Executive Function Deficits in Genetic Frontotemporal Dementia: Results From the GENFI Study

Area of Science:

• Neuroscience
• Genetics
• Cognitive Psychology

Background:

• Executive dysfunction is a hallmark of frontotemporal dementia (FTD).
• Research on executive function impairments in familial FTD is limited compared to sporadic forms.
• Understanding genetic influences on FTD subtypes is crucial for targeted interventions.

Purpose of the Study:

• To investigate executive function differences in carriers of C9orf72, GRN, and MAPT mutations.
• To compare cognitive performance across asymptomatic, prodromal, and symptomatic stages of familial FTD.
• To correlate executive function deficits with disease severity and neuroanatomy.

Main Methods:

• Recruited 752 individuals: 214 C9orf72, 205 GRN, 86 MAPT mutation carriers, and 247 controls.
• Assessed attention and executive function using standardized neuropsychological tests (WMS-R DSB, WAIS-R Digit Symbol, TMT A/B, D-KEFS Color Word Interference).
• Employed linear regression with bootstrapping and correlation analyses to evaluate group differences, disease severity correlations, and neuroanatomical correlates.

Main Results:

• Symptomatic carriers of C9orf72, GRN, and MAPT mutations showed significant impairments across most tasks compared to controls (p < 0.001).
• Asymptomatic and prodromal C9orf72 carriers exhibited differences, while GRN and MAPT carriers in these stages did not show significant deficits.
• All assessed tasks significantly correlated with disease severity in all genetic groups (p < 0.001).

Conclusions:

• C9orf72 mutation carriers may experience executive function difficulties early in the disease, worsening with severity.
• GRN and MAPT mutation carriers tend to develop executive function impairments in later disease stages.
• Differential cognitive profiles across familial FTD genetic subtypes necessitate tailored neuropsychological assessments for clinical trials.