Effect of Increasing Age on Brain Dysfunction in Cirrhosis

Area of Science:

• Neuroscience
• Hepatology
• Gerontology

Background:

• Cirrhosis is increasingly prevalent in older populations.
• Aging may exacerbate cirrhosis-related brain dysfunction beyond hepatic encephalopathy.

Purpose of the Study:

• To investigate the combined effects of aging and cirrhosis on brain inflammation and degeneration.
• To compare human and animal models to understand these neurobiological changes.

Main Methods:

• Human study: Age-matched cirrhotic patients and controls (65-85 years) underwent cognitive testing, QOL assessment, and brain MR spectroscopy/rs-fMRI.
• Animal study: Young and old mice were induced with cirrhosis (CCl4) or vehicle control.
• Analyzed cortical mRNA expression of inflammatory mediators, sirtuin-1, and GABA-ergic synaptic plasticity markers.

Main Results:

• Human patients with cirrhosis showed poorer QOL and cognition, with altered brain ammonia metabolism, reduced N-acetyl aspartate, and frontoparietal functional connectivity changes.
• Older mice developed cirrhosis more readily and exhibited higher cortical inflammation (IL-6, IL-1β, TGF-β), increased glial/microglial activation, and lower sirtuin-1.
• Older cirrhotic mice displayed altered synaptic plasticity, with reduced DLG4 and increased NLG2/GABRG1/B1 expression, suggesting enhanced inhibitory signaling.

Conclusions:

• Aging significantly modulates brain changes associated with cirrhosis, affecting QOL, cognition, and neural connectivity.
• Cortical inflammation, microglial activation, and altered GABA-ergic synaptic plasticity are key contributors to age-related brain dysfunction in cirrhosis.