[(11)C]PIB-amyloid binding and levels of Abeta40 and Abeta42 in postmortem brain tissue from Alzheimer patients.

Uppsala University, Department of Biochemistry and Organic Chemistry, Sweden.
Neurochemistry International (Impact Factor: 2.65). 12/2008; 54(5-6):347-57. DOI: 10.1016/j.neuint.2008.12.016
Source: PubMed

ABSTRACT beta-Amyloid (Abeta) deposits are one of the major histopathological hallmarks of Alzheimer's disease (AD). The amyloid-imaging positron emission tomography (PET) tracer [(11)C]PIB (N-methyl[(11)C]2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole) is used in the assessment of Abeta deposits in the human brain. [(11)C]PIB-amyloid interaction and insoluble Abeta40 and Abeta42 peptide levels in the brain were quantified in postmortem tissue from nine AD patients and nine age-matched control subjects in the temporal, frontal and parietal cortices and the cerebellum. Autoradiographical studies showed significantly higher densities of specific [(11)C]PIB-amyloid binding in gray matter in the temporal and parietal cortex (62fmol/mg tissue) in AD patients as compared to control subjects, whereas the density was somewhat lower in the frontal cortex (56fmol/mg tissue). No specific binding could be detected in the AD cerebellum or in the tissues from the control subjects (< or =5fmol/mg tissue). Insoluble Abeta40 and total Abeta levels (i.e. sum of Abeta40 and Abeta42) were significantly higher in patients than in controls in all measured cortical regions as determined using ELISA, which was confirmed using immunohistochemistry. The present findings show a more regional selective distribution of [(11)C]PIB amyloid binding than previously reported. Moreover, it is suggested that some of the [(11)C]PIB binding and insoluble Abeta seen in control subjects may be amyloid in the blood vessels.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cumulated scientific evidence suggests that the pathology causing Alzheimer's disease (AD) occurs many years or even decades before memory impairment and other clinical symptoms arise. Tangible and detailed knowledge about different pathological processes, their interactions, and time course is therefore of the essence both for the development of potentially successful treatments and a reliable early diagnosis of this relentless disorder. The past decade has thus seen an explosion in research on biomarkers that could provide in vivo evidence for these pathological processes, involving β-amyloid (Aβ) production and aggregation into plaques, neurofibrillary tangle formation, neuroinflammation, and eventually neurodegeneration. The rare form of dominantly-inherited early-onset familial AD (eoFAD), with almost complete mutation penetrance and defined age of disease onset, has been proposed as a model to study the very early disease mechanisms that are also supposed to underlie the common sporadic form (sAD). However, more than 200 mutations in three different genes (PSEN1 and 2, APP) have been identified as causing eoFAD, some of which have been shown to differ substantially from others. This work employed multi-tracer positron emission tomography (PET), using the tracers 2-[18F]‐fluoro-2‐deoxy‐D‐glucose (FDG), N-methyl-[11C] 2-(4'- methylaminophenyl)-6-hydroxy-benzothiazole (PIB), and [11C]-L-deuterium-deprenyl (DED) to explore the characteristics, time course and interrelationship of cerebral glucose metabolism, fibrillar Aβ burden, and astrocyte activation (astrocytosis) at different presymptomatic and symptomatic disease stages of eoFAD and sAD, in relationship to cognition, other AD biomarkers, and/or post-mortem pathology. Thalamic hypometabolism in PSEN1 eoFAD mutation carriers was demonstrated in this thesis nearly 20 years before they were expected to develop clinical symptoms. The pattern of hypometabolism studied in several mutation carriers spread subsequently to regions that are also typically affected in sAD, correlating well with cognitive decline at symptomatic disease stages. Regional hypometabolism was furthermore found to correlate with typical AD pathology, namely neuritic Aβ plaques at post-mortem examination, suggesting that FDG PET is an excellent marker of disease progression from early presymptomatic stages to terminal disease. One particular eoFAD mutation, the Arctic APP mutation, has been reported to modify amyloid processing in a way that obviates the formation of fibrillar Aβ, the form of Aβ most prone to aggregate into neuritic plaques. In contrast to carriers of other eoFAD mutations and sAD patients, we found that carriers of the Arctic APP mutation showed no cortical PIB PET retention as a measure of fibrillar Aβ load, while Aβ and tau in cerebral spinal fluid and glucose metabolism, and in advanced disease also medial temporal lobe atrophy as measured by magnetic resonance imaging and cognition were clearly pathological and typical of AD. The findings imply that clinical AD can be caused by forms of Aβ, supposedly oligomeric or protofibrillar, which cannot be detected by PIB PET. Very little is still known from in vivo studies about when and where in the brain neuroinflammation occurs in AD. Here, it could be shown that DED binding as a measure of astrocytosis was elevated in prodromal AD patients, whereas binding levels in AD were comparable to those in controls. PIB PET retention was increased and glucose metabolism decreased in both groups and there was no regional relationship between the three tracers, indicating that astrocytosis is an early phenomenon in AD that follows a different spatial and temporal pattern than Aβ plaque deposition and impaired synaptic activity as measured by glucose metabolism. Multi-tracer PET is in this work proven to provide novel insights in eoFAD and sAD pathogenesis with processes such as astrocytosis and the potential role of different Aβ species. This knowledge is of significance for the understanding of disease mechanisms as well as the comparability of the purely genetic and the sporadic form of AD.
    10/2011, Degree: PhD, Supervisor: Agneta Nordberg, Ove Almkvist, Bengt Långström
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Rapid clearance and disappearance of a tracer from the circulation challenges the determination of the tracer's binding potentials in brain (BP ND) by positron emission tomography (PET). This is the case for the analysis of the binding of radiolabeled [(11)C]Pittsburgh Compound B ([(11)C]PIB) to amyloid-β (Aβ) plaques in brain of patients with Alzheimer's disease (AD). To resolve the issue of rapid clearance from the circulation, we here introduce the flow-independent Washout Allometric Reference Method (WARM) for the analysis of washout and binding of [(11)C]PIB in two groups of human subjects, healthy aged control subjects (HC), and patients suffering from AD, and we compare the results to the outcome of two conventional analysis methods. We also use the rapid initial clearance to obtain a surrogate measure of the rate of cerebral blood flow (CBF), as well as a method of identifying a suitable reference region directly from the [(11)C]PIB signal. The difference of average absolute CBF values between the AD and HC groups was highly significant (P < 0.003). The CBF measures were not significantly different between the groups when normalized to cerebellar gray matter flow. Thus, when flow differences confound conventional measures of [(11)C]PIB binding, the separate estimates of CBF and BP ND provide additional information about possible AD. The results demonstrate the importance of data-driven estimation of CBF and BP ND, as well as reference region detection from the [(11)C]PIB signal. We conclude that the WARM method yields stable measures of BP ND with relative ease, using only integration for noise reduction and no model regression. The method accounts for relative flow differences in the brain tissue and yields a calibrated measure of absolute CBF directly from the [(11)C]PIB signal. Compared to conventional methods, WARM optimizes the Aβ plaque load discrimination between patients with AD and healthy controls (P = 0.009).
    Frontiers in Aging Neuroscience 01/2013; 5:45. · 2.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Several aminophenyl benzothiazoles were prepared with a view to using them as amyloid binding agents for imaging β-amyloid in Alzheimer's disease. These precursors were radiolabeled with (11) C-positron-emitting radioisotope using an automated synthesizer and selected radiolabeled compounds were further purified by HPLC. Our results demonstrate that changes in structure have a major influence on the radioactive yield and the ease with which the radiolabel can be introduced. Aminophenyl benzothiazoles with an attached isopropyl group resisted dialkylation perhaps due to steric hindrance caused by this group. Straight chain attachment of methyl, ethyl, butyl, and crotyl groups in the structure decreased the radiochemical yield. Notably, the o-aminophenyl benzothiazole derivatives were difficult to alkylate despite stringent experimental conditions. This reactivity difference is attributed to the hydrogen bonding characteristics of the o-amino group with the nitrogen atom of the thiazole ring.
    Journal of Labelled Compounds and Radiopharmaceuticals 07/2014; · 1.19 Impact Factor