Neurocognitive patterns across genetic levels in behavioral variant frontotemporal dementia: a multiple single cases...

Area of Science:

• Neuroscience
• Genetics
• Neurology

Background:

• Behavioral variant frontotemporal dementia (bvFTD) is linked to various genetic factors, but the impact of different genetic levels on clinical and neurocognitive phenotypes remains unclear.
• Phenotypic heterogeneity in bvFTD necessitates understanding how genetic mutations, risk variants, and sporadic cases influence disease presentation, especially in underrepresented populations.
• Colombian patients with bvFTD represent an understudied cohort for investigating genetic influences on disease characteristics.

Purpose of the Study:

• To systematically compare cognitive, neuropsychiatric, and brain atrophy patterns in Colombian FTD patients across different genetic levels: genetic mutations (GR1), risk variants (GR2), and sporadic cases (GR3).
• To investigate the overlap between gene expression and brain atrophy in genetically influenced FTD (G-FTD) patients.
• To elucidate the specific impact of genetic factors on the clinical heterogeneity of bvFTD in a novel cohort.

Main Methods:

• A multiple single-case study design was employed on a cohort of 42 FTD patients from Colombia.
• Patients were categorized into three genetic groups: GR1 (known genetic mutations in MAPT, TARDBP, TREM2), GR2 (FTD-associated risk variants like tau H1/H2 and APOE variants), and GR3 (sporadic FTD).
• Comparisons included cognitive assessments, neuropsychiatric evaluations, brain imaging for atrophy, and gene expression-atrophy overlap analysis.

Main Results:

• Patients with genetic mutations (GR1) and risk variants (GR2) showed earlier disease onset, broader cognitive deficits, and greater brain atrophy (prefrontal, cingulate, basal ganglia, inferior temporal) compared to sporadic cases (GR3).
• Neuropsychiatric symptoms were prominent in GR1 patients, who also exhibited more severe clinical and neurocognitive compromise than GR2 patients, though onset and duration did not differ between these two groups.
• APOE and tau-related genetic groups displayed increased neuropsychiatric symptoms and parietal/temporal atrophy compared to other GR1 patients. Gene-atrophy overlap analysis revealed atrophy in regions with specific genetic overexpression across all G-FTD groups.

Conclusions:

• Distinct genetic levels significantly influence the clinical, neurocognitive, and to some extent, neuropsychiatric presentation of bvFTD in this underrepresented Colombian sample.
• The findings support the existence of genotype-phenotype correlations in bvFTD, highlighting the importance of genetic stratification.
• Tailored diagnostic and characterization strategies for bvFTD should consider the identified parallels between genetic levels and neurocognitive profiles.