Thalamo-cortical network hyperconnectivity in preclinical progranulin mutation carriers

Area of Science:

• Neuroscience
• Genetics
• Neurology

Background:

• Progranulin (GRN) gene mutations are associated with diverse neurodegenerative diseases, including frontotemporal dementia, primary progressive aphasia, corticobasal syndrome, and Alzheimer-type dementia.
• Previous human studies indicated reduced salience network connectivity in presymptomatic GRN carriers, while mouse models exhibit thalamo-cortical hypersynchrony.
• A systematic exploration linking human GRN-associated syndromes to intrinsic connectivity networks (ICNs) and bridging human and mouse model findings was lacking.

Purpose of the Study:

• To investigate intrinsic connectivity networks (ICNs) in preclinical progranulin (GRN) mutation carriers.
• To compare connectivity patterns in GRN carriers with healthy controls across networks relevant to GRN-associated dementia syndromes.
• To establish a link between human GRN disease phenotypes and findings in GRN mouse models.

Main Methods:

• Compared 17 preclinical GRN carriers (14 presymptomatic, 3 prodromal) with healthy controls.
• Utilized cognitive testing and gray matter volume assessment.
• Employed task-free functional magnetic resonance imaging (fMRI) to analyze connectivity in the salience, non-fluent variant primary progressive aphasia (nfvPPA), perirolandic (CBS), and default mode (AD-type dementia) networks, alongside whole-brain degree centrality.

Main Results:

• GRN carriers and controls demonstrated comparable cognitive performance and minimal brain atrophy.
• Markedly enhanced connectivity was observed across all four investigated networks in GRN carriers.
• Thalamo-cortical hyperconnectivity emerged as a consistent and unifying feature in GRN carriers, confirmed by voxelwise degree centrality analysis.

Conclusions:

• Human GRN disease and the GRN mouse model share a common thalamo-cortical network hypersynchrony phenotype.
• Enhanced connectivity, particularly thalamo-cortical hyperconnectivity, is an early preclinical manifestation in GRN carriers.
• Longitudinal studies are needed to determine if this observed network physiology is compensatory or an early sign of progranulin haploinsufficiency.