Distinct Neuroanatomical Correlates of Neuropsychiatric Symptoms in the Three Main Forms of Genetic Frontotemporal Dementia in the GENFI Cohort

Abstract

Background: The overlap between frontotemporal dementia (FTD) and primary psychiatric disorders has been brought to light by reports of prominent neuropsychiatric symptoms (NPS) in FTD-related genetic mutations, particularly among C9orf72 and GRN carriers. It has been recently demonstrated that early neuroanatomical changes in genetic FTD may be different across the major disease-causing mutations.

Objective: We aimed to identify whether NPS could be driven by distinct structural correlates.

Methods: One hundred and sixty-seven mutation carriers (75 GRN, 60 C9orf72, and 32 MAPT) were included from the Genetic FTD Initiative (GENFI) study, a large international cohort of genetic FTD. Neuropsychiatric symptoms including delusions, hallucinations (visual, auditory, and tactile), depression, and anxiety were investigated using a structured interview. Voxel-based morphometry was performed to identify neuroanatomical correlates of NPS.

Results: Psychotic symptoms correlated mainly with grey matter (GM) atrophy in the anterior insula, left thalamus, cerebellum, and cortical regions including frontal, parietal, and occipital lobes in GRN mutations carriers. GM atrophy in posterior structures of the default-mode network was associated with anxiety in the GRN group. Delusions in C9orf72 expansion carriers were mainly associated with left frontal cortical atrophy. Cerebellar atrophy was found to be correlated only with anxiety in C9orf72 carriers. NPS in the MAPT group were mainly associated with volume loss in the temporal lobe.

Conclusion: Neuroanatomical correlates of NPS appear to be distinct across the main forms of genetic FTD. Overall, our findings support overlapping brain structural changes between FTD and primary psychiatric disorders.

Keywords: Frontotemporal dementia; genetics; magnetic resonance imaging; neuropsychiatry.

Fig.1

VBM analysis showing areas of significant correlation between the presence and severity of visual hallucinations and GM density across the FTD genetic groups. Statistical parametric maps were thresholded at p < 0.001 uncorrected and rendered on a study-specific T1-weighted MRI template in MNI space. Analyses were adjusted for age, gender, total intracranial volume, and scanner type. The color bar indicates the Z-scores.

Fig.2

VBM analysis showing areas of significant correlation between the presence and severity of auditory hallucinations and GM density across the FTD genetic groups. Statistical parametric maps were thresholded at p < 0.001 uncorrected and rendered on a study-specific T1-weighted MRI template in MNI space. Analyses were adjusted for age, gender, total intracranial volume, and scanner type. The color bar indicates the Z-scores.

Fig.3

VBM analysis showing areas of significant correlation between the presence and severity of tactile hallucinations and GM density across the FTD genetic groups. Statistical parametric maps were thresholded at p < 0.001 uncorrected and rendered on a study-specific T1-weighted MRI template in MNI space. Analyses were adjusted for age, gender, total intracranial volume, and scanner type. The color bar indicates the Z-scores.

Fig.4

VBM analysis showing areas of significant correlation between the presence and severity of delusions and GM density across the FTD genetic groups. Statistical parametric maps were thresholded at p < 0.001 uncorrected and rendered on a study-specific T1-weighted MRI template in MNI space. Analyses were adjusted for age, gender, total intracranial volume, and scanner type. The color bar indicates the Z-scores.

Fig.5

VBM analysis showing areas of significant correlation between the presence and severity of depression and GM density across the FTD genetic groups. Statistical parametric maps were thresholded at p < 0.001 uncorrected and rendered on a study-specific T1-weighted MRI template in MNI space. Analyses were adjusted for age, gender, total intracranial volume, and scanner type. The color bar indicates the Z-scores.

Fig.6

VBM analysis showing areas of significant correlation between the presence and severity of anxiety and GM density across the FTD genetic groups. Statistical parametric maps were thresholded at p < 0.001 uncorrected and rendered on a study-specific T1-weighted MRI template in MNI space. Analyses were adjusted for age, gender, total intracranial volume, and scanner type. The color bar indicates the Z-scores.