. Beta-amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer's disease. Brain. 2007 Nov;130(Pt 11):2837-44. PubMed.


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  1. This paper raises the interesting question of the relationship between PIB PET and the Aβ oligomers that have been shown to affect synapses and behavior.

  2. This is a highly interesting study on specific binding behavior of 6-OH-BTA-1, aka Pittsburgh compound B (PIB). Modern molecular imaging tracers such as PIB open the possibility to characterize neurodegenerative disorders on the basis of underlying pathology rather than on clinical symptoms alone. Labeled with the positron emitter C-11, PIB has been recently established as a most successful tracer for positron emission tomography (PET) imaging of cerebral β amlyoid pathology, in particular amyloid plaques in vivo. Amyloid plaques are considered a hallmark pathology in Alzheimer disease and, correspondingly, in a number of studies significantly higher cerebral binding of [11C]PIB has been demonstrated in the brain of AD patients, compared to healthy controls (1-3).

    Apart from amyloid plaques, many different types of pathologic protein aggregations in the brain have been associated with neurodegenerative disorders. Thus, to be valuable for scientific and clinical application, a tracer detecting cerebral molecular pathology should be as specific as possible. For example, in AD, besides amyloid deposits, neurofibrillary tangles (NFT) constituted of tau protein represent another characteristic pathologic entity. The binding of PIB to NFTs has been previously evaluated and is currently regarded to be negligible (4,5). This corresponds well to results of studies that were able to demonstrate a lack of binding of [11C]PIB in frontotemporal dementia, which is primarily characterized by tau and/or ubiquitin pathology and underlines the potential value of this tracer for differential diagnosis of dementia (3) .

    So far, binding of PIB to Lewy bodies has not been systematically addressed. The term “Lewy bodies” describes intracellular aggregations mainly of the α-synuclein peptide in cerebral neurons, named according to Friedrich H. Lewy (a neurologist who also worked with Alois Alzheimer in Munich) (6). These Lewy bodies have originally been associated with Parkinson disease, where they can be found consistently in the brain stem but also in other brain regions. Dementia with Lewy bodies (DLB) probably represents the third most frequent causality of dementia (following AD and vascular dementia) and may account for up to 20 percent of all cases of dementia (but not 20 percent of all elderly patients as accidentally mentioned in the current manuscript) (7). DLB is characterized by the presence of Lewy bodies throughout the neocortex and the limbic system. DLB shares many characteristics (regarding clinical, neuropathological, and imaging findings) with the so-called Parkinson-associated dementia, or PDD, which patients with Parkinson disease may eventually develop in later disease stages. Thus, recently it has been speculated that both disorders may represent different expressions of a disease spectrum. There is also considerable overlap of pathologies between AD and DLB. In many DLB cases, amyloid plaque deposits can be detected, and it has even been discussed that clinical diagnosis of DLB is associated with the presence of Alzheimer pathology rather than on Lewy body distribution (8). It appears that both cases with (DLB/AD) and without amyloid pathology (pure DLB) occur. Also, in AD the presence of Lewy bodies has been described. Nevertheless, AD and DLB are regarded nosologically differently (9).

    Increasing evidence is collected indicating that various pathologies may be present in different types of neurodegeneration, and only differ in their extent and localization. Regarding this confusing overlap of pathologies, it appears particularly relevant to have suitable specific imaging tools at hand to assess the contribution of single abnormalities to different disorders in vivo. Some of the authors of the current study also contributed to a recent work which has demonstrated relevant [11C]PIB-retention in a group of patients with DLB in similar extent and pattern as described in AD (1). These results strongly suggested that one evaluate if Lewy body pathology eventually contributes to the binding of [11C]PIB.

    In the current study, the authors applied modern in-vitro measurement techniques to assess the binding of PIB to α-synuclein-containing Lewy bodies in comparison to binding to β amyloid aggregation pathology. They were able to demonstrate that PIB binds to α-synuclein fibrils only with low affinity and that any contribution of Lewy bodies to the [11C]PIB signal would be negligible. This underlines the high specificity of [11C]PIB for amyloid plaque pathology. Furthermore, it indicates that the detected binding of [11C]PIB in Lewy body patients is actually due to amyloid pathology and not to Lewy bodies. In light of these results, it is plausible that a recent study was able to demonstrate a lack of significant [11C]PIB retention in a small group of patients with cognitively intact Parkinson disease in early stages, corresponding to the idea that Lewy bodies but no amyloid plaques may be present in these patients (10).

    A recent different study demonstrated that PIB may have limited specificity regarding the detection of classical amyloid plaques but appears to bind to Aβ peptide related pathology in general (such as diffuse plaques and cerebrovascular amyloid pathology) (5). However, the current study underlines that the tracer [11C]PIB may indeed open the possibility to specifically assess the extent to which amyloid pathology contributes to different clinical entities, and it may help to identify subtypes of neurodegeneration (e.g., DLB with/without amyloid plaque pathology) which may be of interest for classification, prognosis, and therapy selection in patients suffering from neurodegenerative disorders.

    The significance of the current study is only limited by a few methodological restrictions: results from in-vitro studies never allow absolute conclusions on the behavior of a PET tracer in vivo. Many confounding variables such as blood-brain barrier permeability, metabolism, and reaction of the tracer in the living tissue potentially affect in vivo tracer kinetics. These questions should be a matter of future studies and can only be addressed with the help of suitable animal models and postmortem studies.

    See also:
    Forster E, Lewy FH. Paralysis agitans. Berlin: Springer Verlag 1912;Pathologische Anatomie. Handbuch der Neurologie (edited by M. Lewandowsky):920-933.


    . Imaging beta-amyloid burden in aging and dementia. Neurology. 2007 May 15;68(20):1718-25. PubMed.

    . Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. Brain. 2006 Nov;129(Pt 11):2856-66. PubMed.

    . Imaging of amyloid plaques and cerebral glucose metabolism in semantic dementia and Alzheimer's disease. Neuroimage. 2008 Jan 15;39(2):619-33. PubMed.

    . The binding of 2-(4'-methylaminophenyl)benzothiazole to postmortem brain homogenates is dominated by the amyloid component. J Neurosci. 2003 Mar 15;23(6):2086-92. PubMed.

    . PIB is a non-specific imaging marker of amyloid-beta (Abeta) peptide-related cerebral amyloidosis. Brain. 2007 Oct;130(Pt 10):2607-15. PubMed.

    . A systematic review of prevalence and incidence studies of dementia with Lewy bodies. Age Ageing. 2005 Nov;34(6):561-6. PubMed.

    . In dementia with Lewy bodies, Braak stage determines phenotype, not Lewy body distribution. Neurology. 2007 Jul 24;69(4):356-9. PubMed.

    . Dementia with Lewy bodies: reclassification of pathological subtypes and boundary with Parkinson's disease or Alzheimer's disease. Neuropathology. 2004 Mar;24(1):72-8. PubMed.

    . [(11)C]-PIB imaging in patients with Parkinson's disease: preliminary results. Parkinsonism Relat Disord. 2008;14(4):345-7. PubMed.

  3. Besides the interesting issues already discussed at length and in depth, the data bring to mind the problem of why N-terminally directed antibodies—and particularly those against the EFRH epitope as demonstrated by Beka Solomon and coworkers—are most efficient in passive vaccination. The explanation is that the N-terminal is "dangling" outside the amyloid fibers and thereby accessible.

    Then I wonder about antibodies that react about two orders of magnitude less well with pE-Aβ (i.e., Aβ3-42 peptide, starting with pyroglutamyl at residue Glu-3), than with wt-Aβ (Gardberg et al., 2007). Are these acting not or less well on pE-Aβ in human brain and thereby explaining differences in efficacy of passive vaccination in mouse models and human patients?


    . Molecular basis for passive immunotherapy of Alzheimer's disease. Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15659-64. PubMed.

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