title: Positron emission tomography imaging and clinical progression in relation to molecular pathology in the first Pittsburgh Compound B positron emission tomography patient with Alzheimer's disease.
abstract: The accumulation of β-amyloid in the brain is an early event in Alzheimer's disease. This study presents the first patient with Alzheimer's disease who underwent positron emission tomography imaging with the amyloid tracer, Pittsburgh Compound B to visualize fibrillar β-amyloid in the brain. Here we relate the clinical progression, amyloid and functional brain positron emission tomography imaging with molecular neuropathological alterations at autopsy to gain new insight into the relationship between β-amyloid accumulation, inflammatory processes and the cholinergic neurotransmitter system in Alzheimer's disease brain. The patient underwent positron emission tomography studies with (18)F-fluorodeoxyglucose three times (at ages 53, 56 and 58 years) and twice with Pittsburgh Compound B (at ages 56 and 58 years), prior to death at 61 years of age. The patient showed a pronounced decline in cerebral glucose metabolism and cognition during disease progression, while Pittsburgh Compound B retention remained high and stable at follow-up. Neuropathological examination of the brain at autopsy confirmed the clinical diagnosis of pure Alzheimer's disease. A comprehensive neuropathological investigation was performed in nine brain regions to measure the regional distribution of β-amyloid, neurofibrillary tangles and the levels of binding of (3)H-nicotine and (125)I-α-bungarotoxin to neuronal nicotinic acetylcholine receptor subtypes, (3)H-L-deprenyl to activated astrocytes and (3)H-PK11195 to microglia, as well as butyrylcholinesterase activity. Regional in vivo (11)C-Pittsburgh Compound B-positron emission tomography retention positively correlated with (3)H-Pittsburgh Compound B binding, total insoluble β-amyloid, and β-amyloid plaque distribution, but not with the number of neurofibrillary tangles measured at autopsy. There was a negative correlation between regional fibrillar β-amyloid and levels of (3)H-nicotine binding. In addition, a positive correlation was found between regional (11)C-Pittsburgh Compound B positron emission tomography retention and (3)H-Pittsburgh Compound B binding with the number of glial fibrillary acidic protein immunoreactive cells, but not with (3)H-L-deprenyl and (3)H-PK-11195 binding. In summary, high (11)C-Pittsburgh Compound B positron emission tomography retention significantly correlates with both fibrillar β-amyloid and losses of neuronal nicotinic acetylcholine receptor subtypes at autopsy, suggesting a closer involvement of β-amyloid pathology with neuronal nicotinic acetylcholine receptor subtypes than with inflammatory processes.
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. agneta.k.nordberg@ki.se
authors.forename: Ahmadul
authors.initials: A
authors.lastname: Kadir
authors.forename: Amelia
authors.initials: A
authors.lastname: Marutle
authors.forename: Daniel
authors.initials: D
authors.lastname: Gonzalez
authors.forename: Michael
authors.initials: M
authors.lastname: Schöll
authors.forename: Ove
authors.initials: O
authors.lastname: Almkvist
authors.forename: Malahat
authors.initials: M
authors.lastname: Mousavi
authors.forename: Tamanna
authors.initials: T
authors.lastname: Mustafiz
authors.forename: Taher
authors.initials: T
authors.lastname: Darreh-Shori
authors.forename: Inger
authors.initials: I
authors.lastname: Nennesmo
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordberg
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000814:Aniline Compounds; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D009483:Neuropsychological Tests; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods*; D013844:Thiazoles
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D013844:Thiazoles