The in vivo imaging probe [11C]-PIB (Pittsburgh Compound B, N-methyl[11C]2-(4'-methylaminophenyl-6-hydroxybenzathiazole) is under evaluation as a key imaging tool in Alzheimer's disease (AD) and to date has been assumed to bind with high affinity and specificity to the amyloid structures associated with classical plaques (CPs), one of the pathological hallmarks of the disease. However, no studies have systematically investigated PIB binding to human neuropathological brain specimens at the tracer concentrations achieved during in vivo imaging scans. Using a combination of autoradiography and histochemical techniques, we demonstrate that PIB, in addition to binding CPs clearly delineates diffuse plaques and cerebrovascular amyloid angiopathy (CAA). The interaction of PIB with CAA was not fully displaceable and this may be linked to the apolipoprotein E-epsilon4 allele. PIB was also found to label neurofibrillary tangles, although the overall intensity of this binding was markedly lower than that associated with the amyloid-beta (Abeta) pathology. The data provide a molecular explanation for PIB's limited specificity in diagnosing and monitoring disease progression in AD and instead indicate that the ligand is primarily a non-specific marker of Abeta-peptide related cerebral amyloidosis.

Increasing evidence indicates that maintenance of neuronal homeostasis involves the activation of the cell cycle machinery in postmitotic neurons. Our recent findings suggest that cell cycle activation is essential for DNA damage-induced neuronal apoptosis. However, whether the cell division cycle also participates in DNA repair and survival of postmitotic, terminally differentiated neurons is unknown. Here, we tested the hypothesis that G(1) phase components contribute to the repair of DNA and are involved in the DNA damage response of postmitotic neurons. In cortical terminally differentiated neurons, treatment with subtoxic concentrations of hydrogen peroxide (H(2)O(2)) caused repairable DNA double strand breaks (DSBs) and the activation of G(1) components of the cell cycle machinery. Importantly, DNA repair was attenuated if cyclin-dependent kinases CDK4 and CDK6, essential elements of G(0) --> G(1) transition, were suppressed. Our data suggest that G(1) cell cycle components are involved in DNA repair and survival of postmitotic neurons.

A common neuropathological finding associated with both normal ageing and a range of dementias is the presence of senile plaques (SPs) formed from amyloid-beta (Ab) peptides (Braak and Braak 1991;Bouras et al. 1994;Tsuboi and Dickson 2005;Ballard et al. 2006). Their occurrence in sufficient density and distribution, together with neurofibrillary tangles (NFTs), in histological sections of postmortem cerebral cortex is considered diagnostic of Alzheimer's disease (AD) (Mirra et al. 1991 Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.Abbreviations used: AD, Alzheimer's disease; AMY, amygdala; AS, a-synuclein; Ab, amyloid-beta peptide; BF1, 5-bromo-2-(4-dimethylaminophenyl)benzofuran; BTA-1, 2-(4¢-methylaminophenyl)benzothiazole; DLB, dementia with Lewy bodies; FDDNP, 2-(1-{6-[ AbstractAmyloid containing deposits are a defining neuropathological feature of a wide range of dementias and movement disorders. The positron emission tomography tracer PIB (Pittsburgh Compound-B, 2-[4¢-(methylamino)phenyl]-6-hydroxybenzothiazole) was developed to target senile plaques, an amyloid containing pathological hallmark of Alzheimer's disease, formed from the amyloid-b peptide. Despite the fact that PIB was developed from the pan-amyloid staining dye thioflavin T, no detailed characterisation of its interaction with other amyloid structures has been reported. In this study, we demonstrate the presence of a high affinity binding site (K d 4 nM) for benzothiazole derivatives, including [3H]-PIB, on a-synuclein (AS) filaments generated in vitro, and further characterise this binding site through the use of radioligand displacement assays employing 4-N-methylamino-4¢-hydroxystilbene (SB13) (K i = 87 nM) and 2-(1-{6-[(2-fluoroethyl (methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) (K i = 210 nM). Despite the presence of a high-affinity binding site on AS filaments, no discernible interaction of [3H]-PIB was detected with amygdala sections from Parkinson's disease cases containing frequent AS-immunoreactive Lewy bodies and related neurities. These findings suggest that the density and/or accessibility of AS binding sites in vivo are significantly less than those associated with amyloid-b peptide lesions. Lewy bodies pathology is therefore unlikely to contribute significantly to the retention of PIB in positron emission tomography imaging studies.