Cognitive and brain markers in presymptomatic genetic behavioural variant frontotemporal dementia: a case-control study

Abstract

This thesis investigated presymptomatic family members of a kindred carrying the MAPT genetic variant for behavioural variant frontotemporal dementia (bvFTD-MAPT), who are part of the FTDGeNZ study, with the aim of identifying early behavioural, cognitive and neural changes in gene-positive family members. Study one aimed to characterise signs of neuropsychological and behavioural changes in presymptomatic bvFTD-MAPT, with the novel corollary of exploring episodic memory (EM), autobiographical memory (AM) and episodic future thinking (EFT) to determine whether a ‘true’ medial temporal-based memory deficit is an early feature. Using an age-matched case-control design, participants were stratified into ‘younger’ (<40 years old; cases n=3; controls n=9) and ‘older’ (>40 years old; cases n=3; controls n=8) groups. Results highlight heterogeneous patterns of performance across gene-positive cases. Reduced performance emerged in domains of attention and processing speed, and language/semantic capacity. Findings were not consistent enough to indicate EM, AM and EFT were early markers of change, nor did we observe a true medial temporal-based memory deficit. Study two sought to identify the earliest neural changes occurring in presymptomatic bvFTD-MAPT by measuring grey matter volume and cortical thickness in a case-control design, covarying for age (cases n=5; controls n=16). Reductions in regions varied across cases, with more extensive reductions in some cases than others. Volumetric and cortical thickness findings showed the amygdala, insula, inferior/superior temporal gyrus most frequently implicated. Medial temporal lobe changes were not as prominent as predicted. Study three used fMRI to measure neural activity during AM and EFT compared to semantic memory, to determine if differences in activation could be observed in the core network supporting episodic autobiographical thinking in presymptomatic bvFTD-MAPT. Results of this case-control design, covarying for age (cases n=5; controls n=16) showed three of five cases activated a similar spatio-temporal pattern as the control group. The remaining two cases deviated from the control group’s pattern of activation, one showing a compensatory pattern of activation, and the other, dedifferentiation. Combined, the three studies in this thesis present a nuanced examination of the cognitive, behavioural, and neural characteristics of a presymptomatic bvFTD-MAPT kindred, and contribute to understanding the bvFTD-MAPT disease course.