Altered functional connectivity in asymptomatic MAPT subjects: a comparison to bvFTD

Abstract

Objective: To determine whether functional connectivity is altered in subjects with mutations in the microtubule associated protein tau (MAPT) gene who were asymptomatic but were destined to develop dementia, and to compare these findings to those in subjects with behavioral variant frontotemporal dementia (bvFTD).

Methods: In this case-control study, we identified 8 asymptomatic subjects with mutations in MAPT and 8 controls who screened negative for mutations in MAPT. Twenty-one subjects with a clinical diagnosis of bvFTD were also identified and matched to 21 controls. All subjects had resting-state fMRI. In-phase functional connectivity was assessed between a precuneus seed in the default mode network (DMN) and a fronto-insular cortex seed in the salience network, and the rest of the brain. Atlas-based parcellation was used to assess functional connectivity and gray matter volume across specific regions of interest.

Results: The asymptomatic MAPT subjects and subjects with bvFTD showed altered functional connectivity in the DMN, with reduced in-phase connectivity in lateral temporal lobes and medial prefrontal cortex, compared to controls. Increased in-phase connectivity was also observed in both groups in the medial parietal lobe. Only the bvFTD group showed altered functional connectivity in the salience network, with reduced connectivity in the fronto-insular cortex and anterior cingulate. Gray matter loss was observed across temporal, frontal, and parietal regions in bvFTD, but not in the asymptomatic MAPT subjects.

Conclusions: Functional connectivity in the DMN is altered in MAPT subjects before the occurrence of both atrophy and clinical symptoms, suggesting that changes in functional connectivity are early features of the disease.

Figure 1. Resting-state fMRI results from the default mode network seed-based analysis of the precuneus

The top row shows the results for the asymptomatic MAPT subjects and the MAPT controls, while the bottom row shows the results for the subjects with behavioral variant frontotemporal dementia (bvFTD) and the bvFTD controls. Left: Patterns of in-phase voxelwise connectivity observed in control subjects. Middle: Patterns of in-phase voxelwise connectivity observed in the disease groups. Right: Patterns of reduced (shown in blue) and increased (shown in yellow) in-phase connectivity in the disease groups compared to the age-matched controls. Results are shown after cluster-level correction for multiple comparisons at p < 0.05.

Figure 2. Box plots showing the distribution of mean functional connectivity (FC) and total intracranial volume–corrected gray matter (GM) volumes for the 4 regions of interest

Data are plotted separately for each of the 4 subject groups. Partial residuals from the analysis of covariance model are plotted. The value on the y-axis can be interpreted as the observed value minus what would be expected under the model given the subject's age. The boxes indicate the 25th, 50th (median), and 75th percentiles of the distributions while the horizontal lines extending from the boxes stop at the most extreme data points. The p values indicate the significance of differences between the asymptomatic MAPT subjects and their age-matched controls, and between the subjects with behavioral variant frontotemporal dementia (bvFTD) and their age-matched controls, using the Wilcoxon rank sum test. Four of the subjects with bvFTD had mutations in MAPT (shown in red).

Figure 3. Resting-state fMRI results from the Salience network seed-based analysis of the fronto-insular cortex

Results are shown only for the behavioral variant frontotemporal dementia (bvFTD) comparisons, since no significant changes in functional connectivity were observed in the asymptomatic MAPT subjects. Left: Patterns of in-phase voxelwise connectivity observed in the bvFTD control subjects. Middle: Patterns of in-phase voxelwise connectivity observed in the subjects with bvFTD. Right: Patterns of reduced (shown in blue) and increased (shown in yellow) in-phase connectivity in the subjects with bvFTD compared to the age-matched controls. Results are shown after cluster-level correction for multiple comparisons at p < 0.05.

Figure 4. Patterns of gray matter loss in the asymptomatic MAPT subjects and the subjects with behavioral variant frontotemporal dementia (bvFTD) when compared to their age-matched controls

Results are shown on 3-dimensional renderings of the brain after correction for multiple comparisons using the false discovery rate at p < 0.0005.