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.

Characterizing the Clinical Features and Atrophy Patterns of MAPT -Related Frontotemporal Dementia With Disease Progression Modeling

“…SuStaIn identified a strong relationship between P301L mutations and assignment to the frontotemporal subtype, with nine out of ten subtypable P301L mutation carriers being assigned to the frontotemporal subtype. This is in agreement with the results of Whitwell et al 7 and Chu et al 14 , who also identified P301L mutation carriers as having a different atrophy pattern to those with intronic mutations. Interestingly, individuals assigned to the frontotemporal subtype all had mutations occurring earlier in the MAPT gene (L266V and G272V, both in exon 9, and P301L in exon 10), suggesting a possible relationship between location in the MAPT gene and atrophy pattern.…”

“…Both subtypes have early volume loss in the anterior insula and lateral temporal lobe, but in the early stages of the temporal subtype, this atrophy is more widespread across other temporal lobe regions, including the hippocampus and amygdala, as well as the posterior insula, while in the early stages of the frontotemporal subtype there is additional atrophy in frontal regions. Our findings are broadly in agreement with the patterns identified in the studies by Whitwell et al 7 and Chu et al, 14 but account for variability in disease stage across individuals and use a larger sample size. Using SuStaIn, we are able to automatically group the mutations and reconstruct the full progression of atrophy including very early stages, which we can identify in presymptomatic individuals.…”

“…Our findings are broadly in agreement with the patterns identified in the prior studies by Whitwell et al 7 and Chu et al 14 , but account for variability in disease stage across individuals and use a larger sample size. Importantly, using SuStaIn we are able to automatically group the mutations and reconstruct the full progression of atrophy including very early stages, which we can identify in presymptomatic individuals.…”

Acetylcholine Muscarinic Receptors in Ventral Hippocampus Modulate Stress-Induced Anxiety-Like Behaviors in Mice

“…This is consistent with the previous finding that in the dorsal CA1 region of the hippocampus, ACh released from cholinergic fibers modulates hippocampal synaptic plasticity through the postsynaptic M1 mAChR activation (Shinoe et al, 2005). Our in vivo data show that transient restraint stress induces ACh release in vHPC ( Figure 2); this is consistent with previous studies showing that stress increases ACh level in the hippocampus (Mark et al, 1996;Dong et al, 2004). Furthermore, pharmacological and molecular genetic decreases in hippocampal AChE activity increased anxiety-like behaviors (Mineur et al, 2013;Fernandes et al, 2018).…”

“…Unbalanced ACh levels in the hippocampus cause abnormal emotional behaviors (Mineur et al, 2013). Inescapable stress can elevate ACh levels in the hippocampus (Mark et al, 1996). Increased ACh levels by inhibiting acetylcholinesterase (AChE) in the hippocampus of mice induce anxiety-like and depression-like behaviors (Mineur et al, 2013).…”