The prognostic value of amyloid imaging

Department of Neurology and Nuclear Medicine, University of Milano-Bicocca, Monza, Italy.
European Journal of Nuclear Medicine (Impact Factor: 5.38). 04/2012; 39(7):1207-19. DOI: 10.1007/s00259-012-2108-x
Source: PubMed


Mild cognitive impairment is characterized by a decline in cognitive performance without interference with activities of daily living. The amnestic subtype of mild cognitive impairment progresses to Alzheimer's disease at a rate of 10-15% per year and in the majority the neuropathology is intermediate between the neuropathological changes of typical ageing and Alzheimer's disease. Amyloid deposition occurs over a decade before the development of noticeable cognitive symptoms in a continuous process that starts in healthy elderly individuals. Newly developed PET amyloid imaging agents provide noninvasive biomarkers for the early in vivo detection of Alzheimer's pathology in healthy elderly individuals and those with mild cognitive impairment. Exclusion of amyloid pathology should allow a more accurate prognosis to be given and ensure appropriate recruitment into clinical trials testing the efficacy of new putative antiamyloid agents at an earlier disease stage. The development of (18)F-labelled amyloid imaging agents has increased the availability of this new technology for clinical and research use since they can be used in PET centres where a cyclotron and radiochemistry are not available. This review discusses the role of PET imaging for assessing the amyloid load in cognitively normal elderly subjects and subjects with mild cognitive impairment at risk of conversion to Alzheimer's disease.

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    • "Tau is a microtubule-stabilizing protein that maintains neuronal cell structure and axonal transport (reviewed in [5] [7]). Neither senile plaques nor NFTs are absolute hallmarks of AD because cognitively intact aged individuals may exhibit both pathological changes upon postmortem brain examination or as assessed by newly developed positron emission tomography (PET) amyloid imaging agents [8] [9] [10] [11] [12]. "
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    ABSTRACT: Unlabelled: Imaging of amyloid-β (Aβ) plaques by PET is more and more integrated into concepts for Alzheimer disease (AD) diagnosis and drug development. The objective of this study was to find novel chemical entities that can be transformed into (18)F-labeled Aβ tracers with favorable brain washout kinetics and low background signal. Methods: High-throughput screening of a large chemical library was used to identify new ligands for fibrillar aggregates of Aβ(1-42) peptide. Thirty-two fluorinated derivatives were synthesized and tested for their affinity toward AD brain homogenate. Twelve ligands have been radiolabeled with (18)F. The pharmacokinetic properties of the radioligands were investigated in mouse and monkey biodistribution studies. Binding characteristics were determined by autoradiography of AD brain sections in vitro and using amyloid precursor protein transgenic mice in vivo. Results: The systematic search for Aβ imaging agents revealed several fluorinated derivatives with nanomolar affinity for Aβ. The fluoropyridyl derivative BAY 1008472 showed a high initial brain uptake (6.45 percentage injected dose per gram at 2 min) and rapid brain washout (ratio of percentage of injected dose per gram of tissue at 2 and 30 min after injection, 9.2) in mice. PET studies of healthy rhesus monkeys confirmed the high initial brain uptake of BAY 1008472 (2.52 standardized uptake value at peak) and a fast elimination of total radioactivity from gray and white matter areas (ratio of standardized uptake value at peak uptake and 60 min 11.0). In autoradiographic analysis, BAY 1008472 selectively detected Aβ deposits in human AD brain sections with high contrast and did not bind to τ- or α-synuclein pathologies. Finally, ex vivo autoradiography of brain sections from amyloid precursor protein-transgenic mice confirmed that BAY 1008472 is indeed suitable for the in vivo detection of Aβ plaques. Conclusion: A new chemical class of Aβ tracers has been identified by high-throughput screening. The fluoropyridyl derivative BAY 1008472 shows a favorable preclinical profile including low background binding in gray and white matter. These properties might qualify this new tracer, in particular, to detect subtle amounts or changes of Aβ burden in presymptomatic AD and during therapy.
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    ABSTRACT: We conducted a meta-analysis of relationships between amyloid burden and cognition in cognitively normal, older adult humans. Methods of assessing amyloid burden included were CSF or plasma assays, histopathology, and PET ligands. Cognitive domains examined were episodic memory, executive function, working memory, processing speed, visuospatial function, semantic memory, and global cognition. Sixty-four studies representing 7,140 subjects met selection criteria, with 3,495 subjects from 34 studies representing independent cohorts. Weighted effect sizes were obtained for each study. Primary analyses were conducted limiting to independent cohort studies using only the most common assessment method (Pittsburgh compound B). Exploratory analyses included all assessment methods. Episodic memory (r = 0.12) had a significant relationship to amyloid burden. Executive function and global cognition did not have significant relationships to amyloid in the primary analysis of Pittsburgh compound B (r = 0.05 and r = 0.08, respectively), but did when including all assessment methods (r = 0.08 and r = 0.09, respectively). The domains of working memory, processing speed, visuospatial function, and semantic memory did not have significant relationships to amyloid. Differences in the method of amyloid assessment, study design (longitudinal vs cross-sectional), or inclusion of control variables (age, etc.) had little influence. Based on this meta-analytic survey of the literature, increased amyloid burden has small but nontrivial associations with specific domains of cognitive performance in individuals who are currently cognitively normal. These associations may be useful for identifying preclinical Alzheimer disease or developing clinical outcome measures.
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