning and blood analysis equipment. The authors also thank Piramal Life Sciences/Life Molecular Imaging for providing the 18F-florbetaben and permission to acquire unlabelled florbetaben. We thank Dementia Platform UK (DPUK) and GSK for the generous funding for this project. This research was co-funded by the NIHR Imperial Biomedical Research Centre, and was supported by the NIHR Imperial Clinical Research Facility. The views expressed are those of the authors and not necessarily those of NHS, the NIHR nor the Department of Health. The study was funded by the Dementia Platform UK and the National Institutes of Health Research Imperial College Healthcare Trust Biomedical Research Centre. PE was funded by the Medical Research Council and now by Higher Education Funding Council for England (HEFCE). He has also received grants from Alzheimer’s Research, UK, Alzheimer’s Drug Discovery Foundation, Alzheimer’s Society, UK, Medical Research Council, Novo Nordisk, Piramal Life Sciences and GE Healthcare. PMM
Funding Information:
PE is a consultant to Roche, Pfizer and Novo Nordisk. He has received speaker fees from Novo Nordisk, Pfizer, Nordea, Piramal Life Science. He has received educational and research grants from GE Healthcare, Novo Nordisk, Piramal Life Science/Life Molecular Imaging, Avid Radiopharmaceuticals and Eli Lilly. He is an external consultant to Novo Nordisk and a member of their Scientific Advisory Board. PMM acknowledges consultancy fees from Roche, Adelphi Communications, Celgene and Biogen. He has received honoraria or speakers’ honoraria from Novartis, Biogen and Roche and has received research or educational funds from Biogen, Novartis, GlaxoSmithKline and Nodthera.
Publisher Copyright:
© 2021, The Author(s).
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/10
Y1 - 2021/10
N2 - 11C-BU99008 is a novel positron emission tomography (PET) tracer that enables selective imaging of astrocyte reactivity in vivo. To explore astrocyte reactivity associated with Alzheimer’s disease, 11 older, cognitively impaired (CI) subjects and 9 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging (MRI),
18F-florbetaben and
11C-BU99008 PET. The 8 amyloid (Aβ)-positive CI subjects had higher
11C-BU99008 uptake relative to HC across the whole brain, but particularly in frontal, temporal, medial temporal and occipital lobes. Biological parametric mapping demonstrated a positive voxel-wise neuroanatomical correlation between
11C-BU99008 and
18F-florbetaben. Autoradiography using
3H-BU99008 with post-mortem Alzheimer’s brains confirmed through visual assessment that increased
3H-BU99008 binding localised with the astrocyte protein glial fibrillary acid protein and was not displaced by PiB or florbetaben. This proof-of-concept study provides direct evidence that
11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life cognitive impairment and Alzheimer’s disease. Our results confirm that increased astrocyte reactivity is found particularly in cortical regions with high Aβ load. Future studies now can explore how clinical expression of disease varies with astrocyte reactivity.
AB - 11C-BU99008 is a novel positron emission tomography (PET) tracer that enables selective imaging of astrocyte reactivity in vivo. To explore astrocyte reactivity associated with Alzheimer’s disease, 11 older, cognitively impaired (CI) subjects and 9 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging (MRI),
18F-florbetaben and
11C-BU99008 PET. The 8 amyloid (Aβ)-positive CI subjects had higher
11C-BU99008 uptake relative to HC across the whole brain, but particularly in frontal, temporal, medial temporal and occipital lobes. Biological parametric mapping demonstrated a positive voxel-wise neuroanatomical correlation between
11C-BU99008 and
18F-florbetaben. Autoradiography using
3H-BU99008 with post-mortem Alzheimer’s brains confirmed through visual assessment that increased
3H-BU99008 binding localised with the astrocyte protein glial fibrillary acid protein and was not displaced by PiB or florbetaben. This proof-of-concept study provides direct evidence that
11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life cognitive impairment and Alzheimer’s disease. Our results confirm that increased astrocyte reactivity is found particularly in cortical regions with high Aβ load. Future studies now can explore how clinical expression of disease varies with astrocyte reactivity.
UR - http://www.scopus.com/inward/record.url?scp=85110595736&partnerID=8YFLogxK
U2 - 10.1038/s41380-021-01193-z
DO - 10.1038/s41380-021-01193-z
M3 - Article
SN - 1359-4184
VL - 26
SP - 5848
EP - 5855
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 10
ER -