Pathophysiology of dementia from the viewpoint of differences in brain network findings in normal aging and early dementia

Hirohisa Watanabe

Department of Neurology, Fujita Health University, School of Medicine

In neurodegenerative dementia, there is a prolonged period in which people show no abnormal symptoms irrespective of pathological protein accumulation （preclinical phase）.　Some patients may return to the preclinical phase after reaching the mild cognitive impairment phase―furthermore, many “normal cognitive people” who had significant pathological protein accumulation in the brain exist.　However, there is still no clear answer to the fundamental questions of why such clinical manifestations occur and the mechanism that overcomes the pathological protein accumulation.　We found that the human functional brain network had a multi-layered hierarchy of hub regions.　 Dynamic change of the resting state networks with age might be a representative system for maintaining cognitive function and resisting the accumulation of pathological proteins.　On the other hand, the hub region was a common site of lesions in neurodegenerative dementia.　Using a newly developed data-driven and voxel-based detection method for connector hub regions, we found that connector hub regions in the cerebral cortex mainly connected networks related to cognitive functions.　Interestingly, the thalamus and cerebellum also had connector hub regions.　Generally, connector hub regions were believed to require large amounts of energy.　In contrast, age-related mitochondrial dysfunction could associate with an inappropriate energy supply.　The “energy gap” caused by the increased activity of hub regions and decreased energy supply from astrocytes might be a trigger for the acceleration of neurodegenerative processes resulting in dementia.

Address correspondence to Dr. Hirohisa Watanabe, Department of Neurology, Fujita Health University, School of Medicine (1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan)