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Different aspects of Alzheimer's disease-related amyloid ?-peptide pathology and their relationship to amyloid positron emission tomography imaging and dementia.

ABSTRACT: Alzheimer's disease (AD)-related amyloid ?-peptide (A?) pathology in the form of amyloid plaques and cerebral amyloid angiopathy (CAA) spreads in its topographical distribution, increases in quantity, and undergoes qualitative changes in its composition of modified A? species throughout the pathogenesis of AD. It is not clear which of these aspects of A? pathology contribute to AD progression and to what extent amyloid positron emission tomography (PET) reflects each of these aspects. To address these questions three cohorts of human autopsy cases (in total n?=?271) were neuropathologically and biochemically examined for the topographical distribution of A? pathology (plaques and CAA), its quantity and its composition. These parameters were compared with neurofibrillary tangle (NFT) and neuritic plaque pathology, the degree of dementia and the results from [18F]flutemetamol amyloid PET imaging in cohort 3. All three aspects of A? pathology correlated with one another, the estimation of A? pathology by [18F]flutemetamol PET, AD-related NFT pathology, neuritic plaques, and with the degree of dementia. These results show that one aspect of A? pathology can be used to predict the other two, and correlates well with the development of dementia, advancing NFT and neuritic plaque pathology. Moreover, amyloid PET estimates all three aspects of A? pathology in-vivo. Accordingly, amyloid PET-based estimates for staging of amyloid pathology indicate the progression status of amyloid pathology in general and, in doing so, also of AD pathology. Only 7.75% of our cases deviated from this general association.

SUBMITTER: Thal DR

PROVIDER: S-EPMC6854805 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Different aspects of Alzheimer's disease-related amyloid β-peptide pathology and their relationship to amyloid positron emission tomography imaging and dementia.

Thal Dietmar Rudolf DR Ronisz Alicja A Tousseyn Thomas T Rijal Upadhaya Ajeet A Balakrishnan Karthikeyan K Vandenberghe Rik R Vandenbulcke Mathieu M von Arnim Christine A F CAF Otto Markus M Beach Thomas G TG Lilja Johan J Heurling Kerstin K Chakrabarty Aruna A Ismail Azzam A Buckley Christopher C Smith Adrian P L APL Kumar Sathish S Farrar Gill G Walter Jochen J

Acta neuropathologica communications 20191114 1

Alzheimer's disease (AD)-related amyloid β-peptide (Aβ) pathology in the form of amyloid plaques and cerebral amyloid angiopathy (CAA) spreads in its topographical distribution, increases in quantity, and undergoes qualitative changes in its composition of modified Aβ species throughout the pathogenesis of AD. It is not clear which of these aspects of Aβ pathology contribute to AD progression and to what extent amyloid positron emission tomography (PET) reflects each of these aspects. To address ...[more]

PMID: 31727169

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Project description:BackgroundDisclosure of amyloid positron emission tomography (PET) results to individuals without dementia has become standard practice in secondary prevention trials and also increasingly occurs in clinical practice. However, this is controversial given the current lack of understanding of the predictive value of a PET result at the individual level and absence of disease-modifying treatments. In this study, we systematically reviewed the literature on the disclosure of amyloid PET in cognitively normal (CN) individuals and patients with mild cognitive impairment (MCI) in both research and clinical settings.MethodsWe performed a systematic literature search of four scientific databases. Two independent reviewers screened the identified records and selected relevant articles. Included articles presented either empirical data or theoretical data (i.e. arguments in favor or against amyloid status disclosure). Results from the theoretical data were aggregated and presented per theme.ResultsOf the seventeen included studies, eleven reported empirical data and six provided theoretical arguments. There was a large variation in the design of the empirical studies, which were almost exclusively in the context of cognitively normal trial participants, comprising only two prospective cohort studies quantitatively assessing the psychological impact of PET result disclosure which showed a low risk of psychological harm after disclosure. Four studies showed that both professionals and cognitively normal individuals support amyloid PET result disclosure and underlined the need for clear disclosure protocols. From the articles presenting theoretical data, we identified 51 'pro' and 'contra' arguments. Theoretical arguments in favor or against disclosure were quite consistent across population groups and settings. Arguments against disclosure focused on the principle of non-maleficence, whereas its psychological impact and predictive value is unknown. Important arguments in favor of amyloid disclosure are the patients right to know (patient autonomy) and that it enables early future decision making.DiscussionBefore amyloid PET result disclosure in individuals without dementia in a research or clinical setting is ready for widespread application, more research is needed about its psychological impact, and its predictive value at an individual level. Finally, communication materials and strategies to support disclosure of amyloid PET results should be further developed and prospectively evaluated.

Project description:The accumulation of ?-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 ?-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 ?-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 ?-amyloid, neurofibrillary tangles and the levels of binding of (3)H-nicotine and (125)I-?-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 ?-amyloid, and ?-amyloid plaque distribution, but not with the number of neurofibrillary tangles measured at autopsy. There was a negative correlation between regional fibrillar ?-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 ?-amyloid and losses of neuronal nicotinic acetylcholine receptor subtypes at autopsy, suggesting a closer involvement of ?-amyloid pathology with neuronal nicotinic acetylcholine receptor subtypes than with inflammatory processes.

Dataset Information

Different aspects of Alzheimer's disease-related amyloid ?-peptide pathology and their relationship to amyloid positron emission tomography imaging and dementia.

Publications

Different aspects of Alzheimer's disease-related amyloid β-peptide pathology and their relationship to amyloid positron emission tomography imaging and dementia.

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