The role of beta-2-microglobulin (B2M) in chemotherapy-induced cognitive dysfunction

Chemobrain

Brain Protection

Cognitive impairment is a common side effect of chemotherapy, affecting up to 75% of treated cancer patients. Symptoms include decreased short-term memory, word-finding problems, limited attention span and difficulty with concentration and multitasking. While most patients' symptoms improve within a year, 10-20% experience long-term effects. Despite its social and economic importance, this phenomenon has not received enough attention for a long time. The underlying neurotoxic mechanism of the "chemobrain" is not fully understood and includes oxidative stress, immune activation, metabolic changes and neuroinflammation. A better understanding could help prevent or mitigate cognitive impairment. B-cell neoplasms such as multiple myeloma (MM) or B-cell non-Hodgkin's lymphoma (B-NHL) exhibit systemic accumulation of β-2-microglobulin (B2M). Our research shows that B2M is taken up by myeloid cells, forms fibrils and activates the inflammasome. At the same time, it promotes neuroinflammation and neurological ageing.
This study investigates whether B2M levels are important factors in cognitive impairment caused by chemotherapy. We will study patients with B-cell derived malignancies undergoing high-dose chemotherapy and stem cell transplantation. Important endpoints include neurocognitive performance, systemic inflammatory markers and advanced imaging findings. Patient observations will be translated to preclinical models to investigate the impact of B2M (+ chemotherapy) on neuroinflammation and microglia activation in particular. As an intervention strategy, mainly neutralising anti-B2M antibodies are tested, which have already been explored in early clinical trials for neurodegenerative diseases.