Clinical and volumetric changes with increasing functional impairment in familial frontotemporal lobar degeneration

Abstract

IntroductionThe Advancing Research and Treatment in Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects longitudinal studies were designed to describe the natural history of familial‐frontotemporal lobar degeneration due to autosomal dominant mutations.MethodsWe examined cognitive performance, behavioral ratings, and brain volumes from the first time point in 320 MAPT, GRN, and C9orf72 family members, including 102 non–mutation carriers, 103 asymptomatic carriers, 43 mildly/questionably symptomatic carriers, and 72 carriers with dementia.ResultsAsymptomatic carriers showed similar scores on all clinical measures compared with noncarriers but reduced frontal and temporal volumes. Those with mild/questionable impairment showed decreased verbal recall, fluency, and Trail Making Test performance and impaired mood and self‐monitoring. Dementia was associated with impairment in all measures. All MAPT carriers with dementia showed temporal atrophy, but otherwise, there was no single cognitive test or brain region that was abnormal in all subjects.DiscussionImaging changes appear to precede clinical changes in familial‐frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals.

Brain volumetric deficits in MAPT mutation carriers: a multisite study

“…Our results showed that in all MAPT carriers combined, poorer memory performance was correlated with lower hippocampal volumes. Although hippocampal atrophy has been reported in MAPT , 2,3,6,8,17,36,38 to our knowledge, previous studies have not directly correlated memory performance with hippocampal volume in MAPT mutation carriers. The hippocampus is well‐established for its importance in episodic memory 19,20 and our results support that this structure underlies the memory impairment in MAPT .…”

“…Although mean group w‐maps did not identify regions of low matter in presymptomatic carriers, frequency w‐maps revealed that 20% of this group had low mesial temporal volume. While early studies suggested that gray matter abnormalities were undetectable in presymptomatic MAPT mutation carriers, 4,5 recent larger studies suggested that presymptomatic carriers have low hippocampal and amygdalar volumes 6,8,17,38 . Several potential explanations may account for these varied results.…”

“…We created group mean w‐maps for 1) presymptomatic and 2) symptomatic carriers by averaging participants’ w‐scores voxelwise and thresholded the maps at w≤‐2 16,17 . To create frequency gray and white matter w‐maps, we determined the percentage of participants with gray or white matter values of w≤‐2 voxelwise.…”

Rates of Brain Atrophy Across Disease Stages in Familial Frontotemporal Dementia Associated With MAPT, GRN, and C9orf72 Pathogenic Variants

“…Pathogenic variants in each of these genes are associated with overlapping but unique clinical and neuroimaging manifestations. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 …”

“…Many studies have used brain atrophy to describe the evolution of neurodegeneration in f-FTLD, yielding the following observations: (1) cross-sectional atrophy can be detected in the presymptomatic stages, and each genetic group has different regional predilection for atrophy 3 , 6 , 8 , 12 , 13 , 14 ; (2) atrophy rates in the presymptomatic stages may exceed those of age-matched control cases 5 , 15 , 16 ; (3) the rate of volume loss may accelerate near the transition from asymptomatic to symptomatic 5 , 13 ; and (4) volume loss in symptomatic cases is usually well in excess of that in control cases. 16 , 17 , 18 However, conclusions from these observations are tempered because many analyses focused only on 1 genetic group or disease stage, limiting comparisons across genes and stages.…”