Brain volumetric deficits in MAPT mutation carriers: a multisite study

Abstract

Objective: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach.

Methods: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers' clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson's disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype.

Results: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers.

Interpretation: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.

Figure 1

Gray and white matter frequency w‐maps grouped by clinical stage. Frequency w‐maps show the percentage of subjects within the group, ranging from 1% (magenta) to 100% of subjects (red), who have low gray or white matter volumes with w≤‐2 in a given voxel. Top row, left: All MAPT mutation carriers within the symptomatic group have anteromesial temporal atrophy. Top row, right: Symptomatic carriers have atrophy in the uncinate fasciculi, corpus callosum, and anterior corona radiata. Bottom row, left: Approximately 20% of presymptomatic MAPT mutation carriers show low gray matter volume in the mesial temporal lobes. Bottom row, right: Few carriers show low white matter volume before symptom onset. All maps are shown on the Montreal Neurological Institute template brain with the left side of the axial and coronal slices corresponding to the left side of the brain.

Figure 2

Gray and white matter frequency w‐maps of presymptomatic carriers grouped by age decade. Gray matter (left) and white matter (right) frequency w‐maps for presymptomatic carriers divided by age decade (rows). Color bar indicates the percentage of subjects within each age decade with low gray or white matter volumes of w≤‐2 in a given voxel. Low mesial temporal lobe volumes arise in about 20% of MAPT mutation carriers as early as their thirties. All maps are shown on the Montreal Neurological Institute template brain with the left side of the axial and coronal slices corresponding to the left side of the brain.

Figure 3

Gray and white matter frequency w‐maps of symptomatic carriers grouped by symptom severity. Gray matter (left) and white matter (right) frequency w‐maps for symptomatic carriers binned by symptom severity, as defined by the CDR® plus NACC FTLD global score (FTLD‐CDR). Color bar indicates the percentage of subjects within each symptom severity category with gray or white matter atrophy of w≤‐2 in a given voxel. Mesial temporal lobe atrophy becomes ubiquitous in those with an FTLD‐CDR score of 1. With worsening severity, atrophy within temporal and frontal lobes, insula and anterior cingulate are increasingly more common and extensive. All maps are shown on the Montreal Neurological Institute template brain with the left side of the axial and coronal slices corresponding to the left side of the brain.

Figure 4

Voxelwise correlations between memory measures and gray matter. Maps show regions where verbal (top row) or spatial (bottom row) memory z‐scores were significantly correlated with regions of low gray matter volume across all MAPT mutation carriers. Lower scores on a verbal memory measure was associated with low volume in bilateral hippocampi and inferior temporal regions. Lower scores on a spatial memory measure was associated with low gray matter in small scattered clusters including the left hippocampus, right middle frontal gyrus, frontal pole, and left dorsal parietal lobe. Maps were thresholded at P < 0.05, corrected for family‐wise error. Color bars show t‐value ranges. All maps are shown on the Montreal Neurological Institute template brain with the left side of the axial and coronal slices corresponding to the left side of the brain.

Figure 5

Atrophy patterns by MAPT mutation subtype —mean w‐maps. Mean w‐maps show the mean w‐score in gray and white matter across all subjects grouped by clinical stage. Rows reflect five different mutation subtype groupings. Frontotemporal atrophy patterns are similar across mutation groups, except for the amnestic type R406W mutation group, which lacks frontal atrophy. Mutation subtypes associated with progressive supranuclear palsy or parkinsonism distinctly show midbrain atrophy for both the symptomatic and presymptomatic groups. The decade of the mean age for each group is indicated rather than the specific mean age in order to protect participant anonymity. Group maps are thresholded from w≤‐13 to −2. All maps are shown on the Montreal Neurological Institute template brain with the left side of the axial and coronal slices corresponding to the left side of the brain. DD: disease duration.