Standardized uptake value ratios (SUVR) are commonly used for quantification of 18F-Florbetaben (FBB) scans. Cerebellar gray matter is used as the reference region for quantification. However, cerebellar plaques may be present in Alzheimer disease (AD). The aim of this study was to assess the influence of cerebellar plaques in FBB SUVR, when using cerebellar gray matter as the reference. Neuropathological assessment of cerebral (frontal, occipital, anterior and posterior cingulate) cortex and cerebellar cortex tissue from 87 end of life patients (64 AD, 14 other dementia, 9 non-demented aged volunteers; 80.4±10.2 yrs) who underwent a FBB PET before death was performed using the Bielschowsky silver stain and Amyloid β (Aβ) immunohistochemistry to quantify neuritic/cored and diffuse plaques, as absent, sparse, moderate and frequent. Mean cortical SUVRs were compared among brains with different cerebellar plaque loads. None from the 83 evaluable cerebellar samples showed frequent cerebellar plaques. Only 1 sample showed both sparse neuritic/cored and sparse diffuse plaques. Sparse diffuse plaques were found in 33 samples, and moderate diffuse plaques in 5. Subjects with higher cerebellar plaque loads showed higher cortical Aβ loads and standardized uptake values. Thus, cortical SUVRs significantly increased with cerebellar plaque load (table, figure 1). However, in cortical regions with moderate or frequent Aβ plaques no significant SUVR differences were found among brains showing different cerebellar plaque loads (table, figure 2). Full sample. Moderate or frequent cortical AB plaques. In brains with higher cerebral cortical Aβ loads, cerebellar plaques were found in 47% of cases, mostly as sparse diffuse plaques (40%). However, the presence of cerebellar plaques did not influence the SUVRs in these subjects with moderate or frequent cortical Aβ. Therefore, the effect of cerebellar plaques in FBB SUVR appears to be negligible even in advanced stages of AD with a high cortical Aβ load.

The drastic loss of cholinergic projection neurons in the basal forebrain is a hallmark of Alzheimer's disease (AD), and drugs most frequently applied for the treatment of dementia include inhibitors of the acetylcholine-degrading enzyme acetylcholinesterase (AChE). This protein is known to act as a ligand of beta-amyloid (Abeta) in senile plaques, a further neuropathological sign of AD. Recently, we have shown that the fluorescent, heterodimeric AChE inhibitor PE154 allows for the histochemical staining of cortical Abeta plaques in triple-transgenic (TTG) mice with age-dependent beta-amyloidosis and tau hyperphosphorylation, an established animal model for aspects of AD. In the present study, we have primarily demonstrated the targeting of Abeta-immunopositive plaques with PE154 in vivo for 4 h up to 1 week after injection into the hippocampi of 13-20-month-old TTG mice. Numerous plaques, double-stained for PE154 and Abeta-immunoreactivity, were revealed by confocal laser-scanning microscopy. Additionally, PE154 targeted hippocampal Abeta deposits in aged TTG mice after injection of carboxylated polyglycidylmethacrylate nanoparticles delivering the fluorescent marker in vivo. Furthermore, biodegradable core-shell polystyrene/polybutylcyanoacrylate nanoparticles were found to be suitable, alternative vehicles for PE154 as a useful in vivo label of Abeta. Moreover, we were able to demonstrate that PE154 targeted Abeta, but neither phospho-tau nor reactive astrocytes surrounding the plaques. In conclusion, nanoparticles appear as versatile carriers of AChE inhibitors and other promising drugs for the treatment of AD.

Einleitung: Das kurative Potenzial von zelltherapeutischen Ansätzen auf Basis von Knochenmark konnte in der Vergangenheit bereits wiederholt demonstriert werden. Die Überführung präklinischer Befunde in den klinischen Einsatz erfordert jedoch praxisnahe Großtiermodelle, die idealerweise näher an der Situation menschlicher Schlaganfallpatienten stehen als Rattenmodelle. In unserer Studie untersuchten wir den Einfluss der Gabe autologer mononukleärer Zellen des Knochenmarks 24 Stunden nach experimentellem Schlaganfall, ausgelöst durch permanenten Verschluss der mittleren Hirnarterie, in einem eigens entwickelten Schafmodell.

For the delivery of drugs into the brain, the use of nanoparticles as carriers has been described as a promising approach. Here, we prepared nanoparticles as carriers for the model drugs thioflavin T and thioflavin S that bind fibrillar amyloid β peptides (Aβ). These polymer colloids are composed of a polystyrene core and a degradable PBCA [poly(butyl-2-cyanoacrylate)] shell with a diameter of 90–100nm as shown by dynamic light scattering. Fluorescence spectrophotometric analysis revealed that encapsulated thioflavin T exhibited significantly stronger fluorescence than the free fluorophore. The enzymatic degradation of core-shell nanoparticles, as required in vivo, was shown after their treatment with porcine liver esterase, a non-specific esterase, in vitro. Shells of nanoparticles were dose-dependently degraded while their polystyrene cores remained intact. In the cortices of 7–14 months old APP/PS1 mice with age-dependent β-amyloidosis, thioflavins selectively targeted fibrillar Aβ after biodegradation-induced release from their nanoparticulate carriers upon intracerebral injection. Collectively, our data suggest that core-shell nanoparticles with controlled degradation in vivo can become versatile tools to trace and clear Aβ in the brain.