Capture enhanced neutron irradiation for the treatment of the Alzheimer Disease: Micro-nanodosimetric characterization of beta amyloid peptide samples

Abstract

Alzheimer Disease (AD) is the most common cause of dementia. 46.8 million people live with AD worldwide, with numbers projected to almost double every 20 years. The etiological mechanisms underlying the neuropathological changes in AD remain unclear. The beta amyloid peptide Aβ is considered to be the main culprit of the pathological processes. NECTAR (NEutron Capture-enhanced Treatment of neurotoxic Amyloid aggRegates) project proposes an alternative and revolutionary strategy to address AD, investigating the safety, feasibility and effectiveness of a Capture-Enhanced Neutron Irradiation to structurally damage Aβ aggregates, by exploiting capture agent vectors containing B-10 and Gd-157.Among many others, one of the goals of the project is to perform calculations and measurements of microdosimetric and nanodosimetric quantities to characterize the effect of reaction products at local level and to link it to the fibrils depolymerization process. In this framework, a new low-pressure tissue-equivalent proportional counter (TEPC) was designed and developed. The system is a wall-free TEPC able to measure micro-nanometric dose deposition for different biological samples. It is characterized by two main features: i) a wall-less structure allows the charged particles produced by the sample to access the sensitive volume, where their effects are studied; ii) a trigger system enables the assessment of the number of ionizations induced in the sensitive volume related to a single primary particle for obtaining nandosimetric information.The prototype system was tested in the PGNAA (Prompt Gamma Neutron Activation Analysis) facility of the LENA reactor (Pavia) to directly study secondary particles from Aβ fibrils, loaded with Boron. Results of the micro-nanodosimetric characterization of high LET secondaries from Aβ-fibrils were compared to a reference Boron sample. For a 500 nm simulated site size, the presence of Boron in the Aβ sample greatly populates microdosimetric spectra at high lineal energy values. Instead, lower LET particles (photons, protons) from reactions on the other Aβ aggregate solution molecules populate the low lineal energy portion of the distribution.The nanodosimetric distributions highlights the presence of different field components on the nanodosimetric spectra: low LET particles (protons/electrons) produce small ionization clusters, while alpha and Lithium ions induce larger clusters, thus have a higher biological effect. The nanodosimetric measurements have been compared with Monte Carlo simulations performed with a track-structure code, showing a good agreement.This multi-level approach provides a deeper physical understanding of the mixed secondaries field coming from B-enriched target, as well as a reference for the biological effect on Aβ fibrils at nanometer level. These preliminary measurements represent the first microdosimetric and nanodosimetric characterization of the secondary mixed field directly emitted by a biological sample irradiated with neutrons.