TDP-43 Cohort and Neuropathology

1

Hi SEA-AD Team,

I have a general question regarding TDP-43 within the cohort and neuropathology data sets. I have made the following observations that I hope to garner more insight on:

On the cohort metadata file, I observed that

  • 56 of 84 donors are classified as either LATE stage 1, 2 or 3
  • 28 of 84 donors are classified as “not identified” or “unclassifiable.”

However, when observing the neuropathology

  • 15 of 84 donors have some TDP-43 pathology
  • 69 of 84 donors have 0 TDP-43 pathology

I recognize that your team mentioned this in your paper.

“pTDP-43 and α-Syn pathologies were detected in the relatively small number of donors with high stage LATE-NC(76) and neocortical LBD, respectivley”.

Questions 1: Am I correctly interpreting the LATE and LATE-NC definitions? I assume they mean limbic-predominant age-related TDP-43 encephalopathy and LATE neuropathological change.

Questions 2: If I am interpreting this correctly, can you assist me in understanding the 69 donors with 0 TDP-43 QNP when 56 donors are classified as LATE?

Thank you so much for your assistance on this SEA-AD Team!

2

Thanks for your question, I spoke with one of our team’s neuropathologists about your questions.

Firstly yes, the definitions you list are correct.

Second, I think the perceived discrepancy is that for the LATE stage, we just need to see an inclusion or two. The quantitative neuropathology (QNP) in the paper just looked at MTG, and most of the donors with LATE have LATE 1 or 2, which means almost all of them will not have TDP-43 in the MTG (we see TDP in that location in some cases with LATE stage 2 and most to all cases with LATE stage 3, which suggests it is a ‘transition region’ in between LATE 2 and 3. MTG itself is not part of standard LATE-staging.