Age and diet modify acute microhemorrhage outcome in the mouse brain

Cerebral microhemorrhages (CMHs) are considered as asymptomatic lesions, but might impair cognition in non-demented elderly individuals. The aging process includes poor vascular health, enhanced at midlife by metabolic disturbances upon high-fat diet (HFD). The onset of CMHs could thus have more serious consequences in midlife subjects with metabolic disturbances. This hypothesis was tested through the induction of multiple CMHs, using cyclodextrin nanoparticles injection, in mice at midlife (14 month old) or at a younger stage (5 month old) after 12 months or 3 months of normal diet or HFD (40% of animal fat) respectively. When induced at 14 months of age, CMHs were not larger but were more numerous (+25%) in mice on HFD compared with mice on normal diet. They slowed down the locomotor activity significantly but caused neither a change in the working memory nor a difference in the visual recognition memory decline. When induced at 5 months of age, CMHs provoked slighter locomotor and cognitive symptoms, regardless the diet. No spontaneous progression of CMHs toward larger hemorrhages was observed after onset when HFD was prolonged up to midlife. Consistently, no precipitated cognitive decline was observed. Middle-age plus time of metabolic disturbances represent enhanced risk factors for CMH outcome.