Characteristics of Neural Network Changes in Normal Aging and Early Dementia.

Hirohisa Watanabe,Aya Ogura,Masahisa Katsuno,Gen Sobue,Epifanio Bagarinao,Kazuhiro Hara,Sayuri Shima,Kazuya Kawabata,Mizuki Ito,Reiko Ohdake,Satoshi Maesawa,Yasuaki Mizutani,Akihiro Ueda

doi:10.3389/fnagi.2021.747359

Abstract

To understand the mechanisms underlying preserved and impaired cognitive function in healthy aging and dementia, respectively, the spatial relationships of brain networks and mechanisms of their resilience should be understood. The hub regions of the brain, such as the multisensory integration and default mode networks, are critical for within- and between-network communication, remain well-preserved during aging, and play an essential role in compensatory processes. On the other hand, these brain hubs are the preferred sites for lesions in neurodegenerative dementias, such as Alzheimer’s disease. Disrupted primary information processing networks, such as the auditory, visual, and sensorimotor networks, may lead to overactivity of the multisensory integration networks and accumulation of pathological proteins that cause dementia. At the cellular level, the brain hub regions contain many synapses and require a large amount of energy. These regions are rich in ATP-related gene expression and had high glucose metabolism as demonstrated on positron emission tomography (PET). Importantly, the number and function of mitochondria, which are the center of ATP production, decline by about 8% every 10 years. Dementia patients often have dysfunction of the ubiquitin-proteasome and autophagy-lysosome systems, which require large amounts of ATP. If there is low energy supply but the demand is high, the risk of disease can be high. Imbalance between energy supply and demand may cause accumulation of pathological proteins and play an important role in the development of dementia. This energy imbalance may explain why brain hub regions are vulnerable to damage in different dementias. Here, we review (1) the characteristics of gray matter network, white matter network, and resting state functional network changes related to resilience in healthy aging, (2) the mode of resting state functional network disruption in neurodegenerative dementia, and (3) the cellular mechanisms associated with the disruption.

Highlights

Patients with dementia have limitations in activities of daily living due to impaired memory, language comprehension, executive function, visuospatial function, and judgment
Using fixel-based analysis (FBA), we examined the relationships between age and FBA parameters, such as fiber density (FD), fiber cross-section (FC), and the combined measure of fiber density and cross section called FDC (FD × FC), in 293 healthy participants aged 21–86 years (Choy et al, 2020)
We further evaluated whether connectivity measures associated with resting-state functional networks or age affects the Addenbrooke’s Cognitive Examination-Revised (ACE-R) scores, using mediation analysis, and observed that changes in a resting-state functional network had a stronger influence on ACE-R scores compared to age

Summary

INTRODUCTION

Patients with dementia have limitations in activities of daily living due to impaired memory, language comprehension, executive function, visuospatial function, and judgment. A more recent study identified white matter-associated microglia, which form in a TREM2-dependent but APOE-independent manner in aging white matter, where they form nodules that are engaged in phagocytosing damaged myelin (Safaiyan et al, 2021) These findings suggest that there are dynamic changes in the white matter of the brain that regenerate and manage degenerated myelin during aging, which may be associated with healthy cognitive function and toward disease progression. Accumulation of damaged mitochondria is a universal feature of aging, and increased oxidative damage to mtDNA, mitochondrial lipids, and proteins correlates with the accumulation of dysfunctional, damaged organelles (Mecocci et al, 1993; López-Otín et al, 2013) These sequence of events can be most likely to affect neurons in the cortex, hippocampus, and basal ganglia, which have long unmyelinated axons, numerous synaptic connections, and high energy metabolism (Camandola and Mattson, 2017; Mattson and Arumugam, 2018; Vandoorne et al, 2018; Diederich et al, 2019). Treatment with febuxostat and inosine increased blood hypoxanthine and ATP in healthy adults, and a preliminary trial in 30 patients with Parkinson’s disease demonstrated symptomatic improvement (Watanabe et al, 2020)

LIMITATIONS AND FUTURE

Findings

CONCLUSION