Changes of plasma Aβ and t-tau along with 18F-florbetapir PET in a cohort of cognitive decline

Background Blood based biomarkers for Alzheimer’s disease (AD) are becoming increasingly promising. Although plasma amyloid-β (Aβ) and total tau (t-tau) showed a potential ability in identifying cerebral amyloid deposition and AD. Comparisons of these plasma biomarkers along with Aβ-PET in a cohort of normal controls (NC), subjective cognitive decline (SCD), objectively-defined subtle cognitive decline (Obj-SCD), mild cognitive impairment (MCI) and AD remained lacking. Methods A total of 407 individuals aged from 40 to 90 years old were recruited, including 76 of NC, 77 of SCD, 61 of obj-SCD, 92 of MCI and 101 of AD. Plasma Aβ40, Aβ42 and t-tau were examined via single-molecule array (Simoa) immunoassay. A subset of 132 individuals underwent cerebral amyloid scans with 18F-florbetapir PET. Comparisons of plasma t-tau, Aβ40, Aβ42 and Aβ42/Aβ40 ratio were conducted between different diagnostic groups and cerebral Aβ burdens. Pearson correlation analysis was used to evaluate the correlation between Aβ42, Aβ42/Aβ40 ratio and 18F-florbetapir SUVR. Receiver operating characteristic (ROC) curve analyses were carried out to evaluate the capacity of plasma biomarkers in identifying high brain Aβ burden and diagnosis of AD. Results Plasma Aβ42 was significantly higher in SCD and obj-SCD than NC, MCI and AD. Plasma Aβ40 was significantly higher in SCD and obj-SCD than NC and AD. The lowest levels of plasma Aβ42 and Aβ42/Aβ40 ratio were found in AD. No significant difference of plasma t-tau was found among groups. Plasma Aβ42 and Aβ42/Aβ40 ratio were inversely correlated with 18F-florbetapir SUVR (r=-0.272, P = 0.003; r=-0.211, P = 0.021 respectively). Aβ42/Aβ40 ratio performed well in predicting high brain Aβ burden (area under the curve, AUC = 0.762). Plasma Aβ42 and Aβ42/Aβ40 ratio had acceptable diagnostic accuracy for AD (AUC = 0.714 and 0.706 respectively), even in Aβ-PET (+) individuals (AUC = 0.728 and 0.808 respectively). Conclusions Plasma Aβ40 and Aβ42 measured by Simoa immunoassay showed a significantly bidirectional trend of initially increasing from NC to SCD and obj-SCD, and then declining to MCI and AD. In addition, plasma Aβ was significantly correlated with 18F-florbetapir PET SUVR and showed potential value in predicting cerebral Aβ deposition and risk of AD.

Discovery of HBW-3-20, the first potent reversible inhibitor of Bruton’s tyrosine kinase (BTK) with high brain exposure.

e15068 Background: It has been an on-demand task to develop a BTK inhibitor of significant brain exposure, a critical property for extending its usages to treat Primary Central Nervous System Lymphoma (PCNSL) and autoimmune disorders. PCNSL is an aggressive extra nodal non-Hodgkin lymphoma that exclusively invades the central nervous system (CNS). Tirabrutinib, an irreversible BTK inhibitor with limited brain exposure, is the first BTK inhibitor approved for the treatment of recurrent or refractory primary central nervous system lymphoma recently. PRN2246 is another irreversible BTK inhibitor claimed to be of brain exposure, and is currently in clinical trials for the treatment of multiple sclerosis. Methods: New reversible BTK inhibitors were designed, synthesized and tested for enzymatic activities against wild-type and C481S-mutated BTK. Highly active compounds were confirmed for growth effects in diffuse large B-cell lymphoma derived TMD8 cells. Their microsomal stability and ADME properties were also assessed. Potent and bioavailable compounds were further measured for brain exposures in rats. Results: HBW-3-20 has excellent potency against both wild-type and C481S-mutated BTK, with IC50 of 2.5 and 3.8 nM, respectively. Its TMD8 cellular potency is 72 nM. In a head-to-head direct comparison of brain exposure experiment, HBW-3-20, tirabrutinib and PRN2246 were all dosed at 10mg/kg orally. The brain and plasma concentration were measured after 1 hour and the data are shown in the table below. The brain to plasma ratio for HBW-3-20, tirabrutinib and PRN2246 are 58%, 11.8% and 4.2% respectively. Our results show that HBW-3-20 has much greater brain permeability than tirabrutinib or PRN2246 in rats. Conclusions: HBW-3-20 is the first potent reversible BTK inhibitor that shows promisingly high brain permeability. HBW-3-20 provides a very valuable clinical candidate for treating B-cell malignancies in brain and autoimmune disorders![Table: see text]

Synthesis and pharmacological evaluation of [18F]PBR316: a novel PET ligand targeting the translocator protein 18 kDa (TSPO) with low binding sensitivity to human single nucleotide polymorphism rs6971

PBR316 has high brain uptake, biodistribution consistent with TSPO expression and is insensitive to rs6971 polymorphism with a LAB:HAB ratio of 1.5. It can be prepared in >99% radiochemical purity, 160–400 GBq μmol−1 and >98.5% stability after 4 h.

Nanoparticle size and chemical modification play a crucial role in the interaction of nano gold with the brain: extent of accumulation and toxicity

Short Mph-GNR show high brain accumulation percentage, while long GNR show low brain accumulation and high delivery into other organs.