HMGB1 and Cognitive impairment: Concurrently, HMGB1 emerges as a risk factor for cognitive impairment in patients with CSVD, as increased levels of HMGB1 promote the activation of microglia, leading to a sustained inflammatory response that disrupts the neurovascular unit and the blood-brain barrier, resulting in neurodegenerative necrosis and ultimately cognitive impairment and cerebral microbleeds (127).