Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a quite hot topic these days among those who are concerned with dementia, memory deficits and neurodegenerative diseases.
It has been suggested that LATE is distinguished from frontotemporal lobar degeneration (FTLD) with TDP-43 pathology based on its epidemiology.
What do you think about this newly recognized disease?
Any idea about the potential or promising diagnostic approaches?
Possible future biomarkers and mechanisms...
Source: https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awz099/5481202
Bahman,
Thanks for sharing.
Regarding, potential biomarkers, the paper that you mentioned addresses them: Optimal biomarkers for LATE, including biofluids or PET ligands, would be specific for the disease-defining feature, namely TDP-43 proteinopathy (Steinacker et al., 2018). At this time, no biofluid or PET biomarker satisfies this essential criterion of molecular specificity. Nor do PET ligands for LATE seem to be on the near-term horizon. The problems of intracellular location and small pathological burden of TDP-43 proteinopathy are obstacles that limit signal-to-noise ratio for biomarkers.
Thanks Donna.
Yes, I know that the paper has proposed those biomarkers as potential ones. But as you know LATE is a recently recognized disease that has been mistaken with AD or FTLD before. Thus, I linked to the original article to open a discussion for those who would like to present their ideas as alternative possibilities for this newly found but yet unknown disease.
Interestingly you quoted a part of the paper that I provided the link that directly states that the obstacles that limit SNR for proposed biomarker and thus make them less reliable.
Of course, further basic and clinical studies should be performed on animals to safely shift to human trials but what is interesting here in this discussion is to see whether there are alternative explanations for such intricate distinctions between LATE and typical TDP-43 proteinopathy.
Imaging as a rather reliable and robust technique had also shown to be still faulty. Yet I think that SPECT as a multi-modal bioimaging approach with specific quantitative imaging biomarkers can be a potential approach, if not a propitious biomarker.
For instance: Could we assume that astrocytic activation marker YKL-40 (chitinase-3-like protein 1) can also be a potential biomarker for LATE since it has been shown that it can be a promising biomarker for FTLD-TDP?...
As far as YLK-40, I’m not sure how specific this will be because I just wrote an article on precision medicine applied to respiratory diseases and YLK-40 is being explored as a biomarker for asthma and COPD.
Also too, I think that we need to look at alternatives to animal
models, especially given species differences and the complexity of the human brain- http://www.altex.ch/resources/altex_2014_3_279_302_Cavanaugh3.pdf
Thanks Donna.
Yes, it has been shown that YLK-40 is also a potential biomarker of ALS as there is an increase in the expression of its gene in ALS cases. This protein seems to be less specific but a robust biomarker also in dementia-like disorders.
(Meanwhile, CHIT1 as a marker of microglial activation has been indicated to be up-regulated in sALS corticospinal tract white matter and to be increased in the CSF compared to other neurodegenerative diseases.)
Anyways, I wonder whether mutations in genes such as C9orf72 and GRN that are underlying TDP-43 neuropathy can also be of significant prognosticators of LATE?
Another propitious biomarker for TDP-43 pathology in C9orf72 mutation carriers is shown by DPR proteins translated from the hexanucleotide repeats.
This also can be a plausible idea to be tested experimentally for LATE as the DPR pathology contributes to the second form of inclusions besides TDP-B-type.
GRN mutations also are common in FTLD cases, and since LATE has been mistaken mostly for FTLD because of congruent symptoms and mechanisms, it is possible that GRN mutations could be potential tracers for LATE too.
Additionally, miRNAs in TDP-FTD can also be considered as pathophysiological markers to be tested or traced in LATE.
There is a nice article in Nature Neuroscience 2019;22:65-77.... "TDP-43 extracted from FTD brains displays distinct aggregate assemblies and neurotoxic effects."
They showed that FTD-TDP type A patients were more likely to manifest signs of behavioral variant FTD, and that FTD-TDP type B patients were more likely to manifest signs of the motor neuron variant of FTD, while the FTD-TDP type C patients showed signs of semantic dementia.
Thanks Linda. This is fascinating!
I wonder whether the DPR pathology, as I mentioned in my last comment, plays a notable role in TDP-A and C types, or this is remarkably a mere indicative of the FTD-induced motoneuron dysfunction?
I think that it is not still incontrovertible to certainly claim that these are the common hallmarks of LATE too. But it is conceivable to hypothesize if such manifestations will be substantiated by experimentation on miRNAs in both LATE and TDP-B-FTD.
It's too bad we have to wait for autopsy to learn about these protein subtypes!
- Badges
- Science topic
- Similar topics
- Geoscience
- Asia
- India