Longitudinal changes in network homogeneity in presymptomatic C9orf72 mutation carriers

Area of Science:

• Neuroscience
• Genetics
• Neurology

Background:

• C9orf72 repeat expansion mutations increase risk for ALS and FTD.
• Symptomatic carriers show reduced functional connectivity, but the lifelong pattern is unknown.
• Investigating if connectivity decline in carriers accelerates normal aging is crucial.

Purpose of the Study:

• To examine longitudinal changes in functional brain network homogeneity (NeHo) in presymptomatic C9orf72 carriers.
• To compare these changes against healthy controls and symptomatic carriers.
• To determine if observed connectivity changes reflect an accelerated aging process.

Main Methods:

• Functional magnetic resonance imaging (fMRI) was used to assess NeHo in 5 functional networks.
• 15 presymptomatic C9+ carriers were scanned over 18 months.
• Data were compared with 34 healthy controls and 27 symptomatic C9+ carriers.

Main Results:

• Longitudinal NeHo trajectories in somatomotor, dorsal attention, and default mode networks differed between presymptomatic carriers and controls/symptomatic carriers.
• In somatomotor networks, NeHo increased near areas of reduced NeHo in symptomatic carriers.
• The posterior cingulate in the default network showed age-dependent NeHo increases in presymptomatic carriers.

Conclusions:

• The findings challenge the hypothesis that reduced connectivity in symptomatic C9orf72 carriers is a lifelong acceleration of healthy aging.
• Presymptomatic C9orf72 carriers exhibit unique longitudinal brain network changes.
• This suggests distinct pathophysiological processes rather than a simple accelerated aging model.