Project Details
Description
PROJECT SUMMARY
The first two cycles of our R01 entitled, “Understanding the role of TDP-43 in Alzheimer's disease and FTLD”
were very successful with over 50 peer-reviewed publications and many novel discoveries. In the 2nd cycle we
focused mainly on how TDP-43, tau and beta-amyloid contributed to neurodegeneration in those with
Alzheimer's disease neuropathologic changes (ADNC). Our studies were conducted on a cohort of 756 ADNC
cases. We discovered that TDP-43 deposition in ADNC was heterogeneous and for the first time showed that
there are two distinct types of TDP-43 deposition in ADNC that we termed TDP type-α and type-β. What is
most interesting about this discovery is that TDP type-α have strikingly similar features to one pathological type
of FTLD-TDP (FTLD-TDP type A) while TDP type-β is strongly associated with the presence of neurofibrillary
tangles, and hence tau. A second discovery was that different inclusions associated with the different
pathological types of FTLD-TDP (type A, type B and type C) had different molecular compositions of TDP-43
specie. For example, while most inclusions consisted of C-terminal fragments of TDP-43, pre-inclusions and
perivascular inclusions consisted of a greater burden of full-length TDP-43 than C-terminal fragments.
Therefore, one of the main goals of the 3rd cycle is to further assess how ADNC TDP types (type-α and type-β)
are related to FTLD-TDP types (type-A, type-B, type-C) by investigating associations with the different
molecular specie of TDP-43 including C-terminal fragments, full-length and phosphorylated TDP-43. A second
goal of the R01 is to further our findings from the 2nd cycle in order to better understand how TDP types (type-α
and type-β) modifies the associations between TDP-43 and neurodegeneration. We will investigate,
specifically, how TDP, including TDP types, tau and beta-amyloid and other pathological and genetic factors
are associated with trajectories of volume loss of hippocampus and neocortex over time. Our cohort will consist
of cases with multiple head MRI scans (range: 2-13 yearly MRI scans; total scans=2316) prior to death. Last,
but not least, we will address one of the biggest knowledge gaps in the field, the lack of a biomarker that can
help predict the presence of TDP-43 in ADNC during life. We will use [18F]fluorodeoxyglucose PET, which we
have shown is superior to MRI, to predict TDP-43. We will first develop the biomarker and then test it in an
independent cohort. In order to accomplish all the aims of the 3rd cycle we will upgrade our cohort size to 1303
pathologically confirmed cases of ADNC and FTLD. Findings from this 3rd cycle will significantly improve
understanding of TDP-43, and TDP-43 types, and help to address the nagging issue of where the boundary
lies between TDP-43 in ADNC and FTLD-TDP. Given that TDP-43 is a potential therapeutic target for the
treatment of FTLD and now Alzheimer's disease, the 3rd cycle will likely also have a significant impact on the
field.
Status | Finished |
---|---|
Effective start/end date | 7/1/10 → 4/30/24 |
Funding
- National Institute on Aging: $324,925.00
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