To compare rates and trajectories of TDP-43-associated atrophy in brains with and without frontotemporal lobar degeneration (FTLD) and to explore whether neurodegeneration also varies by TDP-43 morphologic type.

TDP-43, a primary pathologic substrate in tau-negative FTLD, is often found in the brains of elderly individuals without FTLD and is a key player in the process of neurodegeneration. Non-FTLD TDP-43 inclusions are not homogeneous and can be divided into two morphologic types: type-α and neurofibrillary tangle-associated type-β. Patterns of TDP-43-associated brain atrophy in presence/absence of FTLD or by morphologic subtype are unknown.

In this longitudinal retrospective study of 295 autopsied cases with 2541 MRI scans spanning over decade, we used a Bayesian hierarchical linear model to quantify similarities and differences between non-FTLD TDP-43 (type-α/type-β) and FTLD-TDP (n=68) in 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). This study is funded by NIH grants: R01-AG037491-11, P30-AG062677, U01-AG006786, R35-AG11378, R01-AG041851.

FTLD-TDP was associated with faster atrophy rates in the hippocampus, inferior temporal (IT) and middle frontal cortices, with IT lobe being the region distinguishing FTLD-TDP from non-FTLD groups. The atrophy rate in the frontal lobe was modulated by age with younger FTLD-TDP having the fastest rates. In older FTLD-TDP patients, hippocampus and IT lobe are the main targets for neurodegeneration. Pure-TDP was associated with slowest rates and less atrophy in all brain regions.

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. Brain atrophy regional rates also vary by non-FTLD TDP-43 type.