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- Kadir, Ahmadul, et al.
(author)
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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
- 2011
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In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 134:1, s. 301-317
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Journal article (peer-reviewed)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 18F-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 3H-nicotine and 125I-α-bungarotoxin to neuronal nicotinic acetylcholine receptor subtypes, 3H-L-deprenyl to activated astrocytes and 3H-PK11195 to microglia, as well as butyrylcholinesterase activity. Regional in vivo 11C-Pittsburgh Compound B-positron emission tomography retention positively correlated with 3H-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 3H-nicotine binding. In addition, a positive correlation was found between regional 11C-Pittsburgh Compound B positron emission tomography retention and 3H-Pittsburgh Compound B binding with the number of glial fibrillary acidic protein immunoreactive cells, but not with 3H-L-deprenyl and 3H-PK-11195 binding. In summary, high 11C-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.
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| 2. |
- Mustafiz, Tamanna
(author)
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Age dependent beta-amyloid isoforms and implications of different drug treatments as studied in different transgenic mouse models and cell lines
- 2012
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Doctoral thesis (other academic/artistic)abstract
- The Amyloid-β (Aβ) peptide is the main component of the the amyloid plaques in Alzheimer’s Disease (AD) and has been implicated to be the cause of the disease. During the last decade it has become increasingly evident that soluble, oligomeric forms of Aβ are more toxic to neurons than the plaques and might play an important role in the disease pathogenesis. The aim of this thesis was to investigate the time course of different Aβ isoforms and species and how these forms affects the neuro-pathological changes seen in AD and how different cholinergic drugs can modulate Aβ and it’s processing. A translational approach ranging from transfected human neuroblastoma SH-SY5Y/APPswe cells, APPswe and hAChE-Tg//APPswe transgenic mouse models of AD to postmortem AD brain tissue were used to study how changes of different levels of Aβ influence the brain and related processes. APPswe transgenic mice showed already at 7-days of age, high levels of soluble form of Aβ, as a sign for that Aβ starts to aggregate from birth. Be-tween 7 to 90-days of age, the major Aβ isoforms in brain were shorter forms than Aβ1-40. The levels of Aβ1-40 were high and remained fairly constant up to 15- months of age while Aβ1-42 showed an age-dependent consistent increase from 7- days up to 15-months of age. High levels of Aβ oligomers but low levels of synaphtophysin were observed in 90-days-old APPswe mice probably due to the toxicity of the oligomers. Low levels of α7 neuronal nicotinic acetylcholine receptors (nAChRs) compared to non-transgenic mice were measured in 7-days-old APPswe mice; while an increased number N-methyl-D-aspartate (NMDA) receptors binding sites were found at 21-days of age probably reflecting compensatory mechanisms in response to a high Aβ burden. Epigenetic studies showed increased levels of acetylated (AcH3), and di-methylated (2MeH3) histone H3 at 4-months-old APPswe mice. When a γ-secretase inhibitor reduced Aβ, there was a reduction in AcH3 in SH-SY5Y/ APPswe cells. nAChR agonists showed to influence the Aβ levels in hAChE-Tg//APPswe transgenic mice and in SH-SY5Y/ APPswe cells.
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