TDP-43-associated atrophy in brains with and without frontotemporal lobar degeneration

Abstract

Transactive response DNA-binding protein of ∼43 kDa (TDP-43), a primary pathologic substrate in tau-negative frontotemporal lobar degeneration (FTLD), is also often found in the brains of elderly individuals without FTLD and is a key player in the process of neurodegeneration in brains with and without FTLD. It is unknown how rates and trajectories of TDP-43-associated brain atrophy compare between these two groups. Additionally, non-FTLD TDP-43 inclusions are not homogeneous and can be divided into two morphologic types: type-α and neurofibrillary tangle-associated type-β. Therefore, we explored whether neurodegeneration also varies due to the morphologic type. In this longitudinal retrospective study of 293 patients with 843 MRI scans spanning over ∼10 years, we used a Bayesian hierarchical linear model to quantify similarities and differences between the non-FTLD TDP-43 (type-α/type-β) and FTLD-TDP (n = 68) in both regional volume at various timepoints before death and annualized rate of atrophy. Since Alzheimer's disease (AD) is a frequent co-pathology in non-FTLD TDP-43, we further divided types α/β based on presence/absence of intermediate-high likelihood AD: AD-TDP type-β (n = 90), AD-TDP type-α (n = 104), and Pure-TDP (n = 31, all type-α). FTLD-TDP was associated with faster atrophy rates in the inferior temporal lobe and temporal pole compared to all non-FTLD TDP-43 groups. The atrophy rate in the frontal lobe was modulated by age with younger FTLD-TDP having the fastest rates. Older FTLD-TDP showed a limbic predominant pattern of neurodegeneration. AD-TDP type-α showed faster rates of hippocampal atrophy and smaller volumes of amygdala, temporal pole, and inferior temporal lobe compared to AD-TDP type-β. Pure-TDP was associated with slowest rates and less atrophy in all brain regions. The results suggest that there are differences and similarities in longitudinal brain volume loss between FTLD-TDP and non-FTLD TDP-43. Within FTLD-TDP age plays a role in which brain regions are the most affected. Additionally, brain atrophy regional rates also vary by non-FTLD TDP-43 type.

Keywords: Alzheimer’s disease; LATE; MRI; Old age FTLD; TDP-43.

Fig. 1

Forest plot showing estimates and 90% confidence intervals for longitudinal effects on estimated annualized change in brain volume of patients with TDP-43 compared to healthy controls. Forest plots that do not cross grey line at 0 represent evidence of a nonzero rate of atrophy posterior probability > 0.90).

Fig. 2

Fitted curves showing the relationship between rates of atrophy and regional volumes on the time continuum for the TDP-43 pathologic groups. Covariates are set to reference levels showing the fits for an 85-year-old-at-death female with vascular score 0 and LBD score 0 on a 1.5 T MRI, except for 65-yo FTLD group. Fits are showing rate-volume relationship 10 years prior to death in all groups besides AD-TDP type α where sufficient data are available at 15 years prior to death. Shaded in grey fitted curves for −15 to −10 time period reflect scarce data.

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