Ikonomovic MD, Klunk WE, Abrahamson EE, Mathis CA, Price JC, Tsopelas ND, Lopresti BJ, Ziolko S, Bi W, Paljug WR, Debnath ML, Hope CE, Isanski BA, Hamilton RL, Dekosky ST. Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease. Brain. 2008 Jun;131(Pt 6):1630-45. PubMed.
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Austin Hospital
This paper is the icing on the cake for the validation of what is proving to be an extraordinarily good PET tracer. PIB has shown robust results all around the world in a multitude of centers no matter what analysis method has been applied, ranging from simple visual inspection of a 20-minute scan to complex modeling of 90-minute acquisitions with arterial metabolite-corrected blood sampling. PIB has challenged preconceptions about the distribution of β amyloid plaque and won the arguments. For example, there were many disbelievers that the high frontal lobe binding was due to high concentration of amyloid plaque in this area. This paper confirms that this is indeed the case. The paper also plugs a few gaps by throwing some light on the potential mechanism for the observed marked binding of PIB in the striatum but not the cerebellar cortex when both areas have few neuritic plaques. The current work has demonstrated that PIB does not bind to diffuse plaque in the cerebellum, confirming that the use of the cerebellar cortex to normalize cortical PIB binding measures is valid. The extraordinary specificity of PIB for β amyloid plaque has been repeatedly demonstrated in vitro and now further confirmed by the correlation of histopathology with in-vivo imaging.
We can now say with great confidence that we have an excellent tool for in-vivo measurement of insoluble β amyloid deposition, thanks to the inspired and determined efforts of the University of Pittsburgh researchers over the last 10 or more years. The great remaining challenge is to determine the clinical significance of β amyloid deposition in apparently normal elderly individuals and those with mild cognitive impairment. We should have the answer to this vital question within the next year or two as longitudinal follow-up data accumulate from individual institutions and large multicenter studies such as the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Australian Imaging, Biomarkers and Lifestyle study of the elderly (AIBL).
It is clear that PIB PET can greatly assist differential diagnosis of dementia and earlier diagnosis of Alzheimer disease. But perhaps most importantly, the results in the paper and the myriad of recent PIB publications show that the much-sought tool for preclinical detection of Alzheimer disease that will greatly assist the development of preventative and early intervention therapies is tantalizingly close, if not already here.
Karolinska Institutet
It has been six years now since the first Alzheimer patient was scanned with PIB in Sweden (Klunk et al., 2004). It was quite obvious already from the first PIB scans that there was a robust difference in PIB retention in cortical brain regions of mild AD patients compared to age-matched controls (Klunk et al., 2004). Ikonomovic et al. now report in-vitro PIB binding in the brain of an AD patient who 10 months earlier underwent a PIB scan. A correlation was observed between PIB retention measured in vivo and PIB in-vitro binding. Diffuse plaques in caudate nucleus and presubiculum were labeled, and amorphous Aβ plaques were not detectable in vitro with PIB. Importantly, no binding was observed to neurofibrillary tangles. A direct correlation was observed between in-vitro PIB binding and levels of insoluble Aβ. This study supports the assumption from earlier in-vivo studies that PIB is useful in measuring amyloid plaque load in AD. Further studies are now needed to understand the role of other pathological processes in AD brains. If we can develop imaging ligands to label neurofibrillary tangles, inflammatory processes, (micro)glia, and pre-plaque forms of Aβ, e.g., oligomers, then we will learn and understand much more about the AD pathology that will help us develop new AD drugs and evaluate the underlying mechanisms.
References:
Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergström M, Savitcheva I, Huang GF, Estrada S, Ausén B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Långström B. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol. 2004 Mar;55(3):306-19. PubMed.
Ikonomovic MD, Klunk WE, Abrahamson EE, Mathis CA, Price JC, Tsopelas ND, Lopresti BJ, Ziolko S, Bi W, Paljug WR, Debnath ML, Hope CE, Isanski BA, Hamilton RL, Dekosky ST. Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease. Brain. 2008 Jun;131(Pt 6):1630-45. PubMed.
New diagnostics go hand in hand with new therapies. Are we there yet! Roll on the summer months!
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