TY - JOUR
T1 - Precuneus amyloid burden is associated with reduced cholinergic activity in Alzheimer disease
AU - Ikonomovic, M. D.
AU - Klunk, W. E.
AU - Abrahamson, E. E.
AU - Wuu, J.
AU - Mathis, C. A.
AU - Scheff, S. W.
AU - Mufson, E. J.
AU - DeKosky, S. T.
N1 - Funding Information:
Dr. Ikonomovic has served as a consultant for and received funding for travel from GE Healthcare; serves as an Associate Editor for Cardiovascular Psychiatry and Neurology ; and receives research support from GE Healthcare, Forest Research Institute, Inc., and the NIH. Dr. Klunk serves on scientific advisory boards and as a consultant for GE Healthcare, Neuroptix Corporation, Elan/Janssen AI, Roche, Wyeth/Pfizer, and AstraZeneca; has received funding for travel from Elan/Janssen AI, Roche, and AstraZeneca; is author on patents re: PiB PET imaging and chrysamine-G derivatives for imaging and therapy; receives research support from GE Healthcare, Neuroptix Corporation, the NIH (NIA, NIBIB), Anonymous Foundation, and Cure Alzheimer's Fund; holds stock in Neuroptix Corporation; and receives license fee and royalty payment from GE Healthcare. Dr. Abrahamson reports no disclosures. J. Wuu has received research support from the NIH/NIA, the FDA, the CDC, the ALS Association, the Muscular Dystrophy Association, and the Consolidated Anti-Aging Foundation. Dr. Mathis serves on a scientific advisory board for Neuroptix Corporation; has received funding for travel and speaker honoraria from Elan/Janssen AI, GE Healthcare, Bayer Schering Pharma, Biogen Idec, IBA, and Takeda Pharmaceutical Company Limited; serves on the editorial board of Nuclear Medicine and Biology ; serves/has served as a consultant for GE Healthcare, Elan/Janssen AI, Wyeth/Pfizer, and Novartis; is author on numerous US and international patents re: Amyloid imaging agents; receives/has received research support from GE Healthcare, Neuroptix Corporation, the NIH, the US Department of Energy, the Dana Foundation, and Anonymous Foundation; holds stock options in Neuroptix Corporation; and has received license fees and royalty payments from GE Healthcare and Neuroptix Corporation for patents re: Amyloid imaging agents. Dr. Scheff serves on a scientific advisory board for TIRR; serves on the editorial board of the Journal of Neurotrauma ; and receives research support from the NIH. Dr. Mufson has served as a consultant for Ceregene and NeuroPhage and receives research support from the NIH. Dr. DeKosky has served on a scientific advisory board for Pfizer Inc and as a consultant for Eisai, PsychoGenics Inc., Merck, Elan/Wyeth, Novartis, Eli Lilly, and Janssen; is the site principal investigator at the University of Virginia Memory Disorders Clinics for experimental therapeutic trials of Alzheimer's disease medications for Elan, Novartis, Forest, and Janssen Pharmaceuticals; serves on the editorial boards of Annals of Neurology , Archives of Neurology , Neurodegenerative Diseases , Journal of Alzheimer's Disease , and Alzheimer Disease and Associated Disorders: An International Journal , and as Editor of Up to Date ; receives research support from the NIH; and serves as a board member for the National Center for Complementary and Alternative Medicine, the American Board of Psychiatry and Neurology, and the Alzheimer's Association.
PY - 2011/7/5
Y1 - 2011/7/5
N2 - Objective: This study examined the relationship between postmortem precuneus cholinergic enzyme activity, Pittsburgh compound B (PiB) binding, and soluble amyloid-β concentration in mild cognitive impairment (MCI) and Alzheimer disease (AD). Methods: Choline acetyltransferase (ChAT) activity, [3H]PiB binding, and soluble amyloid-β1-42 (Aβ42) concentration were quantified in precuneus tissue samples harvested postmortem from subjects with no cognitive impairment (NCI), MCI, and mild AD and correlated with their last antemortem Mini-Mental State Examination (MMSE) score and postmortem pathologic evaluation according to the National Institute on Aging-Reagan criteria, recommendations of the Consortium to Establish a Registry for Alzheimer's Disease, and Braak stage. Results: Precuneus ChAT activity was lower in AD than in NCI and was comparable between MCI and NCI. Precuneus [3H]PiB binding and soluble Aβ42 levels were elevated in MCI and significantly higher in AD than in NCI. Across all case subjects, reduced ChAT activity was associated with increased [3H]PiB binding, increased soluble Aβ42, lower MMSE score, presence of the APOE®4 allele, and more advanced AD pathology. Conclusions: Despite accumulating amyloid burden, cholinergic enzyme activity is stable in the precuneus during prodromal AD. A decline in precuneus ChAT activity occurs only in clinical AD, when PiB binding and soluble Aβ42 levels are substantially elevated compared with those in MCI. Anti-amyloid interventions in MCI case subjects with a positive PiB PET scan may aid in reducing cholinergic deficits and cognitive decline later in the disease process.
AB - Objective: This study examined the relationship between postmortem precuneus cholinergic enzyme activity, Pittsburgh compound B (PiB) binding, and soluble amyloid-β concentration in mild cognitive impairment (MCI) and Alzheimer disease (AD). Methods: Choline acetyltransferase (ChAT) activity, [3H]PiB binding, and soluble amyloid-β1-42 (Aβ42) concentration were quantified in precuneus tissue samples harvested postmortem from subjects with no cognitive impairment (NCI), MCI, and mild AD and correlated with their last antemortem Mini-Mental State Examination (MMSE) score and postmortem pathologic evaluation according to the National Institute on Aging-Reagan criteria, recommendations of the Consortium to Establish a Registry for Alzheimer's Disease, and Braak stage. Results: Precuneus ChAT activity was lower in AD than in NCI and was comparable between MCI and NCI. Precuneus [3H]PiB binding and soluble Aβ42 levels were elevated in MCI and significantly higher in AD than in NCI. Across all case subjects, reduced ChAT activity was associated with increased [3H]PiB binding, increased soluble Aβ42, lower MMSE score, presence of the APOE®4 allele, and more advanced AD pathology. Conclusions: Despite accumulating amyloid burden, cholinergic enzyme activity is stable in the precuneus during prodromal AD. A decline in precuneus ChAT activity occurs only in clinical AD, when PiB binding and soluble Aβ42 levels are substantially elevated compared with those in MCI. Anti-amyloid interventions in MCI case subjects with a positive PiB PET scan may aid in reducing cholinergic deficits and cognitive decline later in the disease process.
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UR - http://www.scopus.com/inward/citedby.url?scp=80051520187&partnerID=8YFLogxK
U2 - 10.1212/WNL.0b013e3182231419
DO - 10.1212/WNL.0b013e3182231419
M3 - Article
C2 - 21700583
AN - SCOPUS:80051520187
VL - 77
SP - 39
EP - 47
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 1
ER -