Localized Amyloidosis and Alzheimer's Disease: The Rationale for Weekly Long-Term Low Dose Amyloid-Based Fractionated Radiotherapy

Abstract

Amyloidosis, a plasma cell dyschrasia, is characterized by accumulation in the intercellular spaces of fibrillar proteins with a typical beta-sheet pattern. Vascular-cerebral amyloidosis is the hallmark of Alzheimer's disease and spongiform encephalopathy (Creutzfeldt-Jacob and the like). Current treatment of primary systemic amyloidosis is neither free from complications nor - in some presentations - a mortality rate. Localized tracheo-bronchial amyloidosis (TBA) has been successfully treated with high energy beams of radiation (20 Gy in 10×200 cGy in two weeks). The CT response to radiation takes several months after completion of treatment. As 20 Gy in two weeks are followed by inflammatory reactions, this dosage cannot be suggested in the treatment of amyloidotic radiosensitive organs (e.g. kidneys, liver), or in the hypothetical treatment of Alzheimer's disease. On the basis of the following points: 1) plasma cells in amyloid deposits are not numerous; 2) plasma cells are radioresistant, both in vitro and in vivo (radiotherapy of solitary plasmocytoma); 3) the effects of radiotherapy (20 Gy/2 w) on TBA localizations cannot be exclusively due to plasma cell killing, this study postulates a biophysical mechanism of radiation-induced H-bond breaks in the beta-sheet structure of amyloid, together with depolymerization of glucosaminoglycans, very radiosensitive molecules invariably associated with amyloid fibrils. As both biophysical effects are DNA-independent, the adoption of a definite time/dose ratio (e.g. 20 Gy/2 w) loses much of its importance. Therefore an innovative alternative might be a weekly long-term low-dose fractionated radiotherapy, matching the very slow response of amyloid to radiation. Before being applied to Alzheimer's disease, the proposed radiotherapy (RT) schedule should be tried in TBA patients to compare the new results of long-term fractionated RT with the old results of 20 Gy/2 w. Should long-term fractionated RT prove equally (or almost equally) effective, but certainly much less toxic than 20 Gy/2 w, its application to Alzheimer patients might become an effective and safe treatment, provided clinical and objective control by means of current imaging techniques (MRI, PET) can be assured.